Fruit of the Contemplative Life
Fruit of the contemplative life: => Health, healing and fitness => : Jhanananda May 20, 2014, 02:38:37 PM
-
As many of you know I was diagnosed with diabetes about 3 years ago. Almost 2 years ago a friend instructed me in the low carb diet system as a means of controlling my blood sugar. Within the first month on that diet I found my blood sugar dropped 100 points, and, although it was still high, I felt confident enough in the diet system that I did not need to keep track of my blood sugar, and I hoped that my blood sugar would continue to lower.
About 2 months ago that same friend critiqued my diet as not low enough in carbs, and at that time we checked my blood sugar and found that after the initial lowering of my blood sugar down 100 points, it stabilized there. So, I cut more carbs from my diet and exercised more discipline, and expected greater results. However, I tested my blood sugar last Friday morning at abut 6AM and found it was at 250, which is quite high.
The elevated blood sugar after almost 2 years of discipline was a great disappointment, which produced a considerable health awareness crisis in me. So for the next few days I tested my blood sugar frequently. I also fasted until noon on the first day and found that my blood sugar dropped to 150 by an hour and a half later and stayed there until noon, when I got tired of waiting for my blood sugar to drop further, and ate a low carb meal.
For the next few days I tested my blood sugar every 15 minutes. I observed that my low carb meals only raise my blood sugar 20 point for about 1 hour following the meal; however, I also noticed that my blood sugar would rise without a meal to about 250 by about 5:00AM and 2:30PM.
I pondered where the sugar came from, if I was staying strictly on a low-carb diet. I recalled in anatomy and physiology that the body runs on sugar, and will convert protein and fat to sugar if it cannot find sugar are starch. Additionally, I recalled that when the body fat is exhausted, then muscle mass will be reduced by the physiological needs of the body. With these basic physiological premises in mind I developed a number of hypotheses.
Hypotheses:
1] Without the intake of any food the blood sugar will cycle, as long as there is excess fat, because the liver will pull body fat and turn it into sugar to keep the body going.
2] One cannot understand this daily natural blood sugar cycle without fasting for a day or 2 while measuring the blood sugar hourly.
3] Once the excess fat has been removed, then the blood sugar could be brought down to normal levels, and maintained by eating only when the blood sugar level drops to 75-80 points.
4] The elevated blood sugar of the Diabetic is due to lack of discipline, high levels of nutrition, and/or old age.
5] The reason why the elevated blood sugar of the Diabetic is maintained by the body even when there is low-to- no sugar intake is because the body has become habituated to an elevated blood sugar, and it will attempt to maintain that elevated blood sugar as long as there is any nutrition coming in.
6] However, after a period of time on a low-carb diet, coupled with fasting to: 1 loose body fat; and 2 force the blood sugar down to normal levels, then it is reasonable to consider that the body will eventually realize that a lower (normal) blood sugar level should be maintained.
-
The body will only turn protein into glucose for it's own use but fats will turn into ketones. One must lose the body fat to decrease the blood sugar level in the bloodstream. Magnesium is crucial to carry the glucose in your blood into the muscle tissues, hence lower blood sugar in the bloodstream. Vegetable is also carbohydrate. Take vegetable that has low glycemic index , like green leafy vegetables. Avoid tubers, beans and grains. The kind of fruits that diabetic could take are lemons, lime and pomegranates. The amount of protein should only be 20% of that meal and 10% for carbohydrate and 70% for fats. Exercise also burn blood glucose. I do an hour of brisk walking/running almost every day and I do resistant exercises (weights) once or twice a week to build muscles to burn more glucose. I hope that helps.
Incidentally, my fasting (8 to 12 hours) blood glucose is about 85 to 110. One article I've read says that beer even with very low glycemic index also raise blood sugar slightly.
-
The body will only turn protein into glucose for it's own use but fats will turn into ketones. One must lose the body fat to decrease the blood sugar level in the bloodstream.
This makes sense
Magnesium is crucial to carry the glucose in your blood into the muscle tissues, hence lower blood sugar in the bloodstream. Vegetable is also carbohydrate. Take vegetable that has low glycemic index , like green leafy vegetables. Avoid tubers, beans and grains.
This is what I understand as part of the low carb diet.
The kind of fruits that diabetic could take are lemons, lime and pomegranates.
This is nice to know, because I have been avoiding all fruit.
The amount of protein should only be 20% of that meal and 10% for carbohydrate and 70% for fats.
I will keep this in mind. I have not been paying attention to this.
Exercise also burn blood glucose. I do an hour of brisk walking/running almost every day and I do resistant exercises (weights) once or twice a week to build muscles to burn more glucose. I hope that helps.
I turn waste oils into diesel fuel for exercise.
Incidentally, my fasting (8 to 12 hours) blood glucose is about 85 to 110. One article I've read says that beer even with very low glycemic index also raise blood sugar slightly.
Yes, beer has some carbs in it, but from testing 12oz only raises my blood sugar 20 point for an our.
-
Forgot to mention that organic virgin coconut oil helps increase the sensitivity of insulin which helps to lower blood glucose. Cheers
-
Thanks, Sam, I do not use vegetable oils any more, except as fuel for my vehicles. I now use butter when I am cooking. I use just plain yogurt for salad dressing. I suppose I will have to come up with something that I can put coconut oil in.
-
New research in diabetes has revealed a new enzyme that could be utilized to control blood sugar.
Identification of a mammalian glycerol-3-phosphate phosphatase: Role in metabolism and signaling in pancreatic β-cells and hepatocytes (http://www.pnas.org/content/early/2016/01/07/1514375113)
Significance
Glycerol-3-phosphate (Gro3P) lies at the crossroads of glucose, lipid, and energy metabolism in mammalian cells and is thought to participate in glycolysis or in gluconeogenesis, lipid synthesis, and Gro3P electron transfer shuttle to mitochondria. We now report a previously unidentified pathway of Gro3P metabolism in mammalian cells with the identification of Gro3P phosphatase (G3PP) that can directly hydrolyze Gro3P to glycerol. We observed that G3PP expression level controls glycolysis, lipogenesis, lipolysis, fatty acid oxidation, cellular redox, and mitochondrial energy metabolism in β-cells and hepatocytes, as well as glucose-induced insulin secretion and the response to metabolic stress in β-cells, and in gluconeogenesis in hepatocytes. G3PP is a previously unknown player in metabolic regulation and signaling and offers a potential target for cardiometabolic disorders.
Abstract
Obesity, and the associated disturbed glycerolipid/fatty acid (GL/FA) cycle, contribute to insulin resistance, islet β-cell failure, and type 2 diabetes. Flux through the GL/FA cycle is regulated by the availability of glycerol-3-phosphate (Gro3P) and fatty acyl-CoA. We describe here a mammalian Gro3P phosphatase (G3PP), which was not known to exist in mammalian cells, that can directly hydrolyze Gro3P to glycerol. We identified that mammalian phosphoglycolate phosphatase, with an uncertain function, acts in fact as a G3PP. We found that G3PP, by controlling Gro3P levels, regulates glycolysis and glucose oxidation, cellular redox and ATP production, gluconeogenesis, glycerolipid synthesis, and fatty acid oxidation in pancreatic islet β-cells and hepatocytes, and that glucose stimulated insulin secretion and the response to metabolic stress, e.g., glucolipotoxicity, in β-cells. In vivo overexpression of G3PP in rat liver lowers body weight gain and hepatic glucose production from glycerol and elevates plasma HDL levels. G3PP is expressed at various levels in different tissues, and its expression varies according to the nutritional state in some tissues. As Gro3P lies at the crossroads of glucose, lipid, and energy metabolism, control of its availability by G3PP adds a key level of metabolic regulation in mammalian cells, and G3PP offers a potential target for type 2 diabetes and cardiometabolic disorders.
-
I have spent a great deal of time pondering why obesity, diabetes, kidney disease, and heart disease have increased significantly among US Americans since the 1950s. Most people blame the American fast-food high-carb diet for the increase in these health problems; however, I lead a disciplined life, not eating simple starches and sugars, nor eating more than necessary, and yet I too came down with diabetes. Also, most US Americans are descendants of Europeans, who have eaten a high carbohydrate diet for thousands of years without developing significant levels of these disease.
last summer I met a Hopi woman at the public park. She was obese as many southwestern native Americans are. She said she had diabetes. The argument for why some native American tribes have rampant obesity, diabetes, kidney disease, and heart disease is because alcoholism is so significant among them, and they eat too much junk food.
Well, this argument only works for the native Americans who live in cities; however, many native Americans still live in remote areas on the res, and they still manifest obesity, diabetes, kidney disease, and heart disease in significant numbers. Also, the Hopi and other tribes have eaten a high carbohydrate diet for thousands of years without developing significant levels of these disease. So, why now?
Below are some historic photos of some native Americans.
(http://3.bp.blogspot.com/-wKYIPNkobYI/TzVW0d8xy5I/AAAAAAAAEz4/6BT_a4jgugQ/s640/Hopi-Indian-Farming-picture-reservations.jpg)
19th century Hopi men planting corn.
(http://imagesaz.com/thumbnail/580/300/0/blogs/simple-history-the-1379168123.jpg)
A Hopi today is at least twice the mass of Hopis of the 19th century. Why?
(https://s-media-cache-ak0.pinimg.com/736x/5c/e7/88/5ce788b34b6910f8ff42b45aa1341f32.jpg)
Papago woman brushing girl's hair. Photo: 1916, From Papago Woman, Ruth Underhill.
(http://quailcreekcrossing.com/wp-content/uploads/2014/01/4a.jpg)
Tohono O’odham (Papago) women, and men today are at least twice the mass of Tohono O’odham from 1916. Why?
My hypothesis is at some point in the past the Native American lifestyle changed in some way to cause their diabetes, and I do not believe it is from eating fry-bread. The contenders are:
1] Immunization programs affected the native American friendly flora which upset their health.
2] Their method of making corn and beans may have changed, such as it most probably was part of a fermentation practice, which it no longer is. It is a fact that fermentation reduces the carbs and turns them into protein as well as alcohol.
3] The US government most probably drilled wells on many native American reservations, and that well water might be contaminated with naturally occurring radioactive elements, such as: uranium, radium, and radon.
The Indian Health Service (https://en.wikipedia.org/wiki/Indian_Health_Service) (IHS) is an operating division (OPDIV) within the U.S. Department of Health and Human Services (HHS). IHS is responsible for providing medical and public health services to members of federally recognized Tribes and Alaska Natives. IHS is the principal federal health care provider and health advocate for Indian people, and its goal is to raise their health status to the highest possible level.
IHS provides health care to American Indians and Alaska Natives at 33 hospitals, 59 health centers, and 50 health stations. Thirty-four urban Indian health projects supplement these facilities with a variety of health and referral services.
Formation and mission
IHS was established in 1956 to take over health care of American Indian and Alaska Natives from the Bureau of Indian Affairs (BIA) to the Public Health Service (PHS) in hopes of improving the healthcare of Native Americans living on Reservations. The provision of health services to members of federally recognized tribes grew out of the special government-to-government relationship between the federal government and Indian tribes. This relationship, established in 1787, is based on Article I, Section 8 of the Constitution, and has been given form and substance by numerous treaties, laws, Supreme Court decisions, and Executive Orders. The IHS currently provides health services to approximately 1.8 million of the 3.3 million American Indians and Alaska Natives who belong to more than 557 federally recognized tribes in 35 states. The agency's annual budget is about $4.3 billion (as of December 2011).
It just so happens obesity, diabetes, kidney disease, and heart disease among Native Americans started in the 50s.
I speculate that in the 50s the US government dug wells on reservations to provide Native American communities with water. It is a fact that ALL water wells have elevated concentrations of radon. Is it possible that all of us who are drinking municipal water, Indians included, are being exposed to enough radon, or other radioactive elements, to cause a statistical increase in the incidence of obesity, diabetes, kidney disease, and heart disease?
History of water supply and sanitation (https://en.wikipedia.org/wiki/History_of_water_supply_and_sanitation)
Modern age
Until the Enlightenment era, little progress was made in water supply and sanitation and the engineering skills of the Romans were largely neglected throughout Europe. This began to change in the 17th and 18th centuries with a rapid expansion in waterworks and pumping systems.
Water chlorination
The first continuous use of chlorine in the United States for disinfection took place in 1908 at Boonton Reservoir (on the Rockaway River), which served as the supply for Jersey City, New Jersey.[33] Chlorination was achieved by controlled additions of dilute solutions of chloride of lime (calcium hypochlorite) at doses of 0.2 to 0.35 ppm. The treatment process was conceived by Dr. John L. Leal and the chlorination plant was designed by George Warren Fuller.[34] Over the next few years, chlorine disinfection using chloride of lime were rapidly installed in drinking water systems around the world.[35]
Fluoridation
Further information: History of water fluoridation
Water fluoridation has been carried out since the early 20th century, to decrease tooth decay. The practice remains controversial, though.
Water supply and sanitation in the United States (https://en.wikipedia.org/wiki/Water_supply_and_sanitation_in_the_United_States)
After 1948: Enter the federal government
In the first half of the 20th century water supply and sanitation were a local government responsibility with regulation at the state level; the federal government played almost no role in the sector at that time. This changed with the enactment of the Federal Water Pollution Control Act of 1948, which provided for comprehensive planning, technical services, research, and financial assistance by the federal government to state and local governments for sanitary infrastructure. The Act was amended in 1965, establishing a uniform set of water quality standards and creating a Federal Water Pollution Control Administration authorized to set standards where states failed to do so.
Infrastructure
The centralized drinking water supply infrastructure in the United States consists of dams and reservoirs, well fields, pumping stations, aqueducts for the transport of large quantities of water over long distances, water treatment plants, reservoirs in the distribution system (including water towers), and 1.8 million miles of distribution lines.[25] Depending on the location and quality of the water source, all or some of these elements may be present in a particular water supply system. In addition to this infrastructure for centralized network distribution, 14.5% of Americans rely on their own water sources, usually wells.
Infrastructure
The centralized drinking water supply infrastructure in the United States consists of dams and reservoirs, well fields, pumping stations, aqueducts for the transport of large quantities of water over long distances, water treatment plants, reservoirs in the distribution system (including water towers), and 1.8 million miles of distribution lines.[25] Depending on the location and quality of the water source, all or some of these elements may be present in a particular water supply system. In addition to this infrastructure for centralized network distribution, 14.5% of Americans rely on their own water sources, usually wells.[11][12]
Water sources
About 90% of public water systems in the U.S. obtain their water from groundwater. However, since systems served by groundwater tend to be much smaller than systems served by surface water, only 34% of Americans (101 million) are supplied with treated groundwater, while 66% (195 million) are supplied with surface water.
Groundwater (https://en.wikipedia.org/wiki/Groundwater) (or ground water) is the water present beneath Earth's surface in soil pore spaces and in the fractures of rock formations. A unit of rock or an unconsolidated deposit is called an aquifer when it can yield a usable quantity of water. The depth at which soil pore spaces or fractures and voids in rock become completely saturated with water is called the water table. Groundwater is recharged from, and eventually flows to, the surface naturally; natural discharge often occurs at springs and seeps, and can form oases or wetlands. Groundwater is also often withdrawn for agricultural, municipal, and industrial use by constructing and operating extraction wells. The study of the distribution and movement of groundwater is hydrogeology, also called groundwater hydrology.
Groundwater is often cheaper, more convenient and less vulnerable to pollution than surface water. Therefore, it is commonly used for public water supplies. For example, groundwater provides the largest source of usable water storage in the United States and California annually withdraws the largest amount of groundwater of all the states.[2] Underground reservoirs contain far more water than the capacity of all surface reservoirs and lakes in the US, including the Great Lakes. Many municipal water supplies are derived solely from groundwater.[3]
-
The corn processing technique that I believe has been lost is called nixtamalization (https://en.wikipedia.org/wiki/Nixtamalization). There is a recipe for it in the book Wild Fermentation by Sandor Katz. He says: "nixtamalization is not itself a fermentation process. But the traditional corn fermentation processes use nixtamalized corn as the point of departure". He then includes a recipe for it, and one for sour cornbread and a Cherokee sour corn drink called gv-no-he-nv.
edit: the full text of Wild Fermentation is on archive.org. It seems like it is an authorized open source contribution. It's a great book: https://archive.org/stream/WildFermentation/Wild_Fermentation_djvu.txt (https://archive.org/stream/WildFermentation/Wild_Fermentation_djvu.txt)
-
Thank-you, Zack for providing the two very interesting links. It is my hypothesis that Nixtamalization (https://en.wikipedia.org/wiki/Nixtamalization) is only part of the traditional way most American Indian peoples processed their corn, and other fermentable produce, into food. I believe that all the corn that they ate was first Malted (https://en.wikipedia.org/wiki/Malt), which converts the starches to sugar; then Mashed (https://en.wikipedia.org/wiki/Mashing), then fermented (https://en.wikipedia.org/wiki/Ethanol_fermentation), prior to Nixtamalization (https://en.wikipedia.org/wiki/Nixtamalization).
Malt (https://en.wikipedia.org/wiki/Malt) is germinated cereal grains that have been dried in a process known as "malting". The grains are made to germinate by soaking in water, and are then halted from germinating further by drying with hot air.[1][2][3][4] By malting grains, the enzymes required for modifying the grain's starches into sugars, including the monosaccharide glucose, the disaccharide maltose, the trisaccharide maltotriose, and higher sugars called maltodextrines are developed. It also develops other enzymes, such as proteases, which break down the proteins in the grain into forms that can be used by yeast. Depending on when the malting process is stopped one gets a preferred starch enzyme ratio and partly converted starch into fermentable sugars. Malt also contains small amounts of other sugars, such as sucrose and fructose, which are not products of starch modification but were already in the grain. Further conversion to fermentable sugars is achieved during the mashing process.
Mashing (https://en.wikipedia.org/wiki/Mashing)
In brewing and distilling, mashing is the process of combining a mix of milled grain (typically malted barley with supplementary grains such as corn, sorghum, rye or wheat), known as the "grain bill", and water, known as "liquor", and heating this mixture. Mashing allows the enzymes in the malt to break down the starch in the grain into sugars, typically maltose to create a malty liquid called wort.[1] There are two main methods—infusion mashing, in which the grains are heated in one vessel; and decoction mashing, in which a proportion of the grains are boiled and then returned to the mash, raising the temperature.[2] Mashing involves pauses at certain temperatures (notably 45–62–73 °C or 113–144–163 °F), and takes place in a "mash tun"—an insulated brewing vessel with a false bottom.[3][4][5] The end product of mashing is called a "mash".
Fermention (https://en.wikipedia.org/wiki/Ethanol_fermentation)
Ethanol fermentation, also called alcoholic fermentation, is a biological process which converts sugars such as glucose, fructose, and sucrose into cellular energy, producing ethanol and carbon dioxide as a side-effect. Because yeasts perform this conversion in the absence of oxygen, alcoholic fermentation is considered an anaerobic process.
Ethanol fermentation has many uses, including the production of alcoholic beverages, the production of ethanol fuel, and bread baking.
Biochemical process of fermentation of sucrose
The chemical equations below summarize the fermentation of sucrose (C12H22O11) into ethanol (C2H5OH). Alcoholic fermentation converts one mole of sucrose into two moles of ethanol and two moles of carbon dioxide, producing two moles of ATP (https://en.wikipedia.org/wiki/Adenosine_triphosphate) in the process.
Adenosine triphosphate (ATP (https://en.wikipedia.org/wiki/Adenosine_triphosphate)) is a nucleoside triphosphate used in cells as a coenzyme often called the "molecular unit of currency" of intracellular energy transfer.[1]
ATP transports chemical energy within cells for metabolism. It is one of the end products of photophosphorylation, cellular respiration, and fermentation and used by enzymes and structural proteins in many cellular processes, including biosynthetic reactions, motility, and cell division.[2] One molecule of ATP contains three phosphate groups, and it is produced by a wide variety of enzymes, including ATP synthase, from adenosine diphosphate (ADP) or adenosine monophosphate (AMP) and various phosphate group donors. Substrate-level phosphorylation, oxidative phosphorylation in cellular respiration, and photophosphorylation in photosynthesis are three major mechanisms of ATP biosynthesis.
Metabolic processes that use ATP as an energy source convert it back into its precursors. ATP is therefore continuously recycled in organisms: the human body, which on average contains only 250 grams (8.8 oz) of ATP,[3] turns over its own body weight equivalent in ATP each day.[4]
ATP is used as a substrate in signal transduction pathways by kinases that phosphorylate proteins and lipids. It is also used by adenylate cyclase, which uses ATP to produce the second messenger molecule cyclic AMP. The ratio between ATP and AMP is used as a way for a cell to sense how much energy is available and control the metabolic pathways that produce and consume ATP.[5] Apart from its roles in signaling and energy metabolism, ATP is also incorporated into nucleic acids by polymerases in the process of transcription. ATP is the neurotransmitter believed to signal the sense of taste.[6]
The structure of this molecule consists of a purine base (adenine) attached by the 9' nitrogen atom to the 1' carbon atom of a pentose sugar (ribose). Three phosphate groups are attached at the 5' carbon atom of the pentose sugar. It is the addition and removal of these phosphate groups that inter-convert ATP, ADP and AMP. When ATP is used in DNA synthesis, the ribose sugar is first converted to deoxyribose by ribonucleotide reductase.
Nixtamalization (https://en.wikipedia.org/wiki/Nixtamalization) (IPA: [ˌnɪkstəmɑlɪˈzeɪʃn]) typically refers to a process for the preparation of maize (corn), or other grain, in which the grain is soaked and cooked in an alkaline solution, usually limewater, and hulled. The term can also refer to the removal via an alkali process of the pericarp from other grains such as sorghum.
Maize subjected to the nixtamalization process has several benefits over unprocessed grain: it is more easily ground; its nutritional value is increased; flavor and aroma are improved; and mycotoxins are reduced. Lime and ash are highly alkaline: the alkalinity helps the dissolution of hemicellulose, the major glue-like component of the maize cell walls, and loosens the hulls from the kernels and softens the corn. Some of the corn oil is broken down into emulsifying agents (monoglycerides and diglycerides), while bonding of the corn proteins to each other is also facilitated. The divalent calcium in lime acts as a cross-linking agent for protein and polysaccharide acidic side chains.[1] As a result, while cornmeal made from untreated ground corn is unable by itself to form a dough on addition of water, the chemical changes in masa allow dough formation. These benefits make nixtamalization a crucial preliminary step for further processing of maize into food products, and the process is employed using both traditional and industrial methods, in the production of tortillas and tortilla chips (but not corn chips), tamales, hominy and many other items.
Since the archaeological record shows all agrarian societies around the world practiced fermentation, and the fermentation process clearly converts grains and fruit into a far more nutritious food source, then we can conclude it is very possible that the reason why US Americans, and Native Americans are developing a wide range of related diseases, such as: obesity, diabetes, kidney disease, and heart disease, is because the grain and fruit that we commonly consume has not been processed as above prior to consumption.
-
Sweat-monitoring patch releases diabetes drugs when required (http://www.gizmag.com/responsive-sweat-monitoring-patch-diabetes/42436/?utm_source=Gizmag+Subscribers&utm_campaign=19e4d8f2bc-UA-2235360-4&utm_medium=email&utm_term=0_65b67362bd-19e4d8f2bc-90144161)
This device could be useful for all diabetics.
-
good news for all diabetics
Creation of insulin-releasing cells in a dish offers hope of diabetes therapy (http://www.gizmag.com/insulin-releasing-cell-replacement-protein-diabetes/42787/?utm_source=Gizmag+Subscribers&utm_campaign=97a05802e3-UA-2235360-4&utm_medium=email&utm_term=0_65b67362bd-97a05802e3-90144161)
A molecular switch could hold the key to a personalized cell replacement therapy for diabetes. Both Type 1 and Type 2 diabetes are characterized by an inability to produce (or process) insulin, which is required to regulate blood sugar levels. This has been linked to malfunctioning or failing beta cells in the pancreas, but so far scientists have struggled to produce effective replacement cells in the lab. Now a team at Salk Institute believes the problem has been solved.
The Salk scientists found a protein switch – one of several transcription factors in a beta cell – called ERR-gamma that makes the lab-grown cells more responsive to glucose and gets them releasing insulin at a normal rate. This ERR-gamma switch appears to be the master regulator for maturing glucose-responsive beta cells.
To test the discovery, the researchers transplanted mature lab-grown beta cells into Type 1 diabetic mice, with the ERR-gamma protein switched on. Two months after transplantation, around half of the diabetic mice showed normal (non-diabetic) blood glucose levels.
-
Here is a link to another development in sensing technology that is paving a path to real-time biological data of critical importance to some people such as diabetics.
(http://img-2.gizmag.com/e-skin-flexible-1.png?auto=format%2Ccompress&ch=Width%2CDPR&fit=crop&h=394&q=60&rect=7%2C0%2C1910%2C1074&w=700&s=03a6688ebbdd9474e8d4f66ffc575869)
Flexible e-skin display is thinner than Saran wrap and tracks blood oxygen levels (http://www.gizmag.com/e-skin-blood-oxygen-levels/42853/?utm_source=Gizmag+Subscribers&utm_campaign=8cf0b6234e-UA-2235360-4&utm_medium=email&utm_term=0_65b67362bd-8cf0b6234e-90144161)
-
A friend sent me this link for the use of mango leaves (http://www.usefuldiys.com/2016/07/suffering-from-diabetes-just-boil-these-leaves-and-solve-your-problem-without-medications/) to treat diabetes. I will have to try it.
-
Interesting thread. I have been aware of the western metabolic syndrome since a young age. I often remember as a kid my total bemusement at the increasing numbers of fat and increasingly sick in our population. I apologize for my lack of sensitivity in talking about the subject but those were my impressions.
I do think that processed carbs of higher prevalence are a very large part of the equation. Higher amounts of non physical chronic stress and over stimulation an additional component and most importantly lack of the proper short duration high intensity stress ors needed to maintain overall system fitness another component.
I don't think any particular poisons or toxins are the problem in themselves, its that our overall lifestyles have degraded in such a way that we are no longer able to metabolize the higher cumulative toxic loads which primarily come from excessive carb and caloric loads in conjunction with chronic low grade stress.
The most coherent explanation I know of is to view our illness through an evolutionary lens, Art Devany http://getfitboomer.com/downloads/EvolutionaryFitness.pdf does this well.
Through that lens what we are seeing is a systemic failure of our food systems culture acting together to create massive health failures. Its really a paradox of plenty. To much of too little quality is killing us. This is not the environment our genome evolved in and no amount of mechanistic medicinal intervention will fix our issues.
The answer is IMO in imitating the key aspects of our evolutionary past. But obviously its not practical nor desirable to replicate the various harsh aspects of hunter gather lifestyle. What we are after is making the fewest number of changes to salvage the weakest link our our cultures epidemic metabolic failure rates. Maintaining or restoring insulin sensitivity is the lowest hanging fruit here. This is done by the following.
1. Maintaining a carb adequate diet over an average period of time with periods of intermittent fasting . For most people this is roughly 1 carb per lb of lean muscle per day. People think they eat well until they quantify their diet, quality of food is important but irrelevant if average intake exceeds true carb needs over the long run. I can not tell you the number of people who delude themselves on this simple point. It is so easy to do in our carb abundant environment.
2. Intermittent intensity is a must, our energy output ought to follow a fractal expression of a power law, prior cultures expressed this in playing and hunting and wandering. Our mechanistic linearization of the world has eliminated those patterns for most, particularly for the poor.
3. Daily natural movement must accompany number one and two. Being sedentary in a high carb high stress environment is a deadly.
Our evolutionary past contradicts modernizations attempts to eliminate stress-ors and provide a steady amount of plenty. We can overcome it though by consciously changing our patterns to mimic key aspects of our past. Our genes are not a death sentence and though some are more predisposed to western metabolic syndrome none are incapable of applying deep evolutionary patterns to influence overall epigenetic expression, for none of our genes have really changed that much since the recent Pleistocene environment from which we came.
-
Good to read a message from you, roamer. You make some good points; however, the acceleration of diabetes, and its associated diseases, it suggests to me a causal relationship with one or more behaviors of western civilization starting about 1940. I suspect a significant rise in exposure to radioactivity might just be the primary cause. It could also be extensive use of immunizations, and/or antibiotics.
Thanks to Sam, I found this articles of interest. These 11 Foods Have Been Found By Science To Lower Blood Sugar (http://www.herbs-info.com/blog/these-11-foods-have-been-found-by-science-to-lower-blood-sugar/).
-
Jhananda, I have not reviewed datasets which place the prevalance around 1940, but it certainly doesn't contradict anything i've said. 1940 would have been the dramatic rise in chemical assisted monocultures which would have placed an increased amount of processed corn or grain derivatives in our diet. It was also a period of radical mechanization of all labor which altered activity patterns. And of course as you point out also a new era of exposure to toxic previously unencountered chemicals, medicines ect to the human genome.
I do not dismiss some influence of the later, but being a bit of a lifelong athlete and gym buff I have known many people who have maintained health into old age or reversed health and type ii diabetes at old age. They did it through diet and activity manipulation and many of them still had exposure to numerous toxins additional from lab jobs ect and all of them lived in the same toxic environment with immunizations, antibiotics, ect that everyone else is encountering.
-
Jhananda, I have not reviewed datasets which place the prevalance around 1940, but it certainly doesn't contradict anything i've said. 1940 would have been the dramatic rise in chemical assisted monocultures which would have placed an increased amount of processed corn or grain derivatives in our diet. It was also a period of radical mechanization of all labor which altered activity patterns. And of course as you point out also a new era of exposure to toxic previously unencountered chemicals, medicines ect to the human genome.
While I agree with much of what you have to say here; nonetheless, Indians resident on Hopi and Tohono O'odham Indian reservations, who have eaten the same food, with they have grown for thousands of yeas, are developing type II diabetes, and its associated complex. It suggests to me some other influence, which I believe might very well be as simple as: drinking ground water; and/or immunizations; and/or extensive use of antibiotics, all three of which were made available to those tribes in the 30s.
I do not dismiss some influence of the later, but being a bit of a lifelong athlete and gym buff I have known many people who have maintained health into old age or reversed health and type ii diabetes at old age. They did it through diet and activity manipulation and many of them still had exposure to numerous toxins additional from lab jobs ect and all of them lived in the same toxic environment with immunizations, antibiotics, ect that everyone else is encountering.
In my case we will not know until there is more investigation. I have an appointment with a rheumatologist next month. It might just be the key to my health problems starting around 15. It just so happens that I manifest the symptomatology of both Reiter's Syndrome (https://en.wikipedia.org/wiki/Reactive_arthritis) and Ankylosing Spondylitis (https://en.wikipedia.org/wiki/Ankylosing_spondylitis). In both cases there are both genetic and the product of gastrointestinal infection.
-
If indeed the Hopi diet remained the same (which i suspect it did not, likely additional foods were added) I would be very curious to know how overall activity patterns changed.
Causation becomes tricky in such complex systems as the human body. You are probably on to something about your gut changing around 15, this has increasingly been shown to cause cascading changes in the body. However as with dukka the only relevant question is how best to treat. My argument is good food or minimization of environmental toxins simply is not enough. It takes lifestyle reengineering and using a hunter gather energy diet expenditure model as a guideline seems like the most robust model to mimic.
-
If indeed the Hopi diet remained the same (which i suspect it did not, likely additional foods were added) I would be very curious to know how overall activity patterns changed.
Yes, the majority of Native Americans have embraced western diets; however, there are traditional Hopi and Tohono O'odham who live in remote areas, and who live pretty much as they have for 1000s of years, and yet they too are developing diabetes and its associated conditions.
Causation becomes tricky in such complex systems as the human body. You are probably on to something about your gut changing around 15, this has increasingly been shown to cause cascading changes in the body. However as with dukka the only relevant question is how best to treat. My argument is good food or minimization of environmental toxins simply is not enough. It takes lifestyle reengineering and using a hunter gather energy diet expenditure model as a guideline seems like the most robust model to mimic.
Well, I agree that good food and minimization of environmental toxins simply is not enough. It takes lifestyle reengineering and using a hunter gather energy diet; all of which I have done; nonetheless, my health is still in decline. Old-age is certainly and aspect of this decline, but the decline seems much too steep, so I am investigating the genetic component.
-
Jhanananda,
All theories aside it really sucks to hear you are experiencing like far too many a rapid decline in health. I am saddened to hear of your difficulties and really do hope you are able to find some relief, comfort and relative stability in the inevitable aging process. Life has always been transient but my sense is that we really are in strange times concerning general health and I am of course very sympathetic to your situation and hope for the best. On a personal note my father is going through the same health decline with type ii diabetes at 64 years of age. His parents and grandparents never had such a thing and its rather remarkable to me to see my father quite frail and unhealthy when I remember my grandfather at an even older age quite healthy and hard working. In fact my grandfather lived to be 84 and milk cows and ran a dairy farm until 80 years of age, he died of a stroke he incurred while splitting wood. Modernity it seems is not a friend of health and the notion of industrial progress is for most an myth to line the pockets of extraordinarily wealthy and powerful.
-
Jhanananda,
All theories aside it really sucks to hear you are experiencing like far too many a rapid decline in health. I am saddened to hear of your difficulties and really do hope you are able to find some relief, comfort and relative stability in the inevitable aging process. Life has always been transient but my sense is that we really are in strange times concerning general health and I am of course very sympathetic to your situation and hope for the best.
Thank-you for your kind thoughts; and I agree, there are one or more contributing factors to accelerated decline of people in the US American culture.
On a personal note my father is going through the same health decline with type ii diabetes at 64 years of age. His parents and grandparents never had such a thing and its rather remarkable to me to see my father quite frail and unhealthy when I remember my grandfather at an even older age quite healthy and hard working. In fact my grandfather lived to be 84 and milk cows and ran a dairy farm until 80 years of age, he died of a stroke he incurred while splitting wood. Modernity it seems is not a friend of health and the notion of industrial progress is for most an myth to line the pockets of extraordinarily wealthy and powerful.
I have had somewhat the same experience; however, my grandfathers, both farmers, died in their early 60s; whereas, both of my parents died almost 90, and neither farmers, but raised on farms. However, I am inclined to agree with you, that there is something in the rapid industrialization of the USA from the depression to the present that is at the root of the decline of US American culture.
So far my decline seems to be a genetic condition that I may have shared with at least one of my grandparents, which is exacerbated by the presence of naturally occurring radioactive elements in the water that I was drinking and cooking with. So, not consuming ground water from here on out, might just improve my overall health, and that of others.
-
It is hard to believe that there are 20 Fruits that are good For Diabetics (http://www.indiatimes.com/health/healthyliving/top-20-fruits-for-diabetics-236081-1.html) to eat, because fruit tends to be high in carbohydrates, so I will be checking them out. Olives are one of the only exceptions to this rule that I can think of at this time, because they have zero carbs, while black olives containing high levels of anthocynin.
According to various guidelines laid down by nutritionist and medical institutions, at least 4-5 servings of fruits needs to be consumed daily by every individual. If you are diabetic, we are sure that this question has popped up in your head, “is it safe to have fruits?” To help all diabetics with this question, we have Mrs. Kamna Desai – Nutritionist, with us. She says, "Yes, diabetics can have fruits, provided the sugar level of the patient is in control, but these fruits must be consumed in a limited quantity. Diabetics need an equivalent serving of fruits on a day to day basis. One needs to be careful about not going overboard with fruits like bananas, litchis, chickoo, and custard apples." To help diabetic patients, she lists down some fruits which will not affect blood sugar.
1] Kiwi. Many researchers have shown a positive correlation between kiwi consumption and lowering of blood sugar level
2] Black jamun. Undoubtedly, this is one of the best fruits for diabetics. It is known to improve blood sugar control. Seeds of these fruit can be powdered and consumed by patients to control diabetes.
3] White jamun. Diabetic patients can consume jamun fruit daily, to control their sugar levels. White jamuns are also high in fiber.
4] Starfruit. Similar to jamuns, starfruits are good for diabics too as they help improve blood sugar control. But caution needs to be exercised in case the person has diabetes neuropathy.
5] Guava. Guava controls diabetes and it is good for constipation. Guavas are high in vitamin A and vitamin C and contain high amounts of dietary fiber. This fruit has a reasonably low GI.
6] Cherries. Their GI value is 20 (or even less in some varieties) which makes it a good healthy snack for diabetes patients at any time of the day.
7] Peaches. These tasty fruits are a great healthy treat, with a low GI and good for diabetics.
8] Berries. Numerous variety of berries are available throughout the world and almost all seem to be a rich source of antioxidants. Diabetics can include a serving of different berries to keep their sugars in check. To name a few: Strawberries, blueberries and blackcurrants, raspberries, cranberries, chokeberries, blackberries, and acai berries are good for diabetes patients.
9] Apples. Apples contain antioxidants, which help to reduce cholesterol levels, cleanse the digestive system, and boost the immune system. Apples also contain nutrients that help in the digestion of fats.
10] Pineapples. Good for diabetics, pineapples also benefit the body as they are rich in anti-viral, anti-inflammatory and anti-bacterial properties.
11] Pears. These delicious fruits are a good snacking option for diabetics as they are rich vitamins and fiber.
12] Papaya. They are good for diabetics because they are rich in vitamin and other minerals.
13] Figs. Their richness in fibre helps with insulin function in diabetes patients.
14] Oranges. These citrus fruits can be consumed on a daily basis by diabetics, as they are rich in vitamin C.
15] Watermelon. Although watermelons have a high GI value, their glycemic load is low, making them good fruits for diabetes patients. However, consume in moderation.
16] Grapefruit. It is a good option for diabetics as it slows down the blood sugar peak.
17] Pomegranate. These tiny red rubies help diabetic people improve their blood sugar statistics.
18] Cantaloupe. This fruit is high in the Glycemic Index, but has a good amount of fibre. Therefore, within moderation, it can easily be include
19] Jackfruit. Jackfruit contains vitamin A, vitamin C, thiamin, riboflavin, niacin, calcium, potassium, iron, manganese and magnesium among many other nutrients. Good for diabetes as they improve insulin resistance.
20] Amla. A fruit loaded with vitamin C and fiber, Amla is a healthy addition to the diabetic diet.
-
I've recently heard about alpha lipoic acid for diabetes, which apparently helps lower sugar levels. I donated some help over for GWV, but I hope some can be used to acquire some healthy supplements/food for you too. :)
-
Thanks, bodhimind.
-
Could a Diabetes Drug Help Beat Alzheimer's Disease? (https://www.scientificamerican.com/article/could-a-diabetes-drug-help-beat-alzheimer-s-disease/?WT.mc_id=SA_DD_20161031)
Metformin may slow or reverse dementia and cognitive impairment, even in nondiabetics
Most of the 20 million people diagnosed with type 2 diabetes in the U.S. take metformin to help control their blood glucose. The drug is ultrasafe: millions of diabetics have taken it for decades with few side effects beyond gastrointestinal discomfort. And it is ultracheap: a month's supply costs $4 at Walmart. And now new studies hint that metformin might help protect the brain from developing diseases of aging, even in nondiabetics.
Diabetes is a risk factor for neurodegenerative diseases, but using metformin is associated with a dramatic reduction in their incidence. In the most comprehensive study yet of metformin's cognitive effects, Qian Shi and her colleagues at Tulane University followed 6,000 diabetic veterans and showed that the longer a patient used metformin, the lower the individual's chances of developing Alzheimer's disease, Parkinson's disease, and other types of dementia and cognitive impairment.
-
I have been reviewing my log of health data. A year ago in November I was admitted into ER with a blood sugar of 350 and high blood pressure, and pulse rates, and a very low blood oxygen level. Since then I acquired a pulse oxymeter.
I have been trying to make sense of my blood sugar that seems to be steady on a good value for weeks at a time, then it wanders up, as high as 350. Now that I can examine a year of data regarding blood sugar and blood oxygen I saw that when I am having seasonal allergies, which is something that I have had since childhood, my blood oxygen goes down, but what was surprising was my blood sugar goes up.
So, now I may have another causal relationship to my diabetes to deal with, which is good. I just need to move to a place that does not have plant polens that I am allergic to.
-
I've been watching videos by a Dr. Glidden and its his believe that diabetes is caused by a chromium and vanadium deficiency among other possible deficiencies. You may be already aware of this, but check him out. His tutorials are well done and eye opening.
-
Thank-you, DDawson, for posting your comment and suggestion on this thread.
Yes, I have read numerous research reports since the 50s that chromium (cr-3) helped diabetics control their blood sugar. I started cr-3 supplementation on December 3rd of last year at 1000micro grams per day. The next day my blo0od sugar reading was almost normal and the lowest in months.
My blood sugar continued to go up and down, but mostly close to normal for the next month, then it went up at the same time I was experiencing juniper fever. So, my conclusion is cr-3 is something that I need, but allergies seems to have a causal relationship to my diabetes.
Another point needing to be made here is, I had avoided taking benadryl for my seasonal allergies until after my visit to the emergency room a year ago in November. I have found that taking benadryl for my allergies has lowered my blood sugar during allergy season; however, it still rises to about 200 instead of 350.
-
Faux fasting diet regenerates pancreas to reverse diabetes (http://newatlas.com/fmd-fasting-mimicking-diet-reverse-diabetes/48123/?utm_source=Gizmag+Subscribers&utm_campaign=6aae9dc758-UA-2235360-4&utm_medium=email&utm_term=0_65b67362bd-6aae9dc758-90144161)
Using stem cells to create insulin-producing beta cells that could be transplanted into diabetics is being investigated as a possible cure for type 1 diabetes and treatment for type 2, but new research suggests that a special diet could reprogram cells in the pancreas to do the same thing. Researchers at the University of Southern California (USC) claim that a diet that mimics the effects of fasting spurs the growth of new insulin-producing beta cells in the pancreases of mice, essentially reversing the disease.
Both type 1 and type 2 diabetes center around insulin. Put very simply, in type 1 diabetes, the body – specifically, the pancreas – can't produce enough insulin, while in type 2 diabetes, the body doesn't use insulin properly and eventually is unable to produce enough insulin to compensate. In both type 1 and late-stage type 2 diabetes, insulin-producing beta cells in the pancreas are lost, meaning many diabetics need to take insulin to replace what's not being made by the pancreas.
Looking to discover the effects of a fasting-mimicking diet (FMD) on diabetes sufferers, USC researchers used mice with type 2 diabetes and another group in which type 1 diabetes had been simulated by giving them high doses of a drug to kill their insulin-producing beta cells. They found that mice in both groups – even those in the later stages of the disease – regained healthy insulin production, had a reduction in insulin resistance, and had more stable blood glucose levels.
The researchers say the brief, periodic diet, which was designed to mimic the effects of a water-only fast, activated genes that are normally only switched on in the developing pancreases of fetal mice. These genes prompted the production of neurogenin-3 (Ngn3), a protein that led to the generation of healthy new beta cells in the adult mice.
Providing an indication that similar results could be expected in humans, the team, led by Valter Longo, the director of the Longevity Institute at USC's Leonard Davis School of Gerontology, found that fasting also increased the expression of Ngn3 and sped up insulin production in pancreatic cell cultures from human donors with type 1 diabetes.
Such a diet could also have wider health benefits, with a previous study from the team demonstrating that human participants who followed the special FMD for five days each month in a three-month span cut their risks for not only diabetes, but also cancer, heart disease and other age-related diseases. Additionally, in another study that preceded that, the team says diet also showed potential for reducing visceral fat, increasing the effectiveness of chemotherapy for cancer treatments, and alleviating the symptoms of multiple sclerosis.
The FMD, which is being marketed commercially under the name "Prolon," involves cutting one's calorie intake by around two-thirds for five days, during which the person's body doesn't recognize that they are eating, before returning to normal intake for the remainder of the month. The researchers are pursuing a larger FDA trial on the potential of the FMD to treat diabetes in humans, but it should be made clear that no one should embark on such a diet without first consulting their doctor.
The team's most recent study was published in the journal Cell (http://www.cell.com/fulltext/S0092-8674(17)30130-7).
-
Fasting-Mimicking Diet Promotes Ngn3-Driven β-Cell Regeneration to Reverse Diabetes (http://www.cell.com/fulltext/S0092-8674(17)30130-7)
Highlights
• Fasting mimicking diet induces prenatal-development gene expression in adult pancreas
• FMD promotes Ngn3 expression to generate insulin-producing β cells
• Cycles of FMD reverse β-cell failure and rescue mice from T1D and T2D
• Inhibition of PKA or mTOR promotes Ngn3-driven β-cell regeneration in human T1D islets
Summary
Stem-cell-based therapies can potentially reverse organ dysfunction and diseases, but the removal of impaired tissue and activation of a program leading to organ regeneration pose major challenges. In mice, a 4-day fasting mimicking diet (FMD) induces a stepwise expression of Sox17 and Pdx-1, followed by Ngn3-driven generation of insulin-producing β cells, resembling that observed during pancreatic development. FMD cycles restore insulin secretion and glucose homeostasis in both type 2 and type 1 diabetes mouse models. In human type 1 diabetes pancreatic islets, fasting conditions reduce PKA and mTOR activity and induce Sox2 and Ngn3 expression and insulin production. The effects of the FMD are reversed by IGF-1 treatment and recapitulated by PKA and mTOR inhibition. These results indicate that a FMD promotes the reprogramming of pancreatic cells to restore insulin generation in islets from T1D patients and reverse both T1D and T2D phenotypes in mouse models.
View File
Introduction
The ability of animals to survive food deprivation is an adaptive response accompanied by the atrophy of many tissues and organs to minimize energy expenditure. This atrophy and its reversal following the return to a normal diet involve stem-cell-based regeneration in the hematopoietic and nervous systems (Brandhorst et al., 2015, Cheng et al., 2014). However, whether prolonged fasting and refeeding can also cause pancreatic regeneration and/or cellular reprogramming leading to functional lineage development is unknown. β cells residing in pancreatic islets are among the most sensitive to nutrient availability. Whereas type 1 and type 2 diabetes (T1D and T2D) are characterized by β-cell dedifferentiation and trans-differentiation (Cnop et al., 2005, Dor and Glaser, 2013, Talchai et al., 2012, Wang et al., 2014), β-cell reprogramming, proliferation and/or stepwise re-differentiation from pluripotent cells are proposed as therapeutic interventions (Baeyens et al., 2014, Chera et al., 2014, Maehr et al., 2009, Pagliuca et al., 2014, Sneddon et al., 2012, Zhou et al., 2008, Ben-Othman et al., 2017, Li et al., 2017), suggesting that lineage conversion is critical in both diabetes pathogenesis and therapy (Weir et al., 2013).
Although dietary intervention with the potential to ameliorate insulin resistance and type II diabetes has been studied extensively for decades, whether this has the potential to promote a lineage-reprogramming reminiscent of that achieved by iPSCs-based engineering remains unknown. We previously showed that cycles of prolonged fasting (2–3 days) can protect mice and humans from toxicity associated with chemotherapy and can promote hematopoietic stem-cell-dependent regeneration (Cheng et al., 2014, Laviano and Rossi Fanelli, 2012, Raffaghello et al., 2008). In consideration of the challenges and side effects associated with prolonged fasting in humans, we developed a low-calorie, low-protein and low-carbohydrate but high-fat 4-day fasting mimicking diet (FMD) that causes changes in the levels of specific growth factors, glucose, and ketone bodies similar to those caused by water-only fasting (Brandhorst et al., 2015) (see also Figure S1 for metabolic cage studies). Here, we examine whether cycles of the FMD are able to promote the generation of insulin-producing β cells and investigate the mechanisms responsible for these effects.
Results
Cycles of a FMD Rescue Mice from Late-Stage T2D
As a consequence of insulin resistance, the decrease in the number of functional insulin-producing β cells contributes to the pathophysiology of T2D by eventually leading to insulin deficiency (Cnop et al., 2005, Dor and Glaser, 2013). Previously, we showed that a 4-day fasting mimicking diet (FMD) could induce metabolic changes similar to those caused by prolonged fasting and could reduce insulin and glucose levels while increasing ketone bodies and igfbp1 (Brandhorst et al., 2015; Figure S1). Although the role of periodic fasting and fasting mimicking diets on insulin secretion is unknown, the effects of intermittent fasting and chronic calorie restrictions (CR) on insulin sensitivity have been previously reported (Barnosky et al., 2014). Here, our focus is on the putative effects of the FMD in promoting β-cell regeneration, although we have also investigated the effects of the FMD on insulin resistance.
Given that β cells replicate at an extremely low rate in the adult pancreas (Meier et al., 2008, Teta et al., 2005) and that β-cell neogenesis occurs rarely (Xiao et al., 2013), depletion of β cells and the consequent loss of insulin secretion during late-stage diabetes have often been considered conditions whose reversals require islet and stem cell transplantation (Fiorina et al., 2008, Kroon et al., 2008, Milanesi et al., 2012, Pipeleers et al., 2002, Villani et al., 2014). To determine whether the FMD could affect the β-cell deficiency associated with T2D, we studied its effect on mice with a point mutation in the leptin receptor gene (Leprdb/db), which causes insulin resistance in the early stages and failure of β-cell function in the late stages. As reported by others, db/db mice developed hyperglycemia at 10 weeks of age, which we refer to as baseline (BL) (Figure 1A). The insulin levels first increased to compensate for insulin resistance but drastically declined after 2 weeks of severe hyperglycemia (Figures 1B and 1C) (Arakawa et al., 2001). As a result, db/db mice began to die at around 4 months of age. We attempted to reverse these late-stage T2D phenotypes by treating 12-week-old mice (14 days after the hyperglycemia stabilized, baseline) with weekly cycles of the 4-day FMD (Figure 1A). FMD cycles caused a major reduction and return to nearly normal levels of blood glucose in db/db mice by day 60 (Figure 1B). The FMD cycles also reversed the decline in insulin secretion at day 30 and improved plasma insulin levels at day 90 (Figure 1C). A homeostasis model assessment (HOMA) was performed to estimate steady-state β-cell function (%B) and insulin sensitivity (%S), as previously described (Hsu et al., 2013, Matthews et al., 1985). The results indicate that the reversal of hyperglycemia was mainly caused by an induction of steady-state β-cell function (%B) (Figure 1D). Nevertheless, mice receiving the FMD showed improved glucose tolerance and insulin tolerance compared to the ad libitum (AL) fed controls (Figure 1E). Notably, although db/db mice on the FMD diet gained less weight compared to those on the regular diet, they maintained a weight that was ∼22% higher than that of their healthy wild-type (WT) littermates during the entire experiment (Figure S2C). Altogether, these results indicate that FMD cycles rescued mice from late-stage T2D by restoring insulin secretion and reducing insulin resistance, leading to a major improvement in survival (Figure 1F, ∗p < 0.05, log-rank test for trend).
Cycles of FMD Reverse β-Cell Failure in T2D
Dedifferentiation of β cells, which results in increased non-hormone-producing cells within pancreatic islets, is a feature of diabetic β-cell failure (Dor and Glaser, 2013, Kim-Muller et al., 2014, Talchai et al., 2012). Similar to what was previously reported by others, we found an increase in cells producing neither insulin nor glucagon (i.e., non-α/β) and a decrease in β-cell number in pancreatic islets of late-stage T2D mice, but not in age-matched WT controls (Figures 1G and S2, db/db BL compared to WT/AL). We also found that β-cell proliferation was low in the late stage of the disease (Figure 1H, AL day 60 compared to BL). Whereas db/db mice fed ad libitum (db/db:AL) showed a 60%–80% reduction in β-cell count at day 60, db/db mice receiving FMD cycles (db/db:FMD) displayed a major improvement in the number and proliferation of insulin-generating β cells (comparing db/db BL, Figures 1G-1I). Pancreatic islets collected from db/db mice treated with FMD cycles (day 60) displayed increased glucose-stimulated insulin secretion (GSIS), compared to that of islets from db/db:AL mice (Figure 1J). We also determined that a longer exposure time (time point 120) was necessary to distinguish between the functionality of islets from db/db:AL and db/db:FMD group mice (Figure 1J). Overall, these results suggest that, in addition to improving insulin sensitivity, FMD induced β-cell regeneration to reverse β-cell loss, which may alleviate late-stage T2D symptoms and mortality.
FMD Cycles Restore Insulin-Dependent Glucose Homeostasis in STZ-Induced T1D
To examine further the role of FMD cycles in stimulating β-cell regeneration, we applied FMD cycles on a T1D model in which high-dose streptozotocin (STZ) treatment causes the depletion of insulin-secreting β cells (Wu and Huan, 2008, Yin et al., 2006). Starting 5 days after STZ treatment, which we refer to as baseline (STZ BL), hyperglycemia (>300 mg/dl) was observed in both mice fed AL and those subjected to multiple cycles of the 4-day FMD every 7 days (4 days of FMD followed by 3 days of re-feeding, every 7 days per cycle) (Figures 2A and 2B ). Levels of blood glucose continued to increase in STZ-treated mice receiving the AL diet and reached levels above 450 mg/dl at both days 30 and 50. On the other hand, in mice receiving FMD cycles, hyperglycemia and insulin deficiency were both significantly alleviated on day 30 (Figure 2B, sample size indicated in parentheses). Remarkably, the levels of these physiological parameters returned to a nearly normal range at days 50–60 after the FMD cycles (Figures 2B and 2C, sample size indicated in parentheses). Intraperitoneal glucose tolerance tests (IPGTTs) at day 50 confirmed that STZ-treated mice undergoing the FMD cycles have improved capacity to clear exogenous blood glucose (STZ+ FMD), compared to mice on the regular chow (STZ) (Figure 2D).
Levels of certain circulating cytokines have been used as indicators to determine islet pathological status in patients with recent-onset T1D (Baeyens et al., 2014, Grunnet et al., 2009, Lebastchi and Herold, 2012). We performed a 23-plex immunoassay to determine the effects of the FMD on inflammatory markers. We found that FMD cycles not only suppressed the circulating cytokines associated with β-cell damage (e.g., TNFα and IL-12), but also increased circulating cytokines associated with β-cell regeneration (e.g., IL-2 and IL-10) (Figure 2E, day 30) (Dirice et al., 2014, Rabinovitch, 1998, Zhernakova et al., 2006).
Taken together, these results indicate that FMD cycles reduce inflammation and promote changes in the levels of cytokines and other proteins, which may be beneficial for the restoration of insulin secretion and the reversal of hyperglycemia.
FMD Cycles Reverse STZ-Induced β-Cell Depletion
The characterization of pancreatic islet cells indicates a strong association between restored glucose homeostasis and the replenishment of pancreatic β cells in animals undergoing FMD cycles. STZ treatments resulted in an increase of non-α/β cells (Figure S3) and an ∼85% depletion of insulin-secreting β cells (Figure 2F, STZ BL). The transient increase of non-α/β cells was reversed by day 30 in both groups (Figures S2D and S2E). Mice receiving weekly cycles of the FMD showed a major increase in proliferative β cells followed by a return to a nearly normal level of insulin-generating β cells by d50 (Figures 2F–2H). In contrast, mice that received ad libitum access to regular chow remained depleted of β cells for >50 days (Figures 2F and 2H). Overall, the increase of non-α/β prior to β-cell proliferation raises the possibility that weekly cycle of the FMD might mediate the fate conversion of non-α/β cells to β cells to reverse the STZ-induced β-cell depletion, although other scenarios are possible.
FMD and Post-FMD Re-feeding Promote β-Cell Regeneration in Non-diabetic Mice
We investigated whether and how the FMD and the post-FMD re-feeding period could regulate the cell populations within the islets to promote β-cell regeneration independently of diabetes, with a focus on the non-α/β cells and proliferative β cells. To characterize cellular and hormonal changes, pancreatic samples and peripheral blood of wild-type C57Bl6 mice fed with the FMD for 4 days were collected before the diet (BL), at the end of the diet (day 4), and 1 or 3 days after mice returned to the normal diet (RF1d or RF3d). The FMD caused a trend of decrease in the number and size of pancreatic islets (Figure 3A) and reduced the proportion of β cells by 35% (Figures 3B and 3C; see also Figure S4 for absolute numbers). These effects were reversed within 3 days of re-feeding (Figures 3A and 3C). Non-α/β cells began to proliferate at the end of the FMD, and this proliferation persisted until 1 day after re-feeding (RF1d), leading to a 2.5-fold increase in non-α/β cells (proportion per islet) at RF1d (Figure S4). By RF3d, the number of non-α/β cells had dropped and that of β cells returned to basal levels (BL), although β cells remained in a much more proliferative state in the FMD group (Figure 3B and 3C). The expression of the proliferation marker PCNA was elevated in β cells, but not α cells, after re-feeding post FMD (Figures 3B and 3C and S4). Despite the number of α cells per islet remaining the same, the transitional α-to-β or β-to-α cells that co-express both α (i.e., glucagon) and β cell (i.e., Pdx-1 or insulin) markers were increased in mice that received the FMD (Figure 3D). In summary, the FMD promotes a decrease in the numbers of differentiated or committed cells, followed by the induction of transitional cells and major increases in the proliferation and number of insulin-generating β cells (Figure 3E).
-
FMD Promotes a Gene Expression Profile in Adult Mice Similar to that Observed during Embryonic and Fetal Development
To identify the genes that may mediate the FMD-induced pancreatic regeneration, we measured gene expression in pancreatic islets at the end of the FMD and post-FMD re-feeding. At both time points, we observed a transient upregulation of Foxo1 (6.9-fold at FMD, 5.3-fold at RF1d, ∗p < 0.05 comparing to AL) and of a set of genes that have been previously identified as dual regulators for both fat metabolism and fate determination in mammalian cells (Cook et al., 2015, Haeusler et al., 2014, Johnson et al., 2004, Kim-Muller et al., 2014, Mu et al., 2006, Stanger, 2008, Talchai et al., 2012, Talchai and Accili, 2015, Tonne et al., 2013) (Figure 4A), in agreement with the metabolic changes found in mice receiving the FMD (Figure S1). We further examined whether the metabolic reprogramming caused by the FMD affects lineage determination in pancreatic islets. In Figure 4B, the expression of lineage markers was determined by the mRNA expression of purified islets from mice fed ad libitum (AL) or the FMD. Results from the qPCR array indicate that upregulation of the following genes was statistically significant (∗p < 0.05 comparing to AL, Figure 4B; see also Figure S5): (1) pluripotency markers (e.g., Lefty1, 3.0-fold during FMD, 7.0-fold at RF1d; Podx1, 3.9-fold during FMD, 9.8-fold at RF1d; Nanog, 2.6-fold during FMD and 5.4-fold RF1d, and Dnmt3b, 31.6-fold during FMD and 18.3-fold RF1d), (2) embryonic development markers (e.g., Sox17, 3.4-fold during FMD and Gata6 3.1-fold during FMD and 2.7-fold at RF1d), (3) pancreatic fetal-stage markers, and (4) β-cell reprogramming markers (e.g., Mafa, 4.7-fold at RF1d; Pdx-1 3-fold during FMD, 5.07-fold at RF1d; and Ngn3, 21.5-fold during FMD, 45.6-fold at RF1d) (Figure 4B; Zhou et al., 2008). These changes in gene expression suggest that the FMD causes either: (1) a de-differentiation of pancreatic cells toward pluripotency at the end of the diet followed by re-differentiation to pancreatic β-cell lineage during early re-feeding (RF1d) or (2) recruitment of cells with these features from outside of the pancreatic islets. The assessment of protein expression of cells within the islets was also carried out by immunostaining for key proteins associated with pancreatic development (Figures 4C and 4D). In agreement with the results of qPCR array (Figure 4B), we found that protein levels of Sox17, as the early lineage marker, were elevated at the end of the FMD (FMD-4d) and protein levels of Ngn3, a marker for endocrine progenitors, were transiently upregulated during early re-feeding (FMD-4d to RF1d) (Figure 4C).
To determine whether stepwise β-cell conversion from the dedifferentiated cells occurs during early refeeding, we performed double-staining for the targeted developmental markers (i.e., Sox17, Pdx-1, Ngn3) across the time points of FMD treatment. We also measured the expression of Oct4 (Pou5f1), which has been previously reported to be expressed in the nucleus of adult pancreatic islets in association with Foxo-1-related diabetic β-cell dedifferentiation (Talchai et al., 2012, Xiao et al., 2013). Oct4 (Pou5f1) mRNA expression showed a trend for an increase in mice on the FMD, which is not significant (Figure 4C, p > 0.05). Results of immunostaining indicate that Oct4 (Pou5f1) and Sox17 may only be co-expressed very transiently after overnight re-feeding (Figure S5B, RF12hr) followed by robust expansion of Sox17+Pdx1+ and then Pdx1+Ngn3+ cells at RF1d (Figure 4D and see also Figure S5B for all time points). Although Ngn3+ cells were also detectable in AL mice, they were mainly located outside or on the edge of the islets, in agreement with what was reported in previous studies (Baeyens et al., 2014, Gomez et al., 2015; Figure 4D). The number of Ngn3+ cells was increased both inside and outside of the islets during the FMD and re-feeding (Figure 4D).
These results suggest that, as a result of the FMD and re-feeding cycle, the pancreatic islets contain an elevated number of cells with features of progenitor cells, which may differentiate and generate insulin-producing cells.
FMD Induces Ngn3 Expression to Generate Insulin-Producing β Cells
Ngn3+ cells within the pancreatic islets have been previously described as progenitor cells able to generate all lineages of endocrine cells, including the insulin-producing β cells, although the role of Ngn3 in adult β-cell regeneration remains unclear (Baeyens et al., 2014, Van de Casteele et al., 2013, Xu et al., 2008). To investigate whether the FMD causes de novo expression of Ngn3 and whether Ngn3+ cells may contribute to FMD-induced β-cell regeneration, we generated Ngn3-CreER;tdTomatoLSL-reporter mice to trace the lineage of putative Ngn3-expressing cells and their progeny in the adult mice treated with the FMD (Figure 5A). To initiate the loxP recombination for lineage tracing, low-dose tamoxifen injections (2 mg per day for 3 days) inducing the recombination (maximized at 48 hr and minimized within a week) were given to mice before or after the FMD and to mice fed ad libitum (AL control) (Figure 5A). Tissue collection time points are relative to the time of injection and to that of FMD treatments (Figure 5A). Results indicate that the FMD induces the expansion of the Ngn3-derived lineages (Figure 5B and 5C). Characterization of tdTomato+ cells by immunostaining indicates that tdTomato+ cells contributed 50.8% ± 8.3% of the overall β-cell pool following the FMD (Figure 5C, group C).
To confirm the contribution of FMD-induced Ngn3 lineages in reconstituting insulin-secreting β cells, we generated another mouse model (Ngn3-CreER/LSL-R26RDTA) and performed lineage-ablation experiments in both wild-type non-diabetic mice and STZ-treated mice (Figure 5D). The results indicate that ablation of Ngn3+ lineage reverses FMD-induced β-cell regeneration and its effects on fasting glucose levels (Figures 5E and 5F and S5) and glucose clearance capacities (IPGTT assay) in STZ-treated diabetic mice (Figure 5G), confirming that the FMD-induced β-cell regeneration is Ngn3 dependent and suggesting a critical role for this in glucose homeostasis.
Fasting Conditions or Inhibition of Nutrient-Signaling Pathways Promote Ngn3 Expression and Insulin Production in Human Pancreatic Cells
In both mouse and humans, Ngn3 expression occurs right before and during endocrine cell generation. Ngn3 mRNA expression in the developing mouse pancreas peaks around E15.5, which is roughly equivalent to week 7–8 (Carnegie stages 21–22) in human development. Expression of Ngn3 in adult mouse islets, although rare, has been demonstrated by rigorous lineage reporter analysis (Wang et al., 2009). In agreement with results from others, our data (Figures 5 and S5) indicate that Ngn3+ cells in adult pancreas islets are important for β-cell regeneration in mice. On the other hand, the role of Ngn3 in human islet development and β-cell regeneration in adulthood remains poorly understood (McKnight et al., 2010).
To investigate how the fasting mimicking conditions affect Ngn3 expression and β-cell function in human pancreatic cells, we performed ex vivo experiments using primary human pancreatic islets (Figure 6A). Briefly, the pancreatic islets from healthy and T1D subjects (HI and T1DI, respectively) were cultured according to the manufacturer’s instructions. The cultured islets were then treated with serum from subjects enrolled in a clinical trial testing the effects of a low-protein and low-calorie FMD lasting 5 days (NCT02158897). Serum samples were collected at baseline and at day 5 of the fasting mimicking diet in five subjects. We then measured IGF-1, glucose, and ketone bodies and treated human pancreatic islets with the subject-derived serum (Figure 6B and Table S1). In both healthy islets and T1D islets exposed to the serum of FMD-treated subjects, we observed a trend for glucose-dependent induction in the expression of Sox2 and Ngn3 (Figure S6A).
We then applied the low-glucose and low-serum fasting mimicking medium (STS) to the cultured pancreatic islets and found that it significantly stimulated the secretion of insulin in both HI and T1DI (Figure 6C). We further investigated the expression of lineage-reprogramming markers, which we found to be upregulated in mice as a result of the FMD-treatment (i.e., Nanog, Sox17, Sox2, Ngn3, and Ins). The results indicate that the fasting mimicking conditions had strong effects in inducing the expression of Sox2, Ngn3, and insulin in human pancreatic islets from healthy (healthy islets, HI) and T1D subjects (T1D islets, T1DI) (Figures 6D–6F). In cells from normal human subjects, these effects were reversed by IGF-1 treatment (Figure 6G). Notably, in human T1D cells, IGF-1 reversed the increased insulin and Sox 2 gene expression, but not that of Ngn3 expression caused by the STS medium (Figure 6G versus Figures 6D and 6E). Future studies are warranted to further investigate the role of circulating IGF-1 in the expression of lineage-reprogramming markers and pancreatic islet cells regeneration in vivo.
In both healthy and T1D human islets, STS medium significantly reduced the activity of PKA, an effect reversed by IGF-1 treatment (Figure 6H). It also dampened the activity of mTOR, which is a key mediator of amino acid signaling (Figure 6I). To further investigate the role of these nutrient-sensing signaling pathways in regulating the expression of lineage markers (i.e., Sox2 and Ngn3), we tested the role of the mTOR-S6K and PKA pathways, which function downstream of IGF-1, in the reprogramming of pancreatic cells. Human pancreatic islets cultured in standard medium were treated with rapamycin, which inhibits mTOR, and H89, which inhibits PKA. mTOR and PKA were implicated by our group and others in the regeneration of other cell types (Cheng et al., 2014, Yilmaz et al., 2012). We found that, in human islets from T1D subjects (T1DI), expression of the essential lineage markers Sox2 and Ngn3 was not induced by inhibition of either mTOR or PKA but was significantly induced when both mTOR and PKA were inhibited (Figures 6J and 6K). Interestingly, the constitutive mTOR, but not PKA, activity is trending higher in HI compared to T1D1 cells (Figure 6I, lane 1 for both sets for mTOR activity and Figure 6H for PKA activity), which may explain the overall differences between HI and T1DI in Sox2 and Ngn3 expression shown in Figure 6J. Taken together, these results indicate that fasting cycles may be effective in promoting lineage reprogramming and insulin generation in pancreatic islet cells, in part by reducing IGF-1 and inhibiting both mTOR and PKA signaling. Pancreatic cells from T1D subjects displayed constitutively elevated activity of mTOR-S6K and PKA, which points to the potential for inhibitors of both pathways in the induction of Ngn3-mediated lineage reprogramming. These results raise the possibility that the effect of the FMD on pancreatic regeneration in T1D subjects could be mimicked or enhanced by pharmacological inhibition of these pathways.
Discussion
During mouse development, at embryonic day E8.5, pancreatic progenitor cells co-express the SRY-related HMG-box transcription factor Sox17 and the homeodomain transcription factor Pdx1. These multipotent pancreatic progenitors are then converted into bipotent epithelial cells that generate duct cells or a transient population of endocrine precursor cells expressing the bHLH factor Neurogenin3 (Ngn3). Ngn3+ endocrine precursors give rise to all of the principal islet endocrine cells, including glucagon+ α cells and insulin+ β cells (Arnes et al., 2012). In mice, expression of Ngn3 in the developing pancreas is transient, detectable between E11.5 and E18 (Arnes et al., 2012). Whether developmental genes, including Sox17, Pdx-1, and Ngn3, could be activated to generate functional β cells in adults was previously unknown.
Both cell-based therapy and the use of cytokines and hormones that stimulate β-cell self-replication have the potential to restore insulin-producing β cells in diabetic patients (Dirice et al., 2014). However, despite some success with transplantation-based therapy, the short supply of donor pancreata plus the inefficient conversion of stem cells into specialized derivatives have represented obstacles for clinical application, suggesting that a successful β-cell regeneration might depend on the coordinated activation and re-programming of endogenous progenitors (Blum et al., 2014, Sneddon et al., 2012, Wang et al., 2009, Xiao et al., 2013). Recently, this in vivo lineage reprogramming or trans-differentiation has become an emerging strategy to regenerate β cells (Cohen and Melton, 2011, Heinrich et al., 2015, Abad et al., 2013, Xu et al., 2015).
In this study, we discovered that a low-protein and low-sugar fasting mimicking diet (FMD) causes a temporary reduction in β-cell number followed by its return to normal levels after re-feeding, suggesting an in vivo lineage reprogramming. We show that the severe hyperglycemia and insulinemia in both the late-stage Leprdb/db T2 and the STZ-treated T1 mouse diabetes models were associated with severe β-cell deficiency in pancreatic islets. Six to eight cycles of the FMD and re-feeding were required to restore the β-cell mass and insulin secretion function and to return the 6-hr-fasting blood glucose to nearly normal levels. In non-diabetic wild-type mice, the portion of β cells per islet, as well as the total number of β cells per pancreas, were reduced at the end of a 4-day FMD, but their normal level was completely restored within 3–5 days post re-feeding. Also, insulin and blood glucose levels were reduced by 70% or more at the end of the FMD period but returned to normal levels within 24–36 hr of re-feeding. Interestingly, in diabetic mice, the majority of cells residing in the islets expressed neither insulin nor glucagon (i.e., non-α/β). This phenotype was also found in non-diabetic wild-type mice during the FMD and was accompanied by an increase of other transitional cell types (i.e., Pdx1+Glucagon+ cells and Insulin+glucagon+) followed by significant β-cell regeneration upon re-feeding. This suggests that the FMD alters the gene expression profile that normally suppresses the generation of β cells. More importantly, these results suggest that dietary-induced lineage conversion occurring prior to the β-cell proliferation may play an important role in β-cell regeneration across the diabetic and non-diabetic mouse models. One possibility is that glucagon and insulin expression are transiently suppressed in α and β cells during the FMD, followed by lineage reprograming in committed cells. Another possibility is that the FMD may cause cell death and then stimulate progenitor or other cells to regenerate β cells.
The FMD reversed the dedifferentiated expression profile for a number of genes associated with maturity-onset diabetes of the young (MODY) and regulated by Foxo1 (Kim-Muller et al., 2014). The FMD appears to cause pancreatic islets to first increase the expression of Foxo1 and its transcriptional targets, then induce transitionally the expression of the progenitor cell marker Ngn3+ upon re-feeding, leading to β-cell regeneration. We conclude that, together with the changes in a wide range of cytokines associated with β-cell regeneration, FMD and post-FMD re-feeding generate the complex and highly coordinated conditions that promote the generation of stable insulin-producing β-cells to reverse severe β-cell depletion. The key changes priming pancreatic islet cells for regeneration during the FMD appear to be the reduction of IGF-1 levels and the consequent downregulation of PKA and mTor activity, in agreement with the role for these pathways in hematopoietic (Cheng et al., 2014) and intestinal stem-cell self-renewal (Yilmaz et al., 2012). It was proposed that transient de-differentiation of β cells may play a role in their in vivo dynamics (Kim-Muller et al., 2014, Weinberg et al., 2007). The capacity of these de-differentiated cells to re-differentiate fundamentally changes the therapeutic potential of existing cells in promoting β-cell regeneration and reversing T1D symptoms (Blum et al., 2014, Wang et al., 2014). Thus, our study provides an example of a potent and coordinated dietary regulation of cell-fate determination with the potential to serve as a therapeutic intervention to treat diabetes and other degenerative diseases. Our preliminary results from a pilot clinical trial also indicate that the use of periodic cycles of a prolonged FMD is feasible and ready to be tested in large randomized clinical trials for effects on both insulin resistance and pancreatic β-cell regeneration for the treatment of both T1D and T2D.
-
What I get from the above research report is regular fasting is good for people, especially diabetics. So, I plan to start water fasting for 24 hours once a week to see if it helps bring down my daily blood sugar levels.
-
I fasted for 36 hours and only saw my blood sugar continuing to rise. So, while fasting might work for some diabetics, it does not seem to work for me.
-
I have been exploring antihistamines, and I have successfully brought my blood sugar down to normal levels by using both benedryl, and certazine. I am now getting 2 normal blood sugar readings each day out of 3 readings; and it is peak allergy season here, where it is the worst city in the nation for allergies and pollen.
A Brand New Type of Insulin-Producing Cell Has Been Discovered Hiding in the Pancreas (http://www.sciencealert.com/a-brand-new-type-of-insulin-producing-cell-has-been-discovered-hiding-in-plain-sight?utm_source=ScienceAlert+-+Daily+Email+Updates&utm_campaign=5ccf763069-MAILCHIMP_EMAIL_CAMPAIGN&utm_medium=email&utm_term=0_fe5632fb09-5ccf763069-365491701)
According to Huising, there are three main reasons to get excited about the result: firstly, it represents a new beta cell population in both humans and mice that we had no idea about before, and secondly, it also provides a potential new source of beta cells that could be used to treat diabetics.
"Finally, understanding how these cells mature into functioning beta cells could help in developing stem cell therapies for diabetes," a press release explains.
The research could also have benefits for type 2 diabetes, which occurs when beta cells become inactive and stop releasing or secreting insulin.
-
Wow! Great find.
I'm so happy to hear this both from your health point of view and in the interest of science.
-
I'm finally studying about diabetes in my course, and this statement is not very accurate: "The research could also have benefits for type 2 diabetes, which occurs when beta cells become inactive and stop releasing or secreting insulin."
Type 2 diabetes (adult-onset) is mainly because of the unresponsiveness of cells to insulin, therefore any secretion of insulin will have a dampened response. Also, it can be accompanied with a decrease of insulin production, but not in everyone.
The main thing to worry about is hyperlipidemia, where too much fats and bad cholesterol can lead to atherosclerosis, arteriosclerosis or arteriolosclerosis. Therefore cardiovascular disease is a HUGE risk increase in diabetes mellitus. As a side measure because nearly 80% of diabetic patients die from CVD, perhaps Jhanananda can make sure to take foods with HDL (high density lipoprotein or good cholesterol) content as compared to LDL.
Also the complications of diabetes such retinopathy, nephropathy, neuropathy, etc. Normally these happen from high blood sugar causing damage of the vessels in these areas.
Very glad to hear that your blood sugar level is down from the use of antihistamines. I would just add on, to avoid antihistamines with steroids in them, because they stimulate the liver to send more glucose into the bloodstream.
Benadryl causes drowsiness/sleepiness, so perhaps the lack of inflammatory response decreases the need for the body to release sugar for energy. But just a caution in the case that it falls into hypoglycemic emergency.
-
Thanks, bodhimind and Frederick for your kind comments. I just had a difference of opinion with a medical dr. who told me that my findings are just a coincidence. Oddly, the coincidence of consistently higher blood sugar during allergy season for the last 7 years; whereas, during this allergy season, which has been said to be record high, my blood sugar has been consistently lower than it has ever been during the allergy seasons of the last 7 years, is something that he cannot believe. Oh, well. What is knew about me coming into conflict with authority figures?
bodhimind, thanks for your comments. I am well aware of the side effects of diabetes, and I have avoided most of them through living on an ultra-low carb diet, and now taking antihistamines.
-
According to this article, anti-histamines affect blood sugar indirectly by affecting cortisol:
http://www.diabetesforums.com/forum/topic/49176-can-allergies-raise-glucose-level/
-
Thanks, Frederick, for digging up this thread on a diabetes forum. It certainly supports my findings. I have noticed for over a year now that my blood sugar tends to be lower outside of Prescott, AZ. So, I plan to at least spend a few months away from Prescott as soon as I get a more reliable vehicle running, to test this hypothesis.
Here are more links on this subject:
Allergies and blood glucose? (https://www.diabetesdaily.com/forum/type-2-diabetes/32111-allergies-blood-glucose/)
Seasonal Allergies May Irritate Your Blood Sugars (https://www.diabetesdaily.com/blog/2011/05/seasonal-allergies-may-irritate-your-blood-sugars/)
There’s not much research available on this topic, so we took our question to the community and posted a poll on Facebook: Do seasonal allergies affect your blood sugars?
A quarter of those who responded said seasonal allergies raise their blood sugars, one per cent said they lower their blood sugars, 43 per cent said their allergies have no impact and 31 per cent said they don’t have season allergies.
-
http://www.diabetesforums.com/forum/topic/49176-can-allergies-raise-glucose-level/
Oh holy heck yes :)
Part of the body's natural allergic response is to produce cortisol (which is a steroid). The intent in the body is to reduce inflamation, but it has the unfortunate effect of causing elevated BG.. the effect varies. The last time I dealt with this I was having scary high numbers.
Antihistamines don't treat the symptoms, they actually do help to reduce the response. My CDE recently turned me on to using flonase to reduce my nasal symptoms, which seems to be the source of the typical seasonal allergy cascade for me.. I was skeptical about adding a steroid into the mix, but since it's localized it does seem to help without a huge impact on my BG. If I am having more systemic allergy issues, nothing really helps... I have to bump up the insulin a LOT.
Cortisol is produced by your adrenal glands. They are little endocrine glands that look like dunce caps sitting upon your kidneys. Cortisol is a hormone that is required for life. It is also a fight or flight hormone (ie stress).
Cortisol does not suppress your immune system, it is Cortisone which is a glucocorticoid steroid that will supress your immune system (along with solumedrol, depomedrol, prednisone, ect).
With extra cortisol coursing throughout your body, your body is either under going stress, or some kind of fight/flight reaction and therefore more cortisol pumped out of your adrenals, the higher your sugars are going to go, and the more insulin resistant you will become (ie in response to allergies/allergic reactions).
I suspect that the 1% who notice that their blood sugar goes down during allergy season are most likely taking antihistamines.
The allergy causes diabetes argument resorts to the rising cortisol argument. And, it turns out that my bone and joint pain is also down. Here, the argument might be the same argument for 25% of the diabetic population, which is no small percentage.
Further using this argument to explain my observations, suggests that cortisol is being triggered by allergies, which raises blood sugar to combat the invasion of allergens, which requires the body to generate sugar for the energy to combat the invasion of allergens, which explains why type II diabetics have plenty of insulin, but it does not bring the blood sugar down. Thus, using antihistamines to combat the allergens, gives the body a break on sugar production from glucogon.
Further, the reason why I have bone and joint pain, is the body stores surplus glucogon in the bones, so when the body is extracting glucogon from the bones produces bone and joint pain.
I found taking 10mg of clariton in the morning plus 25mg of benedryl, plus 10mg of certirizine plus 25mg of benedryl before bed, works for me to normalize my blood sugar. Some other suite of antihistamines might work better for others.
Antihistamines: singular, Zyrtec (Certirizine HCl), Claritin (Loratadine HCl), benadryl (diphenhydromine HCl), Azestilin (Azestiline HCL..nasel spray), Optivar (Azestline HCL.. eye drops) plus prednisone; and possibly an anti-inflammatory.
Allergens: dust, dust mites, mold, mildew, pollens, cat dander, cat saliva, bird feathers, raspberries, strawberries, coconut, coconut oils, walnuts, dairy, eggs.
-
My morning blood sugar is highest. It is known as the Dawn Effect. Now realizing that my high blood sugar seems to be the effect of allergies, and knowing that plants produce their pollen at night, then it is very possible that the Dawn Effect is due to night pollen production.
Why Is My Blood Sugar High in the Morning? (http://www.webmd.com/diabetes/morning-high-blood-sugar-levels)
Do you take insulin for diabetes and have high blood sugar levels in the morning? It happens to a lot of people, and there are solutions -- once you know why it’s happening.
Doctors have narrowed down the reasons for this to two different causes.
The dawn phenomenon. This is the result of several natural body changes that happen while you’re asleep. Between 3 a.m. and 8 a.m., your body starts to ramp up the amounts of certain hormones that work against insulin's action to drop blood sugar levels. They enter your system just as your bedtime insulin is wearing out and sugar levels rise.
The Somogyi effect. Named after the doctor who first wrote about it, doctors also call this "rebound hyperglycemia." The term refers to pattern of your blood sugar being high in the morning, after having been low (hypoglycemia). Usually there are no symptoms, but night sweats can be a sign.
Your blood sugar may drop too low in the middle of the night. In response, your body releases hormones to raise it. This could happen if you took too much insulin earlier or if you didn’t have enough of a bedtime snack.
To learn the reason for your high morning blood sugar, your doctor will likely ask you to check your levels between 2 a.m. and 3 a.m. for a few nights in a row.
If it’s consistently low during this time, the Somogyi effect is probably the cause. If it’s normal or high during this time period, the dawn phenomenon is more likely the reason.
How Do I Treat It?
Once you and your doctor figure out how your blood sugar levels behave overnight, she may suggest changes like these:
Change the type of insulin so it doesn’t peak at the wrong time or in the middle of the night.
Take extra insulin overnight if your blood sugar goes up during the evening.
Switch to an insulin pump, which can be programmed to the release the amount of insulin you need during the problem time periods.
Or, try taking anti-histamines before bed to see if your body is reacting to night time pollen production.
-
This all sounds like a very reasonable argument. It makes sense the body using energy and inflaming in relation to allergens thus causing an increase in glucose production. I feel more stable physically and less ill in general since i began taking an almost daily dose of 25-100mg of dephinhydramine last spring for nausea. It is very possible my body reacts more deeply to allergens than i have been aware of. Very informative thanks!
Rougeleader
-
Thanks, rougeleader115, for your contribution. Yes, I am developing an hypothesis that allergies are far more influential in our life than most of us had here-to-for understood.
-
So, here is an update:
I was diagnosed type 2 diabetic 6 months after arriving in Prescott, AZ, 7 years ago. I had had a physical in Tucson exactly 1 year earlier. Then the physician said that I had the cardio-vascular system of an athlete, and there were no problems to report. I happen to be a field archaeologist by profession, which is very physically demanding, and requires top fitness.
OK, so 7 years ago, after a bout of seasonal allergies, my Prescott physician reported to me, "You are full-on diabetic, with a blood sugar of 250 (150 over normal), you have high blood pressure, and you have very high cholesteral."
So, what changed in a year? I moved to Prescott. I left his office severely depressed, went to the pharmacy to get the blood glucose test meter and blood glucose test strips. I tested my blood sugar every morning, and found it normal every morning for a week, so I determined that the lab must have mixed up my sample with someone else’. However, I had gained 50 pounds in my first 6 months here, which was unusual.
Six months later during another severe bout of seasonal allergies, I went back to my Prescott physician.
He asked me, “Have you been testing your blood sugar?”
I said, “No,” and explained why.
He sent me back to the lab for another blood test. It came back 150 over normal, the same as it was 6 months earlier.
I must also point out that since arriving in Prescott I had been dealing with sever joint and bone pain as well, which was not new, but episodic, and back again.
So, since then I have been doing a great deal of research on diabetes, to understand why I am the only member of my family that has it. I have also scrutinized my health and environment rigorously. There is clearly something about Prescott that causes my blood sugars to rise significantly. I have since come to realize that my diabetes is due to allergies, and all I need to do to control my diabetes is to treat my allergies with antihistamines.
I recently told a doctor about my finding above, and he threw me out of his office, and on my way out I heard him tell his nurse not to treatment.
So, I happened to tell a friend of mine here about my findings.
He said, “It sounds weird, but my sister is an expert in diabetes treatment, and she works for a pharmaceutical company as a consultant in diabetes for them.
He came back to me a few days later and said, “My sister said, ‘Sure, blood sugar can be effected by any stress, and since allergies are a stress on the body, then there is no reason why your friend would not have the results that he has found.’”
Since then my joint and bone pain is down, and I have lost 50lbs.
So, the conclusion is, we should not consider all doctors are experts in all fields of medicine; and we need to become our own advocates, and experts regarding our health; and, if we can develop a means of closely monitoring our health, fitness, and environment, then we may find improved health.
-
I remember an immunologist saying that food allergies have increased over 50 percent over just 5 years. Hygiene hypothesis says that we grew up with lack of exposure to third-party agents like infectious diseases or allergens and this probably makes our immune system oversensitive due to the lack of 'reference points'. For example, the immune system can 'prime' itself against viruses due to weak attacks from vaccines (dead/attenuated viruses). Bacteria, on the other hand, develop resistances very quickly and there's no way to actually 'prime' completely against it, so we use antibiotics.
If we understand that our body is mostly made out of flora, all over the skin and inner linings of our digestive system, then the use of antibiotics can significantly alter the composition of them. I would even say that the warming global climate pays a huge difference to the composition of gut flora.
Given that allergies are classified as a Type I hypersensitive reaction, alongside Type II (autoimmune), Type III (like rheumatoid arthritis), etc... It's all highly associated with the immune system's responding with inflammatory responses.
Perhaps we have an over-sensitive defense system. What was considered normal in the past, such as exposure to pollen or various other allergens like the big 8 food allergens (Milk, eggs, peanuts, tree nuts, soy, wheat, fish and shellfish), is probably toxic to the normal human. It is just that in some compromise of the bodily system, such as breakdown of pancreatic cells or loss of insulin response, the body becomes less able to cope. It could also explain why obesity is highly linked to type 2 diabetes as well.
Curiously, now Alzheimer's disease is also called Type 3 diabetes, which claims there is a huge link between diet itself and neurodegenerative diseases. I wonder if it has to do with hypersensitivity as well.
-
bodhimind, you present a reasonable set of hypotheses. I do not think any of us can say for sure why US Americans are sicker than the rest of the human population of the planet; however, one of more of your hypotheses might be the answer. We will just have to pursue greater understanding over time.
-
Here are 2 good research papers on inflammatory hyperglycemia.
Inflammation, stress, and diabetes (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1087185/)
Over the last decade, an abundance of evidence has emerged demonstrating a close link between metabolism and immunity. It is now clear that obesity is associated with a state of chronic low-level inflammation. In this article, we discuss the molecular and cellular underpinnings of obesity-induced inflammation and the signaling pathways at the intersection of metabolism and inflammation that contribute to diabetes. We also consider mechanisms through which the inflammatory response may be initiated and discuss the reasons for the inflammatory response in obesity. We put forth for consideration some hypotheses regarding important unanswered questions in the field and suggest a model for the integration of inflammatory and metabolic pathways in metabolic disease.
Diabetes, Hyperglycemia, and Inflammation in Older Individuals (http://care.diabetesjournals.org/content/29/8/1902.full)
The Health, Aging and Body Composition study
Abstract
OBJECTIVE—The objective of this study was to assess the association of inflammation with hyperglycemia (impaired fasting glucose [IFG]/impaired glucose tolerance [IGT]) and diabetes in older individuals.
RESEARCH DESIGN AND METHODS—Baseline data from the Health, Aging and Body Composition study included 3,075 well-functioning black and white participants, aged 70–79 years.
RESULTS—Of the participants, 24% had diabetes and 29% had IFG/IGT at baseline. C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) levels (P < 0.001) were significantly higher among diabetic participants and those with IFG/IGT. Odds of elevated IL-6 and TNF-α (>75th percentile) were, respectively, 1.95 (95% CI 1.56–2.44) and 1.88 (1.51–2.35) for diabetic participants and 1.51 (1.21–1.87) and 1.14 (0.92–1.42) for those with IFG/IGT after adjustment for age, sex, race, smoking, alcohol intake, education, and study site. Odds ratios for elevated CRP were 2.90 (2.13–3.95) and 1.45 (1.03–2.04) for diabetic women and men and 1.33 (1.07–1.69) for those with IFG/IGT regardless of sex. After adjustment for obesity, fat distribution, and inflammation-related conditions, IL-6 remained significantly related to both diabetes and IFG/IGT. CRP in women and TNF-α in both sexes were significantly related to diabetes, respectively, whereas risk estimates for IFG/IGT were decreased by adjustment for adiposity. Among diabetic participants, higher levels of HbA1c were associated with higher levels of all three markers of inflammation, but only CRP remained significant after full adjustment.
CONCLUSIONS—Our findings show that dysglycemia is associated with inflammation, and this relationship, although consistent in diabetic individuals, also extends to those with IFG/IGT. Aging is associated with increased inflammatory activity including proinflammatory and anti-inflammatory cytokines and acute-phase proteins (1). Previous studies suggested that low-grade systemic inflammation plays a role in the pathogenesis of some glucose disorders in adults (2). Several cross-sectional studies showed that insulin resistance and type 2 diabetes are associated with higher levels of C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), markers of subclinical systemic inflammation (3–8). Furthermore, various longitudinal studies have shown that elevated levels of CRP and IL-6 predict the development of type 2 diabetes (9–12). Few studies to date have focused on the association between diabetes and inflammation in older individuals, and to our knowledge none of these have studied the relationship of impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) with inflammation in aging.
-
An article on the contaminated water of Prescott, AZ.
Arsenic-tainted discharges into county creek lead to felony charges (https://www.dcourier.com/news/2017/aug/02/arizona-ag-announces-indictment/)
Owners of a Bagdad-area mine that allegedly has been discharging thousands of gallons of arsenic-contaminated water per day into Boulder Creek faces three felony counts for pollutant discharge violations.
On Tuesday, Aug. 1, Arizona Attorney General Mark Brnovich announced that a State Grand Jury had indicted Bagdad Hillside, LLC, for allegedly discharging arsenic-contaminated water into the recreational creek.
“Bagdad Hillside is facing three felony counts of Pollutant Discharge Elimination System Violations,” the news release stated.
It added that in 2013, the Arizona Department of Environmental Quality inspected the inactive Hillside Mine, located four miles north of Bagdad, and found it discharging arsenic-contaminated water directly into adjacent Boulder Creek at a rate of five gallons per minute or about 2.6 million gallons per year.
“Bagdad Hillside allegedly owns the mine and the surrounding property,” the news release stated, adding that according to tests, the water flowing from the mine contains arsenic levels that are more than 100 times the water quality standard.
“Boulder Creek is open to Arizonans for recreational swimming year-round,” the release added. “It is not believed that anyone uses Boulder Creek as a source of drinking water.”
Since 2013, ADEQ representatives reportedly have tried to work with Bagdad Hillside to stop the mine from discharging contaminated water, and the company signed three consent orders agreeing to file a plan to stop the discharge. “Those plans have not been submitted and the mine continues to discharge into Boulder Creek,” stated the news release.
Assistant Attorney General Adam J Schwartz is prosecuting the case.
-
Hello everyone,
I was watching a health program on a Christian TV station and the host, with the last name of Becker, was excitedly promoting a cure all called black seed oil, sometimes called black cumin oil. It's and old middle eastern medicinal that is touted to help with diabetes, auto-immune problems, and a host of many other disorders. The next day I found and bought some and have been taking it for the past two days. It has a strong but not terribly unpleasant taste. Very herby, like rosemary or thyme. We'll see how it works for me, but it looks like it may have potential.
-
I used black seed oil a few times for general health (not diabetes). It made me calmer and helped my indigestion.
-
Perhaps cummin and black seed oil owe their color to a natural anti-inflammatory known as anthocynin, which we have been discussing here. I will have to acquire a bottle of black seed oil to try it out. Thanks for the recommendation.
-
My health continues to improve with the continued use of antihistamines. I am now taking 2 different 1/day antihistamines taken 12 hours apart, plus the occasional use of Benadryl, as needed; along with an ultra-low carb diet. This year I have lost 37 pounds on this regimen.
-
Wow, this is quite interesting.
I read up more on diabetic involvement with histamine action and found the following 2011 animal study: https://www.ncbi.nlm.nih.gov/pubmed/21239440
Also interesting, from a different study:
In particular, based on its vascular actions, histamine has been suggested to be a key triggering stimulus for the functional microangiopathy in diabetes mellitus, from retinopathy to nephropathy. However, its complete functional contribution to diabetes microvascular complications is yet to be elucidated.
Happy that your health is improving :)
-
Thanks, bodhimind, for the link. I searched for you quote and found a published research paper with the quote in it. It was in, Histamine in diabetes: Is it time to reconsider? (https://www.sciencedirect.com/science/article/pii/S1043661816305953) in Pharmacological Research, Volume 111, September 2016, Pages 316-324
Abstract
The first studies of histamine and diabetes date back to the 1950s. Since that time the involvement of histamine in diabetes was related to its well known vasoactive properties and permeability leakage effects. In particular, the first evidence for a correlation between histamine and diabetes arose in 1989 when an increase in plasma and leucocyte histamine content was observed. Limited independent evidence followed in the subsequent two decades, focusing on both histamine glyceamic control and macro- and microvascular complications of diabetes. However, recent observations have sparked the question whether it is time to reconsider the functional contribution of histamine in diabetes. We reveal an interesting upsurge in the field which provides scope for new insights into the role of histamine in diabetes.
It looks like there is a clear connection between histamine and diabetes, and the research supporting this connection date back to the 1950s.
More interesting data comes from your first link, Antidiabetic properties of the histamine H3 receptor protean agonist proxyfan (https://www.ncbi.nlm.nih.gov/pubmed/21239440), Endocrinology. 2011 Mar;152(3):828-35. doi: 10.1210/en.2010-0757. Epub 2011 Jan 14.
Abstract
Proxyfan is a histamine H3 receptor protean agonist that can produce a spectrum of pharmacological effects including agonist, inverse agonist, and antagonist. We have discovered that proxyfan (10 mg/kg orally) significantly improved glucose excursion after an ip glucose tolerance test in either lean or high-fat/cholesterol diet-induced obese mice. It also reduced plasma glucose levels comparable to that of metformin (300 mg/kg orally) in a nongenetic type 2 diabetes mouse model. The dose-dependent decrease in glucose excursion correlated with inhibition of ex vivo H3 receptor binding in the cerebral cortex. In addition, glucose levels were significantly reduced compared with vehicle-treated mice after intracerebroventricular administration of proxyfan, suggesting the involvement of central H3 receptors. Proxyfan-induced reduction of glucose excursion was not observed in the H3 receptor knockout mice, suggesting that proxyfan mediates this effect through H3 receptors. Proxyfan reduced glucose excursion by significantly increasing plasma insulin levels in a glucose-independent manner. However, no difference in insulin sensitivity was observed in proxyfan-treated mice. The H1 receptor antagonist chlorpheniramine and the H2 receptor antagonist zolantidine had modest effects on glucose excursion, and neither inhibited the glucose excursion reduced by proxyfan. The H3 receptor antagonist/inverse agonist, thioperamide, had weaker effects on glucose excursion compared with proxyfan, whereas the H3 receptor agonist imetit did not affect glucose excursion. In conclusion, these findings demonstrate, for the first time, that manipulation of central histamine H3 receptor by proxyfan can significantly improve glucose excursion by increasing plasma insulin levels via a glucose-independent mechanism.
The conclusion is most interesting. I will have to ask my dr about Proxyfan (https://en.wikipedia.org/wiki/Proxyfan).
Proxyfan is a histamine H3 receptor ligand which is a "protean agonist", producing different effects ranging from full agonist, to antagonist, to inverse agonist in different tissues, depending on the level of constitutive activity of the histamine H3 receptor. This gives it a complex activity profile in vivo which has proven useful for scientific research.
And, another interesting article, The H3 receptor protean agonist proxyfan enhances the expression of fear memory in the rat (https://www.ncbi.nlm.nih.gov/pubmed/15695163). Neuropharmacology, 2005 Feb;48(2):246-51.
Abstract
Consolidation of fear memory requires neural changes to occur in the basolateral amygdala (BLA), including modulation of histaminergic neurotransmission. We previously demonstrated that local blockade or activation of histamine H3 receptors in the BLA impaired or ameliorated, respectively, retention of fear memory. The histamine H3 receptor is a G-protein-coupled receptor (GPCR) displaying high constitutive activity that regulates histamine neurons in the brain. Proxyfan is a high-affinity histamine H3 receptor protean agonist exhibiting the full spectrum of pharmacological activities, from full agonist to full inverse agonist depending on the competition between constitutively active and quiescent H3 receptors in a given tissue or brain region. Therefore, protean agonists are powerful tools to investigate receptor conformation and may be useful in designing specific compounds selective for the various receptor conformations. In the present study we examined the effect of post-training, systemic or intra-BLA injections of proxyfan on contextual fear memory. Rats receiving intra-BLA, bilateral injections of 1.66 ng proxyfan immediately after fear conditioning showed stronger memory for the context-footshock association, as demonstrated by longer freezing assessed at retention performed 72 hr later compared to controls. Comparable results were obtained when doses as low as 0.04 mg/kg of proxyfan were injected systemically. Hence, our results suggest that proxyfan behaves as an H3 receptor agonist with a low level of constitutive activity of the H3 receptor in the rat BLA.
-
It seems appropriate to examine what are histamines, to understand how they effect diabetes, and other health conditions.
Histamine (https://en.wikipedia.org/wiki/Histamine)
Histamine is an organic nitrogenous compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter for the brain, spinal cord and uterus.[3][4] Histamine is involved in the inflammatory response and has a central role as a mediator of itching.[5] As part of an immune response to foreign pathogens, histamine is produced by basophils and by mast cells found in nearby connective tissues. Histamine increases the permeability of the capillaries to white blood cells and some proteins, to allow them to engage pathogens in the infected tissues.[6]
Properties
Histamine base, obtained as a mineral oil mull, melts at 83–84 °C.[7] Hydrochloride[8] and phosphorus[9] salts form white hygroscopic crystals and are easily dissolved in water or ethanol, but not in ether. In aqueous solution, histamine exists in two tautomeric forms: Nπ-H-histamine and Nτ-H-histamine. The imidazole ring has two nitrogens. The nitrogen farthest away from the side chain is the 'tele' nitrogen and is denoted by a lowercase tau sign. The nitrogen closest to the side chain is the 'pros' nitrogen and is denoted by the pi sign. The position of the nitrogen with the hydrogen on it determines how the tautomer is named. If the nitrogen with the hydrogen is in the tele position, then histamine is in the tele-tautomer form. The tele-tautomer is preferred in solution.
Histamine has two basic centres, namely the aliphatic amino group and whichever nitrogen atom of the imidazole ring does not already have a proton. Under physiological conditions, the aliphatic amino group (having a pKa around 9.4) will be protonated, whereas the second nitrogen of the imidazole ring (pKa ≈ 5.8) will not be protonated.[10] Thus, histamine is normally protonated to a singly charged cation. Histamine is a monoamine neurotransmitter.
Synthesis and metabolism
Histamine is derived from the decarboxylation of the amino acid histidine, a reaction catalyzed by the enzyme L-histidine decarboxylase. It is a hydrophilic vasoactive amine.
Once formed, histamine is either stored or rapidly inactivated by its primary degradative enzymes, histamine-N-methyltransferase or diamine oxidase. In the central nervous system, histamine released into the synapses is primarily broken down by histamine-N-methyltransferase, while in other tissues both enzymes may play a role. Several other enzymes, including MAO-B and ALDH2, further process the immediate metabolites of histamine for excretion or recycling.
Bacteria also are capable of producing histamine using histidine decarboxylase enzymes unrelated to those found in animals. A non-infectious form of foodborne disease, scombroid poisoning, is due to histamine production by bacteria in spoiled food, particularly fish.
Fermented foods and beverages naturally contain small quantities of histamine due to a similar conversion performed by fermenting bacteria or yeasts. Sake contains histamine in the 20–40 mg/L range; wines contain it in the 2–10 mg/L range.[11]
Storage and release
Most histamine in the body is generated in granules in mast cells and in white blood cells (leukocytes) called basophils. Mast cells are especially numerous at sites of potential injury — the nose, mouth, and feet, internal body surfaces, and blood vessels. Non-mast cell histamine is found in several tissues, including the brain, where it functions as a neurotransmitter. Another important site of histamine storage and release is the enterochromaffin-like (ECL) cell of the stomach.
The most important pathophysiologic mechanism of mast cell and basophil histamine release is immunologic. These cells, if sensitized by IgE antibodies attached to their membranes, degranulate when exposed to the appropriate antigen. Certain amines and alkaloids, including such drugs as morphine, and curare alkaloids, can displace histamine in granules and cause its release. Antibiotics like polymyxin are also found to stimulate histamine release.
Histamine release occurs when allergens bind to mast-cell-bound IgE antibodies. Reduction of IgE overproduction may lower the likelihood of allergens finding sufficient free IgE to trigger a mast-cell-release of histamine.
Mechanism of action
In humans, histamine exerts its effects primarily by binding to G protein-coupled histamine receptors, designated H1 through H4.[12] As of 2015, histamine is believed to activate ligand-gated chloride channels in the brain and intestinal epithelium.[12][13]
Roles in the body
Although histamine is small compared to other biological molecules (containing only 17 atoms), it plays an important role in the body. It is known to be involved in 23 different physiological functions. Histamine is known to be involved in many physiological functions because of its chemical properties that allow it to be versatile in binding. It is Coulombic (able to carry a charge), conformational, and flexible. This allows it to interact and bind more easily.[16]
Vasodilation and a fall in blood pressure
When injected intravenously, histamine causes most blood vessels to dilate, and hence causes a fall in the blood pressure.[17] This is a key mechanism in anaphylaxis, and is thought to be caused when histamine releases nitric oxide, endothelium-derived hyperpolarizing factors and other compounds from the endothelial cells.
This may explain why I observe lower blood pressure during allergies.
Effects on nasal mucous membrane
Increased vascular permeability causes fluid to escape from capillaries into the tissues, which leads to the classic symptoms of an allergic reaction: a runny nose and watery eyes. Allergens can bind to IgE-loaded mast cells in the nasal cavity's mucous membranes. This can lead to three clinical responses:[18]
sneezing due to histamine-associated sensory neural stimulation
hyper-secretion from glandular tissue
nasal congestion due to vascular engorgement associated with vasodilation and increased capillary permeability
Sleep-wake regulation
Histamine is released as a neurotransmitter. The cell bodies of histamine neurons are found in the posterior hypothalamus, in the tuberomammillary nuclei. From here, these neurons project throughout the brain, including to the cortex, through the medial forebrain bundle. Histamine neurons increase wakefulness and prevent sleep.[19] Classically, antihistamines (H1 histamine receptor antagonists) which cross the blood-brain barrier produce drowsiness. Newer antihistamines are designed to not cross into the brain and thus are less likely to cause sedation, although individual reactions, concomitant medications and dosage may increase the sedative effect. Similar to the effect of older antihistamines, destruction of histamine releasing neurons, or inhibition of histamine synthesis leads to an inability to maintain vigilance. Finally, H3 receptor antagonists increase wakefulness.
Histaminergic neurons have a wakefulness-related firing pattern. They fire rapidly during waking, fire more slowly during periods of relaxation/tiredness and completely stop firing during REM and NREM (non-REM) sleep.
Gastric acid release
Enterochromaffin-like cells, located within the gastric glands of the stomach, release histamine that stimulates nearby parietal cells by binding to the apical H2 receptor. Stimulation of the parietal cell induces the uptake of carbon dioxide and water from the blood, which is then converted to carbonic acid by the enzyme carbonic anhydrase. Inside the cytoplasm of the parietal cell, the carbonic acid readily dissociates into hydrogen and bicarbonate ions. The bicarbonate ions diffuse back through the basilar membrane and into the bloodstream, while the hydrogen ions are pumped into the lumen of the stomach via a K+/H+ ATPase pump. Histamine release is halted when the pH of the stomach starts to decrease. Antagonist molecules, like ranitidine, block the H2 receptor and prevent histamine from binding, causing decreased hydrogen ion secretion.
Protective effects
While histamine has stimulatory effects upon neurons, it also has suppressive ones that protect against the susceptibility to convulsion, drug sensitization, denervation supersensitivity, ischemic lesions and stress.[20] It has also been suggested that histamine controls the mechanisms by which memories and learning are forgotten.[21]
Erection and sexual function
Libido loss and erectile failure can occur during treatment with histamine H2 receptor antagonists such as cimetidine, ranitidine, and risperidone.[22] The injection of histamine into the corpus cavernosum in men with psychogenic impotence produces full or partial erections in 74% of them.[23] It has been suggested that H2 antagonists may cause sexual difficulties by reducing the uptake[clarification needed] of testosterone.[22]
Schizophrenia
Metabolites of histamine are increased in the cerebrospinal fluid of people with schizophrenia, while the efficiency of H1 receptor binding sites is decreased. Many atypical antipsychotic medications have the effect of increasing histamine production, because histamine levels seem to be imbalanced in people with that disorder.[24]
I have heard of several cases of people who suffer from Schizophrenia will have their symptoms lowered by simply taking an antihistamine.
Multiple sclerosis
Histamine therapy for treatment of multiple sclerosis is currently being studied. The different H receptors have been known to have different effects on the treatment of this disease. The H1 and H4 receptors, in one study, have been shown to be counterproductive in the treatment of MS. The H1 and H4 receptors are thought to increase permeability in the blood-brain barrier, thus increasing infiltration of unwanted cells in the central nervous system. This can cause inflammation, and MS symptom worsening. The H2 and H3 receptors are thought to be helpful when treating MS patients. Histamine has been shown to help with T-cell differentiation. This is important because in MS, the body's immune system attacks its own myelin sheaths on nerve cells (which causes loss of signaling function and eventual nerve degeneration). By helping T cells to differentiate, the T cells will be less likely to attack the body's own cells, and instead attack invaders.[25]
Disorders
As an integral part of the immune system, histamine may be involved in immune system disorders[26] and allergies. Mastocytosis is a rare disease in which there is a proliferation of mast cells that produce excess histamine.[27]
History
The properties of histamine, then called β-iminazolylethylamine, were first described in 1910 by the British scientists Henry H. Dale and P.P. Laidlaw.[28] By 1913 the name histamine was in use, using combining forms of histo- + amine, yielding "tissue amine".
"H substance" or "substance H" are occasionally used in medical literature for histamine or a hypothetical histamine-like diffusible substance released in allergic reactions of skin and in the responses of tissue to inflammation.
-
Histamine H3 receptor
Histamine H3 receptors are expressed in the central nervous system and to a lesser extent the peripheral nervous system, where they act as autoreceptors in presynaptic histaminergic neurons, and also control histamine turnover by feedback inhibition of histamine synthesis and release.[5] The H3 receptor has also been shown to presynaptically inhibit the release of a number of other neurotransmitters (i.e. it acts as an inhibitory heteroreceptor) including, but probably not limited to dopamine, GABA, acetylcholine, noradrenaline, histamine and serotonin.
The gene sequence for H3 receptors expresses only about 22% and 20% homology with both H1 and H2 receptors respectively.
There is a lot of interest in the histamine H3 receptor as a potential therapeutic target because of its involvement in the neuronal mechanism behind many cognitive H3R-disorders and especially its location in the central nervous system.[6][7]
Tissue distribution
Central nervous system
Peripheral nervous system
Heart
Lungs
Gastrointestinal tract
Endothelial cells
Function
Like all histamine receptors, the H3 receptor is a G-protein coupled receptor. The H3 receptor is coupled to the Gi G-protein, so it leads to inhibition of the formation of cAMP. Also, the β and γ subunits interact with N-type voltage gated calcium channels, to reduce action potential mediated influx of calcium and hence reduce neurotransmitter release. H3 receptors function as presynaptic autoreceptors on histamine-containing neurons.[8]
The diverse expression of H3 receptors throughout the cortex and subcortex indicates its ability to modulate the release of a large number of neurotransmitters.
H3 receptors are thought to play a part in the control of satiety.
This may explain why some type-2 diabetics end up with an eating disorder.
Isoforms
There are at least six H3 receptor isoforms in the human, and more than 20 discovered so far.[10] In rats there have been six H3receptor subtypes identified so far. Mice also have three reported isoforms.[11] These subtypes all have subtle difference in their pharmacology (and presumably distribution, based on studies in rats) but the exact physiological role of these isoforms is still unclear.
Pharmacology
Agonists
There are currently no therapeutic products acting as selective agonists for H3 receptors, although there are several compounds used as research tools which are reasonably selective agonists. Some examples are:
(R)-α-methylhistamine
Cipralisant (initially assessed as H3 antagonist, later found to be an agonist, shows functional selectivity, activating some G-protein coupled pathways but not others)[12]
Imbutamine (also H4 agonist)
Immepip
Imetit
Immethridine
Methimepip
Proxyfan (complex functional selectivity; partial agonist effects on cAMP inhibition and MAPK activity, antagonist on histamine release, and inverse agonist on arachidonic acid release)
Antagonists
These include:[13]
A-349,821[14]
ABT-239
Betahistine (also weak H1 agonist)
Burimamide (also weak H2 antagonist)
Ciproxifan
Clobenpropit (also H4 antagonist)
Conessine
Failproxifan (no tolerance formation, like with Ciproxifan)
Impentamine
Iodophenpropit
Irdabisant
Pitolisant
Thioperamide (also H4 antagonist)
VUF-5681 (4-[3-(1H-Imidazol-4-yl)propyl]piperidine)
Therapeutic potential
The H3-receptor is a promising potential therapeutical target for many (cognitive) disorders that are caused by a histaminergic H3R disfunction, because it is linked to the central nervous system and its regulation of other neurotransmitters.[6][15][16] Examples of such disorders are: sleep disorders (including narcolepsy), Tourette syndrome, Parkinson, OCD, ADHD, ASS and (drug)addictions.[6][16]
This receptor has been proposed as a target for treating sleep disorders.[17] The receptor has also been proposed as a target for treating neuropathic pain.[18]
Because of its ability to modulate other neurotransmitters, H3 receptor ligands are being investigated for the treatment of numerous neurological conditions, including obesity (because of the histamine/orexinergic system interaction), movement disorders (because of H3 receptor-modulation of dopamine and GABA in the basal ganglia), schizophrenia and ADHD (again because of dopamine modulation) and research is underway to determine whether H3 receptor ligands could be useful in modulating wakefulness (because of effects on noradrenaline, glutamate and histamine).[19][7]
There is also evidence that the H3-receptor plays an important role in Tourette syndrome.[20] Mouse-models and other research demonstrated that reducing histamine concentration in the H3R causes tics, but adding histamine in the striatum decreases the symptoms.[21][22][23] The interaction between histamine (H3-receptor) and dopamine as well as other neurotransmitters is an important underlying mechanism behind the disorder.[24]
History
1983 The H3 receptor is pharmacologically identified.[25]
1988 H3 receptor found to mediate inhibition of serotonin release in rat brain cortex.[26]
1997 H3 receptors shown to modulate ischemic norepinephrine release in animals.[27]
1999 H3 receptor cloned[28]
2000 H3 receptors called "new frontier in myocardial ischemia"[29]
2002 H3(-/-) mice (mice that do not have this receptor)[30]
See also
Histamine antagonist#H3-receptor antagonists
-
Antihistamine
Antihistamines are drugs which treat allergic rhinitis and other allergies.[1] Antihistamines can give relief when a person has nasal congestion, sneezing, or hives because of pollen, dust mites, or animal allergy.[1] Typically people take antihistamines as an inexpensive, generic, over-the-counter drug with few side effects.[1] As an alternative to taking an antihistamine, people who suffer from allergies can instead avoid the substance which irritates them.[1] Antihistamines are usually for short-term treatment.[1] Chronic allergies increase the risk of health problems which antihistamines might not treat, including asthma, sinusitis, and lower respiratory tract infection.[1] Doctors recommend that people talk to them before any longer term use of antihistamines.[1]
Although typical people use the word “antihistamine” to describe drugs for treating allergies, doctors and scientists use the term to describe a class of drug that opposes the activity of histamine receptors in the body.[2] In this sense of the word, antihistamines are subclassified according to the histamine receptor that they act upon. The two largest classes of antihistamines are H1-antihistamines and H2-antihistamines. Antihistamines that target the histamine H1-receptor are used to treat allergic reactions in the nose (e.g., itching, runny nose, and sneezing) as well as for insomnia. They are sometimes also used to treat motion sickness or vertigo caused by problems with the inner ear. Antihistamines that target the histamine H2-receptor are used to treat gastric acid conditions (e.g., peptic ulcers and acid reflux). H1-antihistamines work by binding to histamine H1 receptors in mast cells, smooth muscle, and endothelium in the body as well as in the tuberomammillary nucleus in the brain; H2-antihistamines bind to histamine H2 receptors in the upper gastrointestinal tract, primarily in the stomach.
Histamine receptors exhibit constitutive activity, so antihistamines can function as either a neutral receptor antagonist or an inverse agonist at histamine receptor.[3][2][4][5] Only a few currently marketed H1-antihistamines are known to function as inverse agonists.[2][5]
Medical uses
Histamine produces increased vascular permeability, causing fluid to escape from capillaries into tissues, which leads to the classic symptoms of an allergic reaction — a runny nose and watery eyes. Histamine also promotes angiogenesis.[6]
Antihistamines suppress the histamine-induced wheal response (swelling) and flare response (vasodilation) by blocking the binding of histamine to its receptors or reducing histamine receptor activity on nerves, vascular smooth muscle, glandular cells, endothelium, and mast cells.
Itching, sneezing, and inflammatory responses are suppressed by antihistamines that act on H1-receptors.[2][7] In 2014 antihistamines such as desloratadine were found to be effective as adjuvants to standardized treatment of acne due to their anti-inflammatory properties and their ability to suppress sebum production.[8][9]
Types
H1-antihistamines
Main article: H1-antihistamine
H1-antihistamines refer to compounds that inhibit the activity of the H1 receptor.[4][5] Since the H1 receptor exhibits constitutive activity, H1-antihistamines can be either neutral receptor antagonists or inverse agonists.[4][5] Normally, histamine binds to the H1 receptor and heightens the receptor's activity; the receptor antagonists work by binding to the receptor and blocking the activation of the receptor by histamine; by comparison, the inverse agonists bind to the receptor and reduce its activity, an effect which is opposite to histamine's.[4]
The vast majority of marketed H1-antihistamines are receptor antagonists and only a minority of marketed compounds are inverse agonists at the receptor.[2][5] Clinically, H1-antihistamines are used to treat allergic reactions and mast cell-related disorders. Sedation is a common side effect of H1-antihistamines that readily cross the blood–brain barrier; some of these drugs, such as diphenhydramine and doxylamine, are therefore used to treat insomnia. H1-antihistamines can also reduce inflammation, since the expression of NF-κB, the transcription factor the regulates inflammatory processes, is promoted by both the receptor's constitutive activity and agonist (i.e., histamine) binding at the H1 receptor.[2]
Second-generation antihistamines cross the blood–brain barrier to a much lower degree than the first-generation antihistamines. Their main benefit is they primarily affect peripheral histamine receptors and therefore are less sedating. However, high doses can still induce drowsiness through acting on the central nervous system. Some second-generation antihistamines, notably cetirizine, can interact with CNS psychoactive drugs such as bupropion and benzodiazepines.[10]
H1 antagonists
Examples of H1 antagonists include:
Acrivastine (see Benadryl entry in this section)
Azelastine
Benadryl is a brand name for different H1 antagonist anitihistamine preparations in different regions: acrivastine is the active component of Benadryl Allergy Relief and cetirizine of Benadryl One a Day Relief in the UK; Benadryl is diphenhydramine in the US and Canada.(see http://www.benadryl.ca/adult-allergy-medicine/benadryl-caplets)
Bilastine
Bromodiphenhydramine
Brompheniramine
Buclizine
Carbinoxamine
Cetirizine (Zyrtec)
Chlorodiphenhydramine
Chlorphenamine
Clemastine
Cyclizine
Cyproheptadine
Dexbrompheniramine
Dexchlorpheniramine
Dimenhydrinate (most commonly used as an antiemetic)
Dimetindene
Diphenhydramine (see Benadryl entry in this section)
Doxylamine (most commonly used as an over-the-counter drug sedative)
Ebastine
Embramine
Fexofenadine (Allegra)
Hydroxyzine (Vistaril)
Loratadine (Claritin)
Meclizine (most commonly used as an antiemetic)
Mirtazapine (primarily used to treat depression, also has antiemetic and appetite-stimulating effects)
Olopatadine (used locally)
Orphenadrine (a close relative of diphenhydramine used mainly as a skeletal muscle relaxant and anti-Parkinsons agent)
Phenindamine
Pheniramine
Phenyltoloxamine
Promethazine
Quetiapine (antipsychotic; trade name Seroquel)
Rupatadine (Alergoliber)
Tripelennamine
Triprolidine
H1 inverse agonists
The H1 receptor inverse agonists include:[2][5]
Cetirizine (does not cross the blood–brain barrier)
Levocetirizine
Desloratadine (does not cross the blood–brain barrier)
Pyrilamine (crosses the blood–brain barrier; produces drowsiness)
H2-antihistamines
Main article: H2-antihistamine
H2-antihistamines, like H1-antihistamines, occur as inverse agonists and neutral antagonists. They act on H2 histamine receptors found mainly in the parietal cells of the gastric mucosa, which are part of the endogenous signaling pathway for gastric acid secretion. Normally, histamine acts on H2 to stimulate acid secretion; drugs that inhibit H2 signaling thus reduce the secretion of gastric acid.
H2-antihistamines are among first-line therapy to treat gastrointestinal conditions including peptic ulcers and gastroesophageal reflux disease. Some formulations are available over the counter. Most side effects are due to cross-reactivity with unintended receptors. Cimetidine, for example, is notorious for antagonizing androgenic testosterone and DHT receptors at high doses.
Examples include:
Cimetidine
Famotidine
Lafutidine
Nizatidine
Ranitidine
Roxatidine
Tiotidine
Research
These are experimental agents and do not yet have a defined clinical use, although a number of drugs are currently in human trials. H3-antihistamines have a stimulant and nootropic effect, whereas H4-antihistamines appear to have an immunomodulatory role.
H3-antihistamines
Main article: H3-antihistamine
An H3-antihistamine is a classification of drugs used to inhibit the action of histamine at the H3 receptor. H3 receptors are primarily found in the brain and are inhibitory autoreceptors located on histaminergic nerve terminals, which modulate the release of histamine. Histamine release in the brain triggers secondary release of excitatory neurotransmitters such as glutamate and acetylcholine via stimulation of H1 receptors in the cerebral cortex. Consequently, unlike the H1-antihistamines which are sedating, H3-antihistamines have stimulant and cognition-modulating effects.
Examples of selective H3-antihistamines include:
Clobenpropit,[11]
ABT-239[12]
Ciproxifan,[13]
Conessine
A-349,821.[14]
Thioperamide
H4-antihistamines
Examples:
Thioperamide
JNJ 7777120
VUF-6002
Related agents
Histidine decarboxylase inhibitors
Inhibit the action of histidine decarboxylase:
Tritoqualine
Catechin
Mast cell stabilizers
Main article: Mast cell stabilizer
Mast cell stabilizers are drugs which prevent mast cell degranulation.
cromolyn sodium
Nedocromil
β-agonists
History
Currently most people who use an antihistamine to treat allergies use a second generation drug.[1]
The first generation of antihistamine drugs became available in the 1930s.[15] This marked the beginning of medical treatment of nasal allergies.[15] Research into these drugs led to the discovery that they were H1 antagonists and also to the development of H2 antagonists, where H1 antihistamines affected the nose and the H2 antihistamines affected the stomach.[16] This history has led to contemporary research into drugs which are H3 receptor antagonist and which affect the Histamine H4 receptor.[16]
Society and culture
Antihistamines can vary greatly in cost.[1] Some patients consult with their doctor about drug prices to make a decision about which antihistamine to choose.[1] Many antihistamines are older and available in generic form.[1] Others are newer, still under patent, and generally expensive.[1] The newer drugs are not necessarily safer or more effective.[1] Because so many antihistamines are available, patients can have conversations with their health care provider to choose the right drug for them.[1]
The United States government removed two second generation antihistamines, terfenadine and astemizole, from the market based on evidence that they could cause heart problems.[1]
Research
Not much published research exists which compares the efficacy and safety of the various antihistamines available.[1] The research which does exist are mostly short term studies or studies which look at too few people to make general assumptions.[1] Another gap in the research is in information reporting the health effects for individuals with long term allergies to take antihistamines for a long period of time.[1] Newer antihistamines have been demonstrated to be effective in treating hives.[1] However, there is not research comparing the relative efficacy of these drugs.[1]
Special populations
Most studies of antihistamines reported on people who are younger, so the effects on people over age 65 are not as well understood.[1] Older people are more likely to experience drowsiness from antihistamine use than younger people.[1] Also, most of the research has been on white people and other ethnicities are not as represented in the research.[1] The evidence does not report how antihistamines affect women differently than men.[1] Different studies have reported on antihistamine use in children, with various studies finding evidence that certain antihistamines could be used by children 2 years of age, and other drugs being safer for younger or older children.[1]
-
H3 receptor antagonist (https://en.wikipedia.org/wiki/H3_receptor_antagonist)
An H3 receptor antagonist is a classification of drugs used to block the action of histamine at the H3 receptor.
Unlike the H1 and H2 receptors which have primarily peripheral actions, but cause sedation if they are blocked in the brain, H3 receptors are primarily found in the brain and are inhibitory autoreceptors located on histaminergic nerve terminals, which modulate the release of histamine. Histamine release in the brain triggers secondary release of excitatory neurotransmitters such as glutamate and acetylcholine via stimulation of H1 receptors in the cerebral cortex. Consequently, unlike the H1 antagonist antihistamines which are sedating, H3 antagonists have stimulant and nootropic effects, and are being researched as potential drugs for the treatment of neurodegenerative conditions such as Alzheimer's disease.
Examples of selective H3 antagonists include clobenpropit,[1] ABT-239,[2] ciproxifan,[3] conessine, A-349,821,[4] and pitolisant.[5]
History
The histamine H3 receptor (H3R) was discovered in 1983 and was one of the last receptors that were discovered using conventional pharmacological methods.[6] Its structure was discovered later as a part of an effort to identify a commonly expressed G-protein-coupled receptor (GPCR) in the central nervous system (CNS).[7] The pharmacology of H3R is very complicated which has made drug development difficult. Many different functional isoforms of the H3R exist which means it could theoretically be possible to target a single isoform specifically. That may, however, be difficult due to genetic variability of the isoforms as well as differing functionality of each one.[8]
H3R ligands have now been classified as agonists, antagonists or inverse agonists, depending on the signaling assay used.[9][10]
Mechanism of Action
The H3R is a GPCR and it has been described as a presynaptic autoreceptor, regulating the release of histamine and also as a heteroreceptor, regulating neurotransmitters such as acetylcholine, dopamine, serotonin, norepinephrine and GABA.[11] The receptor has a high constitutive activity which means that it can signal without being activated by an agonist.[10] H3R regulates the release of neurotransmitters by influencing the amount of intracellular calcium. When activated, it blocks the influx of calcium which leads to inhibition of the release of neurotransmitters.[7] Antagonists of the receptors cause synthesis and release of these neurotransmitters which promotes waking.[12] H3Rs are mostly expressed on the histaminergic neurons of the CNS but can also be found in various areas of the peripheral nervous system.[10] The H3R has been found in high densities in the basal ganglia, hippocampus and cortical areas which are all regions of the brain associated with cognition.[11] The histaminergic system has been described as having a role in the pathophysiology of cognitive symptoms of diseases such as Alzheimer’s, schizophrenia and narcolepsy.[7]
Development
Early Pharmacophore
In the beginning of development for H3R ligands the focus was on the agonist histamine which contains an imidazole ring in its structure. The structural diversity among H3R is limited and all known H3R agonists today contain an imidazole ring.[10][9] The problem with the imidazole containing compounds was the inhibition of cytochrome P450 isoenzymes which resulted in severe drug interactions.[11][10] They also had difficulty in crossing the blood-brain-barrier. Many compounds were tested but they were too toxic to be useful.[6]
Off target function on H4R and other receptors was also a problem with imidazole-based antagonists. The wide variety of potential pathophysiology of H3R in brain disorders makes H3R antagonists interesting for drug development.[7]
Thioperamide
The first imidazole-based antagonist that was developed was thioperamide which was very potent and selective but was not useable as a drug due to hepatotoxicity. It was originally designed to improve wakefulness and cognition deficit.[6] A recent study showed potential thioperamide treatment of the circadian rhythm of patients with parkinson’s disease.[13]
New Pharmacophore
The focus turned to non-imidazole H3R antagonists.They do not seem to interact with the CYP family on the same level as imidazole-based H3R antagonists and can reach the CNS more easily. Unfortunately other problems have come up such as strong binding to hERG K+ channel, phospholipidosis as well as problems with P-gp substrate. Strong binding to hERG K+ channel can lead to QT prolongation.[11]
Pitolisant
Pitolisant was the first antagonist /inverse agonist to proceed to clinical trials and is the only drug that has been approved by regulatory authorities in the US and Europe. It is highly selective for the H3 receptor. Pitolisant has high oral bioavailability and easily accesses the brain. It undergoes extensive first-pass effects through the CYP4A4 enzyme in the gut. The whole metabolic pathway has not yet been established but involves a few CYP enzymes[14]. It has been proved to be useful for maintaining waking-state in the daytime for people with narcolepsy.[6] Side effects encountered in clinical trials were found to be dose-dependent. As expected, some of the adverse effects were neuropsychiatric in character most common of which were insomnia, headache and anxiety. Pitolisant can also potentially cause a prolonged QT interval so caution is advised in cardiac patients. Keeping doses as low as possible can minimize risk for adverse events.[14]
It can be found under the tradename Wakix and is considered an orphan drug. It was approved by the European Commission on 31 March 2016. It is available in 4.5 mg and 18 mg tablets.[15]
Structure Activity Relationship
A general structural pattern that is necessary for the antagonist affinity for H3R has been described. An H3R antagonist needs to have a basic amine group which is linked to an aromatic/lipophilic region that is connected to either a polar group or another basic group or a lipophilic region.[7]
Clinical Significance
H3R antagonists/inverse agonists demonstrate a possible way to treat diseases of the CNS for example Alzheimer's disease (AD), attention deficit hyperactivity syndrome (ADHD) , schizophrenia (SCH), pain, and narcolepsy.[16]
Narcolepsy
Narcolepsy is a sleeping disorder which is characterised by chronic sleepiness. Cataplexy, hypnagogic hallucinations and sleep paralysis can also be present in narcolepsy.[17] H3R antagonism leads to histamine release into the cerebrospinal fluid which promotes wakefulness. Therefore H3R antagonists have been studied in the hope of treating narcolepsy. Pitosilant has been approved for treatment of narcolepsy[7] and other H3R antagonists are in clinical trials.[8]
Alzheimer's disease (AD)
Alzheimer’s disease is a progressive neurodegenerative disease of the brain. Histamine plays a well documented role in AD, however the varying levels of histamine in different areas of the brain make it hard to demonstrate a direct link between histaminergic neurotransmission and AD pathology.[16] In vivo studies have shown that a number of H3R antagonists facilitate learning and memory.[7] Thioperamide blocks H3R and causes an increase in neuronal histamine release which then modifies cognition processes through H1R and H2R and other receptors (e.g. cholinergic and GABA). Degeneration of histaminergic neurons in AD doesn’t correlate to H3R expressions since a large portion of H3R in the brain are located elsewhere deep in cortical and thalamocortical neurons among others.[16]
Attention deficit hyperactivity disorder (ADHD)
ADHD is a neurodevelopmental disorder which is most pronounced in children. Current pharmacological treatments consist of stimulant medications (e.g. methylphenidate), non-stimulant medication (e.g. atomoxetin) and α2 agonists. These medications have a great deal of adverse effects as well as being potentially addictive. Developing alternative treatments is therefore desirable. In vivo studies show potential of using H3R antagonists in ADHD to aid in attention and cognitive activity by elevating release of neurotransmitters such as acetylcholine and dopamine.[16]
Schizophrenia (SCH)
SCH is a serious neurological syndrome which is characterised by shifting of thinking, behavior and emotion. Disruption of dopamine and other neurotransmitter systems plays a significant role in the development of the disease.[7][16] Current treatments are based on first and second generation antipsychotics which are dopamine antagonists. These drugs have many undesirable side-effects. Histaminergic neurons seem to play a role in schizophrenia and H3R are co-localized with dopamine receptors in GABAergic neurons. Even if H3R antagonist don’t seem to be effective against positive symptoms of SCH studies have shown that H3R antagonists may be useful in treating negative and cognitive symptoms of schizophrenia as an adjunct.[7]
ABT-239 (https://en.wikipedia.org/wiki/ABT-239)
ABT-239 is an H3-receptor inverse agonist developed by Abbott. It has stimulant and nootropic effects, and has been investigated as a treatment for ADHD, Alzheimer's disease, and schizophrenia.[1][2][3][4] ABT-239 is more active at the human H3 receptor than comparable agents such as thioperamide, ciproxifan, and cipralisant. It was ultimately dropped from human trials after showing the dangerous cardiac side effect of QT prolongation,[5] but is still widely used in animal research into H3 antagonists / inverse agonists.
Clobenpropit (https://en.wikipedia.org/wiki/Clobenpropit)
Clobenpropit is a histamine H3 receptor antagonist.[1] It has neuroprotective effects via stimulation of GABA release in the brain.[2]
Ciproxifan (https://en.wikipedia.org/wiki/Ciproxifan)
Ciproxifan is an extremely potent histamine H3 inverse agonist/antagonist.
The histamine H3 receptor is an inhibitory autoreceptor located on histaminergic nerve terminals, and is believed to be involved in modulating the release of histamine in the brain. Histamine has an excitatory effect in the brain via H1 receptors in the cerebral cortex, and so drugs such as ciproxifan which block the H3 receptor and consequently allow more histamine to be released have an alertness-promoting effect.[1][2][3]
Ciproxifan produces wakefulness and attentiveness in animal studies, and produced cognitive enhancing effects without prominent stimulant effects at relatively low levels of receptor occupancy, and pronounced wakefulness at higher doses.[4] It has therefore been proposed as a potential treatment for sleep disorders such as narcolepsy and to improve vigilance in old age, particularly in the treatment of conditions such as Alzheimer's disease.[5][6] It also potentiated the effects of antipsychotic drugs, and has been suggested as an adjuvant treatment for schizophrenia.[7]
Conessine (https://en.wikipedia.org/wiki/Conessine)
Conessine is a steroid alkaloid found in a number of plant species from the Apocynaceae family, including Holarrhena floribunda,[1] Holarrhena antidysenterica[2] and Funtumia elastica.[3] It acts as a histamine antagonist, selective for the H3 subtype (with an affinity of pKi = 8.27; Ki = ~5 nM).[4] It was also found to have long CNS clearance times, high blood-brain barrier penetration and high affinity for the adrenergic receptors.[5]
A-349,821 (https://en.wikipedia.org/wiki/A-349,821)
A-349,821 is a potent and selective histamine H3 receptor antagonist[1] (or possibly an inverse agonist).[2] It has nootropic effects in animal studies,[3] although there do not appear to be any plans for clinical development at present and it is currently only used in laboratory research.
Pitolisant (https://en.wikipedia.org/wiki/Pitolisant)
Pitolisant (INN), also known as tiprolisant (USAN), and sold under the brand name Wakix, is a potent and selective inverse agonist of the histamine H3 receptor (Ki = 0.16 nM) which was approved for the treatment of narcolepsy in 2016.[1][2][3][4] It is also currently in phase III clinical trials for the treatment of hypersomnia.[1]
Pitolisant was developed by Jean-Charles Schwartz, Walter Schunack, and colleagues after the former discovered the H3 receptor.[5] It was the first H3 receptor inverse agonist to be tested in humans or introduced for clinical use.[5]
-
Regular Mouthwash Use Linked to Prediabetes and Diabetes (https://www.care2.com/greenliving/regular-mouthwash-use-linked-to-prediabetes-and-diabetes.html)
research now links regular mouthwash use to an increased risk of diabetes.
New research published in the medical journal Nitric Oxide found that regular mouthwash use destroys beneficial bacteria in the mouth that are needed for our health, which may increase our diabetes risk.
-
Apocynaceae (https://en.wikipedia.org/wiki/Apocynaceae)
Apocynaceae is a family of flowering plants that includes trees, shrubs, herbs, stem succulents, and vines, commonly called the dogbane family,[1] after the American plant known as dogbane, Apocynum cannabinum.[2] Members of the family are native to European, Asian, African, Australian, and American tropics or subtropics, with some temperate members.[1] The family Asclepiadaceae (now known as Asclepiadoideae) is considered a subfamily of Apocynaceae and contains 348 genera.
Many species are tall trees found in tropical rainforests, but some grow in tropical dry (xeric) environments. Also perennial herbs from temperate zones occur. Many of these plants have milky latex, and many species are poisonous if ingested. Some genera of Apocynaceae, such as Adenium, have milky latex apart from their sap, and others, such as Pachypodium, have clear sap and no latex.
Description
The dogbane family includes annual plants, perrenial herbs, stem succulents, woody shrubs, trees, or vines.[1][3] Most[citation needed] exude a milky sap with latex[citation needed], if injured.
Leaves and stems
Leaves are (simple). Leaves may appear one at a time (singly) with each occurrence on alternating sides of the stem (alternate),[3] but usually[citation needed] occur in pairs or in whorls. When paired, they occur on opposite sides of the stem (opposite), with each pair occurring at an angle rotated 90° to the pair below it (decussate).
There is no stipule (a small leaf-like structure at the base of the leaf stem), or stipules are small and sometimes fingerlike.[3]
Inflorescence and fruit
Flowers are usually showy,[citation needed] have radial symmetry (actinomorphic), and are born in head that are cymes or racemes, but can rarely be fasciculate or solitary. They are perfect (bisexual), with a synsepalous, five-lobed calyx united into a tube at the base. Inflorescences are terminal or axillary. Five petals are united into a tube with four or five epipetalous stamens. The style is expanded at the apex into a massive clavuncle just below the stigma. The ovary is usually superior, bicarpellary, and apocarpous, with a common fused style and stigma.
The fruit is a drupe, a berry, a capsule, or a follicle.
Toxicity
All plant-derived (i.e., phytochemical) natural products have some inherent toxicity on ingestion, and many are very toxic, even lethal. This is true of many contained in species of plants from the Apocynaceae family, which include several that are extremely poisonous if parts are ingested, or if they are not handled properly. Members containing cardiac glycosides—genera Acokanthera, Apocynum, Cerbera, Nerium, Thevetia, Strophanthus, etc.[citation needed]—have therapeutic ranges, but often are associated with accidental poisonings, in many cases lethal (see below). Alkaloid-producing species like Rauvolfia, Catharanthus, and Tabernathe are likewise the source of compounds with possible therapeutic ranges, but which have significant associated toxicities if not taken in appropriate doses and in controlled fashion.[citation needed]
Uses
Several plants of the Apocynaceae family members have had economic uses in the past. Several are sources of important natural products—pharmacologic tool compounds and drug research candidates, and in some cases actual prescription drugs.[citation needed] Cardiac glycosides, which affect heart function, are a ready example.[citation needed] Members studied and known to have such glycosides include the Acokanthera, Apocynum, Cerbera, Nerium, Thevetia and Strophanthus.[citation needed] Rauvolfia serpentina (Indian snakeroot) synthesizes the alkaloids reserpine and rescinnamine, which are of interest in studies of the treatment of high blood pressure,[citation needed] as well as some forms of psychosis.[citation needed] Catharanthus roseus yields alkaloids studied with regard to the treatment of cancer.[citation needed] Certain species of the genus Tabernanthe, most notably Tabernanthe Iboga contain tryptamine alkaloids such as ibogaine in the roots.[citation needed]
Several genera are grown as ornamental plants, including Amsonia (bluestar), Nerium (oleander), Vinca (periwinkle), Carissa (Natal plum), Allamanda (golden trumpet), Plumeria (frangipani), Thevetia (lucky nut), Mandevilla (Savannah flower), and Adenium (desert-rose).[citation needed]
In addition, the genera Landolphia, Hancornia, Funtumia and Mascarenhasia were used as a commercial source of inferior rubber (see Congo rubber, made mostly from various Landolphia species harvested in the wild).[citation needed]
There may be reports of limited dietary uses of plants from this family,[clarification needed]—see however the section on toxicity above. The edible flower of Fernaldia pandurata (common name: loroco) is a popular part of El Salvadorian and Guatemalan cooking.[citation needed] Carissa (Natal plum) produces an edible fruit.[citation needed] The genus Apocynum was reportedly used as a source of fiber by Native Americans.[citation needed] The aromatic fruit juice from Saba comorensis (syn. Landolphia comorensis, the Bungo or Mbungo fruit) is a popular drink,[verification needed][citation needed] on Pemba Island and other parts of coastal Tanzania.[8]
Finally, ethnopharmacologic and ethnotoxicologic uses are also known. Ibogaine-type alkaloids from the roots of genus Tabernathe have been used in traditional African tribal ceremonies as a source of hallucinogens,[citation needed] and have been studied with regard to the treatment of drug addiction.[citation needed] The juice of Acokanthera species such as A. venenata and the milky juice of the Namibian Pachypodium have reportedly been used as venom for arrow tips by the San people,[citation needed] though others have reported that Pachypodium do not produce such milk.[9]
-
Wakix (pitolisant) (https://www.drugs.com/uk/wakix.html)
Wakix
Active Substance: pitolisant
Common Name: pitolisant
ATC Code: N07XX11
Marketing Authorisation Holder: Bioprojet Pharma
Active Substance: pitolisant
Status: Authorised
Authorisation Date: 2016-03-31
Therapeutic Area: Narcolepsy
Pharmacotherapeutic Group: Other nervous system drugs
Therapeutic Indication
Wakix is indicated in adults for the treatment of narcolepsy with or without cataplexy (see also section 5.1).
What is Wakix and what is it used for?
Wakix is a medicine used to treat adults with narcolepsy. Narcolepsy is a long-term sleep disorder which affects the brain’s ability to regulate the normal sleep-wake cycle. This leads to symptoms such as an irresistible urge to sleep, even at inappropriate times and places, and disturbed night-time sleep. Some patients also have episodes of severe muscle weakness (cataplexy) that can cause collapse. Wakix is used in patients with or without cataplexy.
Wakix contains the active substance pitolisant. Because the number of patients with narcolepsy is low, the disease is considered ‘rare’, and Wakix was designated an ‘orphan medicine’ (a medicine used in rare diseases) on 10 July 2007.
How is Wakix used?
Wakix can only be obtained with a prescription and treatment should be started by a doctor experienced in the treatment of sleep disorders.
Wakix is available as tablets (4.5 and 18 mg). During the first week of treatment, the recommended dose is 9 mg per day, taken in the morning during breakfast. During the second week of treatment, the dose can be increased to 18 mg per day or decreased to 4.5 mg per day. During the third week, the dose may be further increased to the maximum dose of 36 mg per day. Wakix should always be used at the lowest effective dose.
In patients with moderately reduced liver function or with kidney problems, the maximum dose should be 18 mg per day.
For more information, see the package leaflet.
How does Wakix work?
The active substance in Wakix, pitolisant, works by attaching to receptors in the brain called ‘histamine H3 receptors’. This increases the activity of certain brain cells called ‘histamine neurons’, which are important for keeping the body awake.
What benefits of Wakix have been shown in studies?
Wakix has been investigated in 2 main studies involving a total of 261 adults with narcolepsy, the majority of whom also had cataplexy. The studies compared Wakix with placebo (a dummy treatment). The main measure of effectiveness was based on how sleepy patients felt during daytime, assessed using the Epworth Sleepiness Scale or ESS. This is a standard scale used in patients with narcolepsy which ranges from 0 to 24.
The first study showed that Wakix was more effective than placebo at reducing daytime sleepiness: patients taking Wakix had an average reduction of 3 points more in the ESS scale than those taking placebo after 8 weeks of treatment. Results from this study also showed a decrease in the number of cataplexy attacks. The second study, however, did not show a difference between Wakix and placebo at reducing sleepiness or cataplexy.
When looking at sleepiness with an objective test called Maintenance of Wakefulness Test or MWT, the results of the two studies together showed that Wakix significantly improved wakefulness compared with placebo.
In a further study in 105 patients with narcolepsy and cataplexy, Wakix was also more effective than placebo at reducing the number of cataplexy attacks per week: the number of cataplexy attacks decreased from around 9 to around 3 per week in patients taking Wakix, while it remained at around 7 per week in patients taking placebo.
What are the risks associated with Wakix?
The most common side effects with Wakix (which may affect up to 1 in 10 people) are insomnia (difficulty sleeping), headache, nausea (feeling sick), anxiety, irritability, dizziness, depression, tremor, sleep disorders, tiredness, vomiting, vertigo (a spinning sensation) and dyspepsia (heartburn). Serious but rare side effects are abnormal loss of weight and spontaneous abortion. For the full list of all side effects reported with Wakix, see the package leaflet.
Wakix must not be used in patients with severely reduced liver function and in women who are breastfeeding. For the full list of restrictions, see the package leaflet.
Why is Wakix approved?
The overall data available demonstrate that Wakix has a positive effect on the two major symptoms of narcolepsy, excessive daytime sleepiness and cataplexy. In addition, Wakix works differently from currently available treatments and therefore offers an alternative treatment option. The safety profile of Wakix is considered acceptable, with no major safety concerns identified.
The Agency’s Committee for Medicinal Products for Human Use (CHMP) therefore decided that Wakix’s benefits are greater than its risks and recommended that it be approved for use in the EU.
What measures are being taken to ensure the safe and effective use of Wakix?
A risk management plan has been developed to ensure that Wakix is used as safely as possible. Based on this plan, safety information has been included in the summary of product characteristics and the package leaflet for Wakix, including the appropriate precautions to be followed by healthcare professionals and patients.
In addition, the company that markets Wakix will carry out an observational study to collect information on the safety of the medicine when used in medical practice.
Further information can be found in the summary of the risk management plan.
Other information about Wakix
The European Commission granted a marketing authorisation valid throughout the European Union for Wakix on 31 March 2016.
For more information about treatment with Wakix, read the package leaflet (also part of the EPAR) or contact your doctor or pharmacist.
Source: European Medicines Agency
-
Ciproxifan hydrochloride (https://www.sigmaaldrich.com/catalog/product/sigma/c6492?lang=en®ion=US&utm_term=Ciproxifan%20hydrochloride&utm_medium=cpc&utm_content=SIGMA/C6492&utm_source=bing&utm_campaign=Global%20Bioactive%20Small%20Molecules%20(Bing%20ebizpfs))
Synonym: Cyclopropyl[4-[3-(1H-imidazol-4-yl)propoxyl]phenyl]-methanone hydrochloride ]Ciproxifan hydrochloride
≥98% (HPLC), solid
Synonym: Cyclopropyl[4-[3-(1H-imidazol-4-yl)propoxyl]phenyl]-methanone hydrochloride
Description
Packaging
5, 25 mg in glass bottle
Biochem/physiol Actions
Ciproxifan belongs to a novel chemical series of histamine H3-receptor antagonists. In vitro, it behaved as a competitive antagonist at the H3 autoreceptor controlling 3H histamine release from synaptosomes and displayed similar Ki values (0.5-1.9 nM) at the H3 receptor controlling the electrically-induced contraction of guinea pig ileum or at the brain H3 receptor labeled with 125I-iodoproxyfan. Ciproxifan appears to be an orally bioavailable, extremely potent and selective H3-receptor antagonist whose vigilance- and attention-promoting effects are promising for therapeutic applications in aging disorders.
Features and Benefits
This compound is featured on the Histamine Receptors page of the Handbook of Receptor Classification and Signal Transduction. To browse other handbook pages, click here.
-
New Diabetes Drug Approved by FDA (https://www.webmd.com/diabetes/news/20140108/new-diabetes-drug-approved)
Jan. 9, 2014 -- A new pill to treat adults with type 2 diabetes has been approved by the U.S. Food and Drug Administration.
Farxiga (dapaglifozin) tablets were approved to improve patients' blood sugar control, in combination with diet and exercise. The approval is based on findings from 16 clinical trials that included more than 9,400 people with type 2 diabetes.
An increased number of bladder cancers were diagnosed among patients who took the drug
A Complete List of Diabetes Medications (https://www.healthline.com/health/diabetes/medications-list)
Amylinomimetic drug
Pramlintide (SymlinPen 120, SymlinPen 60) is an amylinomimetic drug. It’s an injectable drug used before meals. It works by delaying the time your stomach takes to empty itself. It reduces glucagon secretion after meals. This lowers your blood sugar. It also reduces appetite through a central mechanism.
lpha-glucosidase inhibitors
These medications help your body break down starchy foods and table sugar. This effect lowers your blood sugar levels. For the best results, you should take these drugs before meals. These drugs include:
acarbose (Precose)
miglitol (Glyset)
Biguanides
Biguanides decrease how much sugar your liver makes. They decrease how much sugar your intestines absorb, make your body more sensitive to insulin, and help your muscles absorb glucose. The most common biguanide is metformin (Glucophage, Metformin Hydrochloride ER, Glumetza, Riomet, Fortamet).
Metformin can also be combined with other drugs for type 2 diabetes. It’s an ingredient in the following medications:
metformin-alogliptin (Kazano)
metformin-canagliflozin (Invokamet)
metformin-dapagliflozin (Xigduo XR)
metformin-empagliflozin (Synjardy)
metformin-glipizide
metformin-glyburide (Glucovance)
metformin-linagliptin (Jentadueto)
metformin-pioglitazone (Actoplus)
metformin-repaglinide (PrandiMet)
metformin-rosiglitazone (Avandamet)
metformin-saxagliptin (Kombiglyze XR)
metformin-sitagliptin (Janumet)
Dopamine agonist
Bromocriptine (Parlodel) is a dopamine agonist. It’s not known exactly how this drug works to treat type 2 diabetes. It may affect rhythms in your body and prevent insulin resistance.
DPP-4 inhibitors
DPP-4 inhibitors help the body continue to make insulin. They work by reducing blood sugar without causing hypoglycemia (low blood sugar). These drugs can also help the pancreas make more insulin. These drugs include:
alogliptin (Nesina)
alogliptin-metformin (Kazano)
alogliptin-pioglitazone (Oseni)
linagliptin (Tradjenta)
linagliptin-empagliflozin (Glyxambi)
linagliptin-metformin (Jentadueto)
saxagliptin (Onglyza)
saxagliptin-metformin (Kombiglyze XR)
sitagliptin (Januvia)
sitagliptin-metformin (Janumet and Janumet XR)
sitagliptin and simvastatin (Juvisync)
Glucagon-like peptides (incretin mimetics)
These drugs are similar to the natural hormone called incretin. They increase B-cell growth and how much insulin your body uses. They decrease your appetite and how much glucagon your body uses. They also slow stomach emptying. These are all important actions for people with diabetes. These drugs include:
albiglutide (Tanzeum)
dulaglutide (Trulicity)
exenatide (Byetta)
exenatide extended-release (Bydureon)
liraglutide (Victoza)
Meglitinides
These medications help your body release insulin. However, in some cases, they may lower your blood sugar too much. These drugs aren’t for everyone. They include:
nateglinide (Starlix)
repaglinide (Prandin)
repaglinide-metformin (Prandimet)
Sodium glucose transporter (SGLT) 2 inhibitors
These drugs work by preventing the kidneys from holding on to glucose. Instead, your body gets rid of the glucose through your urine. These drugs include:
dapagliflozin (Farxiga)
dapagliflozin-metformin (Xigduo XR)
canagliflozin (Invokana)
canagliflozin-metformin (Invokamet)
empagliflozin (Jardiance)
empagliflozin-linagliptin (Glyxambi)
empagliflozin-metformin (Synjardy)
Sulfonylureas
These are among the oldest diabetes drugs still used today. They work by stimulating the pancreas with the help of beta cells. This causes your body to make more insulin. These drugs include:
glimepiride (Amaryl)
glimepiride-pioglitazone (Duetact)
glimeperide-rosiglitazone (Avandaryl)
gliclazide
glipizide (Glucotrol)
glipizide-metformin (Metaglip)
glyburide (DiaBeta, Glynase, Micronase)
glyburide-metformin (Glucovance)
chlorpropamide (Diabinese)
tolazamide (Tolinase)
tolbutamide (Orinase, Tol-Tab)
Thiazolidinediones
These medications work by decreasing glucose in your liver. They also help your fat cells use insulin better. These drugs come with an increased risk of heart disease. If your doctor gives you one of these drugs, they will watch your heart function during treatment. These drugs include:
rosiglitazone (Avandia)
rosiglitazone-glimepiride (Avandaryl)
rosiglitizone-metformin (Amaryl M)
pioglitazone (Actos)
pioglitazone-alogliptin (Oseni)
pioglitazone-glimepiride (Duetact)
pioglitazone-metformin (Actoplus Met, Actoplus Met XR)
Other drugs
Other drugs
People with type 1 and type 2 diabetes often need to take other medications to treat conditions that are common with diabetes. These drugs can include:
aspirin for heart health
drugs for high cholesterol
high blood pressure medications
Top 6 Breakthrough Diabetes Treatments You May Have Missed (https://www.drugs.com/article/new-diabetes-treatments.html)
The American Diabetes Association (ADA) estimates a person diagnosed at age 50 dies six years earlier than a person without diabetes. One in three American adults will have diabetes in the year 2050 if current trends continue.
Close to 29 million Americans, or 9% of the population, currently have diabetes. The vast majority of people, about 90 to 95 percent of those diagnosed with diabetes, have type 2 diabetes, according to the ADA.
However, the latest diabetes news is encouraging. New drugs, improved monitoring devices and an understanding of how diet and exercise can impact diabetes is adding up to positive outcomes for patients. As reported in August 2014 from research in The Lancet Diabetes & Endocrinology, the vast majority of people with type 2 diabetes are living longer lives due to better medications and treatments for both the disease and the numerous complications that result from type 2 diabetes. High blood sugar levels can increase the risk for serious complications due to diabetes such as vision loss, peripheral nerve damage, kidney impairment, hard-to-treat infections, impotence and heart disease.
1. Alogliptin (Nesina, Kazano, Oseni): Approved January 2013
On January 25, 2013, Takeda Pharmaceutical received approval for alogliptin, a type 2 diabetes drug. Alogliptin is a dipeptidyl peptidase IV (DPP-4) inhibitor that stimulates the release of insulin by preventing GLP-1, a compound that helps to lower blood sugar, from breaking down. Alogliptin was approved in three products:
In the stand-alone form as Nesina.
In combination with metformin as Kazano.
Combined with pioglitazone as Oseni.
Oseni’s label contains a boxed warning for congestive heart failure due to the pioglitazone component. Pioglitazone (Actos), an oral thiazolidinedione used in type 2 diabetes, is also made by Takeda, but the Actos patent expired in 3Q 2012, opening the door for generics and competition. Nesina gives Takeda a new exclusive medicine in the diabetes market.
2. Invokana: Approved March 2013
Invokana (canagliflozain) from Janssen Pharmaceuticals is the first in a new class of type 2 diabetes drugs that was FDA approved in March 2013. Invokana is a sodium-glucose co-transporter 2 (SGLT2) inhibitor that blocks the reabsorption of glucose (blood sugar) by the kidneys and increases glucose excretion in the urine. This oral diabetes treatment is indicated to improve blood sugar control in conjunction with diet and exercise in patients with type 2 diabetes.
In clinical trials with Invokana, an improvement in hemoglobin A1c (a measure of blood sugar control) and fasting blood sugar levels in trials of more than 10,000 patients secured FDA approval. Dehydration (the loss of body water and salt), which may lead to dizziness, fainting, especially when standing up, and genital yeast infections are important side effects.
Invokamet was FDA approved in August 2014, and is a combined, fixed-dose tablet of canagliflozin and metformin. Metformin, often a first-line treatment for patients with newly diagnosed type 2 diabetes, decreases the production of glucose in the liver and improves the body’s response to insulin for patients who have developed insulin resistance. Additional treatments like canagliflozin can be added to metformin for better diabetes control.
In May 2015 the FDA warned consumers and healthcare providers on important side effects associated with the class of SGLT-2 inhibitors (Invokana (canagliflozin), Invokamet (canagliflozin and metformin), Farxiga (dapagliflozin), Xigduo XR (dapagliflozin and metformin extended-release), Jardiance (empagliflozin), Glyxambi (empagliflozin and linagliptin), Synjardy (empagliflozin and metformin): a risk of ketoacidosis (too much acid in the blood) and serious urinary tract infections. Patients should stop taking their SGLT2 inhibitor and seek medical attention immediately if they have any symptoms of ketoacidosis such as nausea, vomiting, abdominal pain, tiredness, and trouble breathing. Patients should also be alert for signs and symptoms of a urinary tract infection, such as a feeling of burning when urinating or the need to urinate often or right away; pain in the lower part of the stomach area or pelvis; fever; or blood in the urine.
3. Farxiga: Approved January 2014
In January 2014, the U.S. Food and Drug Administration (FDA) approved Farxiga (dapagliflozin) tablets to improve glycemic (sugar) control, along with diet and exercise, in adults with type 2 diabetes. Like Invokana, Farxiga is also a sodium-glucose co-transporter 2 (SGLT2) inhibitor. Farxiga’s effectiveness was shown in 16 clinical trials involving more than 9,400 patients. Treatment with Farxiga has been studied alone or in combination with other type 2 diabetes medications, including metformin.
The most common side effects of Farxiga include genital yeast infections, urinary tract infections, and changes in urination frequency.
4. Tanzeum: Approved April 2014
GSK’s Tanzeum (albiglutide), approved in April 2014, is classified as a glucagon-like peptide-1 (GLP-1) receptor agonist. GLP-1 is a hormone that helps normalize blood sugar levels in patients with type 2 diabetes. Tanzeum binds to GLP-1 to stimulate the release of glucose-dependent insulin, while blocking release of sugar-boosting glucagon from the pancreas. Tanzeum is given by subcutaneous (under the skin) injection, and, as with most diabetes treatments, is to be used alongside diet and exercise.
The safety and effectiveness of Tanzeum was shown in eight clinical trials involving over 2,000 participants with type 2 diabetes. Tanzeum was studied alone and in use with other type 2 diabetes treatments, including metformin, glimepiride, pioglitazone, and insulin. Tanzeum has a boxed warning that thyroid tumors have been seen in rodent studies with similar drugs (although animal studies do not always translate to human effects). Byetta and Victoza are other popular drugs in the same class as Tanzeum.
5. Jardiance: Approved May 2014
In May 2014, the FDA approved the third SGLT blocker to enter the U.S. market, Jardiance (empagliflozin). In seven type 2 diabetes clinical trials with about 4,500 people, Boehringer Ingelheim’s Jardiance improved hemoglobin A1c levels compared to placebo. Jardiance can also be used with metformin, sulfonylureas, pioglitazone, and insulin.
Jardiance side effects may include dehydration and low blood pressure that can result in dizziness, fainting, yeast infections, low blood sugar with insulin or insulin secretagogues, elevation in LDL cholesterol, and impaired kidney function. The FDA has asked Boehringer Ingelheim for Jardiance post-marketing studies looking at effectiveness and safety in children and at heart outcomes studies in all populations.
6. Afrezza: Approved June 2014
Afrezza (insulin human) Inhalation Powder was approved by the FDA in June 2014. Afrezza is an ultra rapid-acting inhaled insulin that is administered with meals to improve glycemic control in adult diabetics. In clinical trials, Afrezza was evaluated in 24-week studies in both type 1 and type 2 diabetic patients. In 1,026 type 1 patients also using long-acting insulin, Afrezza effectiveness to lower blood sugar (A1c) provided less A1c reduction than insulin aspart (an injectable fast-acting insulin), and the difference was statistically significant. In 1,991 type 2 patients also using oral antidiabetic agents, inhaled Afrezza did significantly lower A1c compared to a placebo group (also using oral antidiabetics) in a 24-week study.
Afrezza, because it is inhaled and not injected, may cause the serious side effect of bronchospasm in patients with asthma or chronic obstructive pulmonary disease (COPD), and should not be used in these patients. The most common adverse reactions associated with Afrezza in clinical trials were hypoglycemia (low blood sugar), cough, and throat pain or irritation.
Exubera, another previously approved inhaled insulin, was withdrawn from the U.S. market in 2007 due to lack of sales. The fate of Afrezza sales waits to be seen, although some analysts predict sales could reach $1.6 billion if the novel dosage form catches on.
-
An interesting article, Is Diabetes Really a Vitamin Deficiency Disease? (https://www.care2.com/greenliving/is-diabetes-really-a-vitamin-deficiency-disease.html)
Ground-breaking new research offers hope for the millions of sufferers of diabetes around the world. While the exact cause of diabetes has eluded researchers and doctors for many years, exciting research shows that a vitamin deficiency may actually be at the cause (or one of the causes) for the debilitating, and frequently, life-threatening disease.
The research, published in Endocrine Journal (https://www.medicalnewstoday.com/articles/317921.php?utm_source=newsletter&utm_medium=email&utm_campaign=weekly-hcp), shows that vitamin A is essential for the proper functioning of the beta cells of the pancreas. The beta cells are responsible for producing insulin, which in turn helps to regulate blood sugar levels. In type 2 diabetes, which makes up about 95 percent of the 29 million diabetics in the United States, the beta cells stop producing sufficient insulin or the body stops responding to it. In the remaining 5 percent of people, type 1 diabetes occurs when the immune system destroys the beta cells, rendering them incapable of producing adequate insulin.
In the new study, researchers found that there are many vitamin A receptors on the surface of beta cells. In an interview with Medical News Today, study co-author Albert Salehi of the University of Lund, Sweden, stated: “When we discovered that insulin cells have a cell surface expressed receptor for vitamin A, we thought it was important to find out why and what the purpose is of a cell surface receptor interacting with vitamin A mediating a rapid response to vitamin A.”
When the researchers partially blocked the vitamin A receptors, thereby eliminating the ability of vitamin A to bind to the beta cells, they made the discovery that the beta cells were unable to adequately secrete insulin in response to sugar. They also found that a vitamin A deficiency prevented the beta cells from coping with inflammation. A complete vitamin A deficiency caused the death of the beta cells.
This new research offers hope for an effective treatment for the millions of diabetics, and many others who may be able to prevent the disease altogether with adequate vitamin A intake.
In other research published in the medical journal Nature Communications, researchers found that vitamin A plays an important role in the prevention and possible treatment of pancreatic cancer. Check out my blog “The Vitamin Discovery that May Help Prevent Pancreatic Cancer” for more information.
Other recent research published in the British Journal of Pharmacology, found that vitamin A offers hope for those suffering from lung diseases like COPD or emphysema.
Well on all 4 counts I could benefit from taking vitamin A, so I am going to try it.
-
I bought the highest dosage of vitamin A that I could find this weekend, and started on it.
This morning someone sent me a link to a rather interesting article, which is about a Common Medication Can Actually Prevent Type 1 Diabetes (https://www.sciencealert.com/common-medication-can-prevent-type-1-diabetes?utm_source=ScienceAlert+-+Daily+Email+Updates&utm_campaign=ec438e2bb0-MAILCHIMP_EMAIL_CAMPAIGN&utm_medium=email&utm_term=0_fe5632fb09-ec438e2bb0-365491701)
There's new hope for stopping Type 1 diabetes in its tracks after researchers discovered an existing drug can prevent the condition from developing – and the same techniques used here could also be applied to other diseases.
The drug in question is methyldopa, currently on the World Health Organisation's list of essential drugs having been used for more than 50 years to treat high blood pressure in pregnant women and children.
By running an analysis of thousands of drugs through a supercomputer, the team of researchers was able to pinpoint methyldopa as a drug able to block the DQ8 molecule. The antigen is found in a proportion of the population and has been implemented in auto immune responses.
It appears in some 60 percent of people at risk from developing Type 1 diabetes.
"This is the first personalised treatment for Type 1 diabetes prevention," says one of the team, Aaron Michels from the University of Colorado Anschutz Medical Campus. "This is very significant development."
Based on the supercomputer calculations, the scientists found that methyldopa not only blocked the binding of DQ8 but didn't harm the immune functions of other cells, which is often the case with drugs that interfere with the body's immune system.
Overall, the research covered a period of 10 years – after the supercomputer analysis, the drug was tested in mice and in 20 patients with Type 1 diabetes through a clinical trial. The new drug is taken orally, three times a day.
While it's not a full cure (work on that continues), methyldopa could help delay, or even limit the onset of Type 1 diabetes – a disease that currently starts mostly in childhood.
"We can now predict with almost 100 percent accuracy who is likely to get Type 1 diabetes," says Michels. "The goal with this drug is to delay or prevent the onset of the disease among those at risk."
That 100 percent prediction rate is made possible by looking at a variety of genetic and biological markers, including autoantibodies in the blood. Those at risk could now be put on a course of treatment to ward of the development of diabetes.
With diagnosed cases of Type 1 and Type 2 diabetes on the rise in the United States – and the Type 1 condition believed to affect around 1.25 million people in the US alone – such treatments could make a huge difference.
Accounting for about 5-10 percent of people with diabetes, Type 1 involves the body's own immune system attacking the pancreas, stopping the production of insulin and hampering the absorption of glucose and the production of energy.
In Type 2 diabetes, the body can't process the insulin it does make properly.
Methyldopa is far from the first drug to show benefits in treating health issues other than the ones it was first designed for, but we now have better ways to spot these extra powers: this idea of identifying certain molecules and then applying modern-day computing power to find drugs that block them could work in other situations too.
"This study has significant implications for treatment of diabetes and also other autoimmune diseases," says one of the researchers, David Ostrov from the University of Florida.
"This study suggests that the same approach may be adapted to prevent autoimmune diseases such as rheumatoid arthritis, coeliac disease, multiple sclerosis, systemic lupus erythematosus and others."
The research has been published in the Journal of Clinical Investigation.
-
with the last entry showing a possible treatment for type 1 diabetes, it makes me curious what specifically defines type 1 verses type 2 diabetes.
Diabetes mellitus (https://en.wikipedia.org/wiki/Diabetes_mellitus)
Diabetes mellitus (DM), commonly referred to as diabetes, is a group of metabolic disorders in which there are high blood sugar levels over a prolonged period.[7] Symptoms of high blood sugar include frequent urination, increased thirst, and increased hunger.[2] If left untreated, diabetes can cause many complications.[2] Acute complications can include diabetic ketoacidosis, hyperosmolar hyperglycemic state, or death.[3] Serious long-term complications include cardiovascular disease, stroke, chronic kidney disease, foot ulcers, and damage to the eyes.[2]
Diabetes is due to either the pancreas not producing enough insulin or the cells of the body not responding properly to the insulin produced.[8] There are three main types of diabetes mellitus:[2]
Type 1 DM results from the pancreas's failure to produce enough insulin.[2] This form was previously referred to as "insulin-dependent diabetes mellitus" (IDDM) or "juvenile diabetes".[2] The cause is unknown.[2]
Type 2 DM begins with insulin resistance, a condition in which cells fail to respond to insulin properly.[2] As the disease progresses a lack of insulin may also develop.[9] This form was previously referred to as "non insulin-dependent diabetes mellitus" (NIDDM) or "adult-onset diabetes".[2] The most common cause is excessive body weight and insufficient exercise.[2]
Gestational diabetes is the third main form, and occurs when pregnant women without a previous history of diabetes develop high blood sugar levels.[2]
-
For the last 8 years my mission has been hijacked by declining health, so my focus has been directed these years to ways of understanding my health issues and coming up with ways to remediate these issues.
For the last year I have been relying upon HEPA air filters, which have improved my health considerably. The problem has been in powering them via solar panels, and batteries. This works on most days in Arizona, where we have 286 sunny days per year, but right now my solar panels are buried in snow, and the batteries are exhausted.
I happen to own 30 18ft long solar panels and 16 golf cart batteries, but my current van (a 1989 Ford Econoline 250) is too short to build a rack for these panels, and it could not carry 16 golf cart batteries. So, I am currently looking into alternatives.
There is at least 1 H3 antihistamine, Ciproxifan (https://www.sigmaaldrich.com/catalog/product/sigma/c6492?lang=en®ion=US&utm_term=Ciproxifan%20hydrochloride&utm_medium=cpc&utm_content=SIGMA/C6492&utm_source=bing&utm_campaign=Global%20Bioactive%20Small%20Molecules%20(Bing%20ebizpfs))available in the US, starting today.
Ciproxifan belongs to a novel chemical series of histamine H3-receptor antagonists. In vitro, it behaved as a competitive antagonist at the H3 autoreceptor controlling 3H histamine release from synaptosomes and displayed similar Ki values (0.5-1.9 nM) at the H3 receptor controlling the electrically-induced contraction of guinea pig ileum or at the brain H3 receptor labeled with 125I-iodoproxyfan. Ciproxifan appears to be an orally bioavailable, extremely potent and selective H3-receptor antagonist whose vigilance- and attention-promoting effects are promising for therapeutic applications in aging disorders.
I have had considerable success in using herbal tonics for my condition for 45 years, however more research is needed to improve the effect of the herbal tonic (https://en.wikipedia.org/wiki/Herbal_tonic).
In herbal medicine, an herbal tonic is used to help restore, tone and invigorate systems in the body or to promote general health and well-being.[1] An herbal tonic is a solution or other preparation made from a specially selected assortment of the kinds of plants known as herbs.
-
Sorry to hear of your troubles, Jeff, and hope your health improves. We value your continued presence here, hell plane though it is. :)
-
Thanks, Alexander, for voicing your kind support.
Yes, I agree, material existence is a hell-plane; or a better way to put it, is biology, by necessity, is cruel.
So, the message is, lead a disciplined, rigorous, self-aware, contemplative life that bares the superior fruit of attainment, and relinquish your entanglements with the material word; which I believe everyone on this forum, including you, are engaged in at one level or another.
-
I have noticed that Prescott seems to have an unusually rich and wide range of fungi. I have seen fungi here that I have seen no where else. One of the interesting fungi is something called, "Fuligo septica (https://en.wikipedia.org/wiki/Fuligo_septica)." Its more common names are: "scrambled egg slime," or "dog vomit slime mold," because it tends to look like bright yellow vomit with a color similar to egg yokes.
This fungus might be the source of my winter time lung infections here, because
Human pathogenicity
This species is known to trigger episodes of asthma and allergic rhinitis in susceptible people.[20][21]
I have seen it grow here, I found it growing in my old van, when I got so sick, and these are my major symptoms.
-
Jhanananda, I am actually quite curious, after reading the history of this thread, to know how your health is doing this Winter?
-
My health most of the year has been quite good with simply sleeping with my windows closed, and a small HEPA filter filtering the air that I breath when the body sleeps. My vitals under this condition are normal, with even normal blood sugars.
However, it is one of Prescott's 2 peek allergy seasons. Consequently my vitals have declined with my blood sugars 4 ti9mes normal. I have been in the ER once, and I am now seeing all of my doctors, who are quite concerned for my health. With it being winter, then solar gain is about 1/2 what it is during the warmer months, which has meant I can only run my HEPA filter for about 4-6 hours a day.
Thus, I am now working on making improvements to my off-grid electrical system so that my camper van can be a 24/7 refuge from the allergens that are swamping us here in Prescott at this time of year. In the long run I will have to increase the number of solar panels from 2 to 8, which will cost me more money than I can muster in a short time.
The previous year has provided ample proof that my health is directly related to allergens in the air here. My allergist did a blood test in 2016 that showed I had extreme allergies to pollen from at least 5 plants in this area.
Last week my allergist conducted an extensive skin test of many common allergens and found that I am allergic to just about everything in the Prescott area, including animal danders and mold spores. It supports the cause of why my health went down the tubes nearly 9 years ago when I arrived here. Prescott has thus become the "perfect storm" for my allergies. However, there is a simple solution to my health problems. Filter the air I breath with a HEPA filter.
Thanks-you for asking
-
Damn, I'm sorry to hear that, but it's good to hear you have a solution. I really hope you can get the HEPA filter running for longer periods of time. It's a shame that you're allergic to so many plants in Prescott. Would it be possible for you to move out of Prescott, or do you have something keeping you tied there?
-
Thank-you, Intuition, for your kind concern. I completed repairs of the RV's electrical charging system, and linking my 4 deep cycle marine batteries to the van's alternator. Now running the engine for 15 minutes gives me 6 hours of HEPA filter use. Yesterday was an allergen spike here, so I stayed in the van running the HEPA filter for 18 hours. After only the first half hour my respiratory symptoms were normalized; and this morning I found my blood sugar significantly reduced. It suggests that I might need to have HEPA filtered air 24-7 during the allergy seasons here.
Now that I have a working solution to running a HEPA filter, then I can keep working on ways to keep it running longer. I happen to own a 2KW gasoline generator, so my next goal is to attach it to the van. At that point I can run it for 6 hour on only 1 gallon of gasoline. Eventually I would like to cover the roof of my van with solar panels, which would mean I would only need to run the generator on cloudy days.
Yes, I can move from Prescott, except my decline in health has made it very difficult for me to do the necessary work to move. In the past I used to just drive until I stopped having an allergy response. I found in most cases all I had to do was change my elevation by 2,000ft to find relief, but it meant I had to move every 3 months, and doing so kept me a victim of my allergies. Being forced to do the necessary research to solve my many health problems has given me the benefit of developing equipment that allows me to remain longer in an area, if necessary.
-
I actually had not heard of ephedra before! I researched it and was amazed by the history and usage. You continuously inspire me with your intelligence and ability to use the natural world scientifically. You have a very wholistic approach to dealing with life and i deeply appreciate learning these things about you.
I will mention this as another alternative for diabetes if you have not heard of it. I did not know we could consume certain types of frankincense. A woman that my herbal teacher learned from mentions in her book that Acacia gum resin is good for diabetes. She said that she makes acacia water for her diabetes, and it reduced her A1c from 6.8 to 5.9 in 2 months. She says it did not help her cholesterol but that it stayed the same.
I'm just going to put the link to that here, but her other items and information are definitely worth investigating.
https://www.robinsresinsplus.com/store/p11//arabic_gum.html#/
Best Wishes,
Rougeleader
-
Thank you, rougeleader115, yes I am very pleased with my recent experiments with ephedra (AKA Mormon tea, Ma Huang). I have been using only a small amount, 1/4 tsp of the chopped herb in my hot drink in the morning. It has definitely lowered my blood sugar and put my chronic fatigue aside. So, since it has been listed as a controlled substance I had to forage it, and it took me 3 hours of hiking to forage a 6 month supply for me, but it definitely works.
I had not heard of using Acacia gum resin to lower blood sugar, but I will give it a try, because my blood sugar is still not normal, but it is now in the pre-diabetic range.
What I have also noticed improved my health since my last posts to this thread is improving my air purifier beyond a HEPA filter to a multi-gas air purifiers and the 3M 60926 Multi-gas respirator cartridges. However, I have also found an evaporative cooler is actually a true multi-gas air purifier as long as its reservoir is drained daily. Since evaporative coolers work by recycling water from a reservoir through a set of porous membranes then it washes the air, and since air pollution is not just solid particles, but gasses and some of those gasses are toxic Volatile Organic Compounds (VOCs) and corrosive gasses known as acid gasses, most often referred to as NOX and SOX. And, once I switched to a wet porous membrane in my CPAP machine my blood sugar dropped 100 units consistently, and I lost the 50lbs I gained when I moved to Prescott, but had not changed my diet. And, after a year on that modified CPAP machine my COPD diagnosis has been cured, which is huge for people with acute and chronic respiratory illnesses.
Here is a link to my CPAP modifications
https://m.facebook.com/groups/1045100886802993/permalink/1045106136802468/?mibextid=Nif5oz