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How Do Incretins Help Regulate Blood Glucose?

The Role Of Incretins In Glucose Homeostasis And Diabetes Treatment

The Role Of Incretins In Glucose Homeostasis And Diabetes Treatment

Go to: I. Background and Introduction Incretins are hormones that are released from the gut into the bloodstream in response to ingestion of food, and they then modulate the insulin secretory response to the products within the nutrients in the food. The insulin secretory response of incretins, called the incretin effect, accounts for at least 50% of the total insulin secreted after oral glucose. Therefore, by definition, incretin hormones are insulinotropic (i.e., they induce insulin secretion) at usual physiological concentrations seen in the plasma after ingestion. The concept of incretins is at least a century old (Table 1). In 1902, Bayliss and Starling published their landmark manuscript, “The Mechanism of Pancreatic Secretion.” The authors found that acid infused into the digestive system caused pancreatic secretion of juices through the pancreatic duct from the pancreas, even after they cut the ennervation to the intestine. Until that time, it was thought that nervous system signals controlled secretion of pancreatic juices. They carried out ground-breaking studies that led them to conclude that the nature of the signal to the pancreas was most likely a chemical stimulus: they removed extracts from the intestinal wall after it had been stimulated by acid, injected the extracts into the bloodstream, and once again they could see juices coming from the pancreatic duct of the animal that had been injected. Therefore, they proved that the extracts must have contained a substance that must normally be secreted from the intestinal wall into the bloodstream to stimulate the flow of pancreatic juice. They called the substance “secretin.” In his “Cronian Lectures,” Starling introduced the word “hormone” (derived from the Greek word meaning “impetus”) Continue reading >>

Incretin Hormone

Incretin Hormone

A hormone that stimulates insulin secretion in response to meals. The two most important incretin hormones are called glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Understanding how these hormones work is helping to yield new treatments for Type 1 and Type 2 diabetes. The whole concept of incretin hormones comes from a decades-old observation that orally administered glucose provokes a far greater release of insulin than the same amount of glucose delivered by injection. Scientists postulated that there must be some signal from the gastrointestinal tract (or “gut”) that increases insulin release whenever food is consumed. A considerable amount of evidence now suggests that GLP-1 and GIP are responsible for most of this increased insulin release. Furthermore, scientists have also observed that people with Type 2 diabetes have diminished insulin release in response to meals and have speculated that they may have defects in the release or action of their incretin hormones. GLP-1 is made in the small intestine and colon and is released in response to food. It stimulates insulin secretion in a glucose-dependent manner — that is, it stimulates insulin secretion only when there is glucose in the bloodstream. GLP-1 has other beneficial effects as well: It delays stomach emptying, which slows the absorption of carbohydrate and the resulting rise in blood glucose level after meals; it curbs appetite; and animal studies have shown that it may promote regeneration of the pancreatic beta cells and fight apoptosis (programmed cell death), improving the survival of existing beta cells. GIP is made by cells in the upper small intestine and is released when glucose comes in contact with these cells. Like GLP-1, GIP affects the pancreatic b Continue reading >>

Therapeutic Applications Of Dpp-iv Inhibitors

Therapeutic Applications Of Dpp-iv Inhibitors

Skyler JS. Diabetes mellitus: pathogenesis and treatment strategies. J Med Chem. 2004;47:4113-4117. Abstract Creutzfeld WO. The incretin concept today. Diabetologia. 1979;16:75-85. Abstract Drucker DJ, Philippe J, Mojsov S, Chick WL, Habener JF. Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line. Proc Natl Acad Sci U S A. 1987;84:3434-3438. Abstract Fehmann H-C, Habener JF. Insulinotropic hormone glucagon-like peptide-I(7-37) stimulation of proinsulin gene expression and proinsulin biosynthesis in insulinoma bTC-1 cells. Endocrinology.1992;130:159-166. Abstract Lu M, Wheeler MB, Leng XH, Boyd AED. Stimulation of insulin secretion and insulin gene expression by gastric inhibitory polypeptide. Trans Assoc Am Physicians.1993;106:42-53. Abstract Brubaker PL, Drucker DJ. Minireview: glucagon-like peptides regulate cell proliferation and apoptosis in the pancreas, gut, and central nervous system. Endocrinology. 2004;145:2653-2659. Abstract Nauck MA, Heimesaat MM, Behle K, et al. Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. J Clin Endocrinol Metab. 2002;87:1239-1246. Abstract Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet. 2002;359:824-830. Abstract Burcelin R, Da Costa A, Drucker D, Thorens B. Glucose competence of the hepatoportal vein sensor requires the presence of an activated glucagon-like peptide-1 receptor. Diabetes. 2001;50:1720-1728. Abstract Knauf C, Cani PD, Perrin C, et al. Brain gl Continue reading >>

Incretin Mimetics For Type 2 Diabetes

Incretin Mimetics For Type 2 Diabetes

Examples Generic Name Brand Name exenatide Bydureon, Byetta liraglutide Victoza Exenatide and liraglutide are a type of medicine called incretin mimetics used to treat people who have type 2 diabetes and who have not been able to control their blood sugar levels with oral medicines. This medicine is given as a shot. This medicine is also known as a glucagon-like peptide 1 (GLP-1) receptor agonist, or GLP-1 agonist. How It Works Incretin is a natural hormone that your body makes. It tells your body to release insulin after you eat. Insulin lowers blood sugar. Incretin mimetics act like (mimic) the incretins in your body that lower blood sugar after eating. Incretin mimetics: Prompt your pancreas to release insulin when blood sugar is rising. Prevent the pancreas from giving out too much glucagon. Glucagon is a hormone that causes the liver to release its stored sugar into the bloodstream. Help to slow the rate at which your stomach empties after eating. This may make you feel less hungry and more satisfied after a meal. Your blood sugar shouldn't get too high too fast after a meal. Why It Is Used These medicines help to keep blood sugar in a target range without causing low blood sugar or weight gain, unless they are taken in combination with medicines that do. Some people feel less hungry and lose weight while taking these medicines. How Well It Works Type 2 diabetes is a disease that can get worse over time, so medicines may need to change. Diabetes medicines work best for people who are being active and eating healthy foods. Studies have suggested that incretin mimetics lower hemoglobin A1c by 0.5% to 1%.1 All medicines have side effects. But many people don't feel the side effects, or they are able to deal with them. Ask your pharmacist about the side effects of each Continue reading >>

Incretin - An Overview | Sciencedirect Topics

Incretin - An Overview | Sciencedirect Topics

Incretins are a kind of protein hormones whose functions include the modulation of glucose metabolism by stimulating the release of insulin by the cells and, at the same time, inhibiting the release of glucagon by pancreatic cells.30,31 Bo Ahrn, ... Carolyn F. Deacon, in Vitamins & Hormones , 2010 Incretin hormones are important for metabolism, and an understanding of the factors regulating their secretion is, therefore, fundamental for full appreciation of the complex regulation of islet function and metabolism. As reviewed here, incretin hormone secretion is influenced by nutrient ingestion, and meal size and composition, in addition to gastric emptying and gastric distension, whereas the roles of the autonomic nerves and other hormones are less clear. Furthermore, there is a diurnal variation with a more rapid incretin response to meal ingestion in the morning than in the afternoon. Incretin hormone secretion is reduced in type 2 diabetes in some, but not all studies, and may also be perturbed in obesity. Finally, to add to the complexity, antidiabetic compounds may have the capacity to affect incretin hormone secretion, either directly or indirectly, which has been demonstrated for metformin and the -glucosidase inhibitors. It is, therefore, apparent that the full picture of the regulation of incretin hormone secretion is far from complete, suggesting that more studies are required. In particular, the issue whether incretin hormone secretion is reduced in type 2 diabetes needs to be examined in larger studies with control of the wash-out period and using subjects with different degrees of glucose dysregulation. Furthermore, the potential increase in incretin hormone secretion by metformin (and, possibly, other antihypeglycemic agents) requires further study. Finall Continue reading >>

Incretins

Incretins

The incretins are hormones that work to increase insulin secretion. The incretin concept was developed when it was observed that there is substantially more insulin secreted in response to oral glucose versus intravenous glucose, as shown in the graph at right. It was hypothesized that glucose in the digestive tract activated a feedforward mechanism that increased insulin secretion, anticipating the rise in blood glucose that would occur following absorption of ingested carbohydrates. There are two main incretin hormones in humans, GIP (glucose-dependent insulinotropic peptide; also known as gastric inhibitory peptide) and GLP-1 (glucagon-like peptide-1). Both hormones are secreted by endocrine cells that are located in the epithelium of the small intestine. Incretin hormone release is regulated in a similar way to other digestive tract hormones. An increase in the concentration of a substance in the lumen of the digestive tract (in this case glucose) acts as the trigger for hormone secretion. The mechanism of incretin action is schematized in the figure below. Glucose in the small intestine stimulates incretin release. Incretins are carried through the circulation to their target tissue: the pancreatic beta cells. Incretin stimulation of beta cells causes them to secrete more insulin in response to the same amount of blood glucose. There has been a lot of interest in developing incretin-based therapies for the treatment of type 2 diabetes mellitus (T2DM). T2DM is characterized by insulin resistance, which is a decreased responsiveness of tissues to insulin, and so it may lead to a relative insulin deficiency. Frequently, T2DM also involves defects in insulin secretion, particularly as the disease advances. There are several reasons why treatments with an incretin analo Continue reading >>

Glucose Metabolism And Regulation: Beyond Insulin And Glucagon

Glucose Metabolism And Regulation: Beyond Insulin And Glucagon

Insulin and glucagon are potent regulators of glucose metabolism. For decades, we have viewed diabetes from a bi-hormonal perspective of glucose regulation. This perspective is incomplete and inadequate in explaining some of the difficulties that patients and practitioners face when attempting to tightly control blood glucose concentrations. Intensively managing diabetes with insulin is fraught with frustration and risk. Despite our best efforts, glucose fluctuations are unpredictable, and hypoglycemia and weight gain are common. These challenges may be a result of deficiencies or abnormalities in other glucoregulatory hormones. New understanding of the roles of other pancreatic and incretin hormones has led to a multi-hormonal view of glucose homeostasis. HISTORICAL PERSPECTIVE Our understanding of diabetes as a metabolic disease has evolved significantly since the discovery of insulin in the 1920s. Insulin was identified as a potent hormonal regulator of both glucose appearance and disappearance in the circulation. Subsequently, diabetes was viewed as a mono-hormonal disorder characterized by absolute or relative insulin deficiency. Since its discovery, insulin has been the only available pharmacological treatment for patients with type 1 diabetes and a mainstay of therapy for patients with insulin-deficient type 2 diabetes.1–7 The recent discovery of additional hormones with glucoregulatory actions has expanded our understanding of how a variety of different hormones contribute to glucose homeostasis. In the 1950s, glucagon was characterized as a major stimulus of hepatic glucose production. This discovery led to a better understanding of the interplay between insulin and glucagon, thus leading to a bi-hormonal definition of diabetes. Subsequently, the discovery of Continue reading >>

Glucose Metabolism

Glucose Metabolism

Despite periods of feeding and fasting, in normal individuals plasma glucose remains in a narrow range between 4 and 7 mM reflecting the balance between: (i) the release of glucose into the circulation by either absorption from the intestine or the breakdown of stored glycogen in the liver and (ii) the uptake and metabolism of blood glucose by peripheral tissues[1]. These processes are controlled by a set of metabolic hormones. For decades diabetes had been viewed from a bi-hormonal perspective of glucose regulation involving insulin (discovered in the 1920s; released by pancreatic β-cells ) and glucagon (discovered in the 1950s; released by the pancreatic α-cells)[2]. In the mid-1970s several gut hormones, the incretins, were identified. One of these, glucagon-like peptide-1 (GLP-1), was recognized as another important contributor to the maintenance of glucose homeostasis. Subsequently the discovery in 1987, of a second pancreatic β-cell hormone, amylin, whose role complemented that of insulin, led to the view of glucose homeostasis involving multiple hormones[2]. Amylin, like insulin is found to be deficient in people with diabetes. Hormones produced by adipose tissue also play a critical role in the regulation of energy intake, energy expenditure, and lipid and carbohydrate metabolism. These include leptin, adiponectin, acylation stimulating protein and resistin . Hormones involved Pancreatic β-cell hormones Insulin is a key anabolic hormone that is secreted from pancreatic β-cells in response to increased blood glucose and amino acids following ingestion of a meal. Insulin, through its action on the insulin receptor decreases blood sugar levels by: (i) increasing glucose uptake in muscle and fat through triggering the translocation of the intracellular glucose Continue reading >>

Roles Of The Gut In Glucose Homeostasis

Roles Of The Gut In Glucose Homeostasis

The gastrointestinal tract plays a major role in the regulation of postprandial glucose profiles. Gastric emptying is a highly regulated process, which normally ensures a limited and fairly constant delivery of nutrients and glucose to the proximal gut. The subsequent digestion and absorption of nutrients are associated with the release of a set of hormones that feeds back to regulate subsequent gastric emptying and regulates the release of insulin, resulting in downregulation of hepatic glucose production and deposition of glucose in insulin-sensitive tissues. These remarkable mechanisms normally keep postprandial glucose excursions low, regardless of the load of glucose ingested. When the regulation of emptying is perturbed (e.g., pyloroplasty, gastric sleeve or gastric bypass operation), postprandial glycemia may reach high levels, sometimes followed by profound hypoglycemia. This article discusses the underlying mechanisms. The Incretin Effect One of the ways to illustrate the role of the gut in glucose homeostasis is to compare the fate of glucose that has been administered orally or infused intravenously. If the same amount of glucose is given, the results may not be particularly remarkable, at least not with relatively small amounts of glucose (25 g or roughly one-half the amount of sugar as in a can of soda). The amount of insulin secreted (estimated from C-peptide responses) may be almost the same, and any differences in peripheral insulin concentrations could be interpreted as indicative of differences in hepatic insulin clearance (1). However, if the intravenous glucose infusion is adjusted so that the resulting plasma glucose concentrations are identical to those after oral or small intestinal administration of glucose, substantially more insulin is secreted Continue reading >>

Incretin Based Treatments

Incretin Based Treatments

Incretin based treatments reduce post meal blood sugars. These medicines are also euglycemics, which help return the blood sugar to the normal range. When you have type 2 diabetes, the blood sugar may be too high after a meal, even if you eat very little carbohydrate (CHO). This, in part, is due to glucagon levels staying too high after meals. Medicines, called incretin based treatments, are now available to control post-meal glucagon, and help reduce the post meal blood sugars. These medicines also are blood sugar normalizing medications or euglycemics (drugs that help return the blood sugar to the normal range). The incretin based medicines are available in two families of medicines: DPP-4 Inhibitors and GLP-1 analogs. Sitagliptin, saxagliptin, and linagliptin (approved May 2011 and is not available yet) are DPP-4 inhibitors and are taken as pills. Exenatide and liraglutide are GLP-1 analogs and are taken by injection. If you have kidney problems, the dose of the incretin based medicines may need to be adjusted. Please tell your doctor if you have kidney problems before starting these medicines. DPP-4 Inhibitors DPP-4 inhibitors are oral medicines for people with type 2 diabetes that help control blood sugar levels, especially after eating. After eating, your gut naturally releases hormones—two important ones are GLP-1 and GIP. These hormones increase insulin release to help control blood sugar levels. GLP-1 also decreases glucagon release at meals, to further control blood sugar levels. However, these hormones are quickly broken down in the body by an enzyme called DPP-4. DPP-4 inhibitors like sitagliptin and saxagliptin block DPP-4 from breaking down GLP-1 as quickly so that GLP-1 can have a longer effect in the body. While DPP-4 inhibitors may be used as an initi Continue reading >>

The Role Of Gut Hormones In Glucose Homeostasis

The Role Of Gut Hormones In Glucose Homeostasis

After food ingestion, the digestion and absorption of nutrients is associated with increased secretion of multiple gut peptides that act on distant target sites to promote the efficient uptake and storage of energy. These peptide hormones are synthesized by specialized enteroendocrine cells located in the epithelium of the stomach, small bowel, and large bowel and are secreted at low basal levels in the fasting state. Plasma levels of most gut hormones rise briskly within minutes of nutrient intake and fall rapidly thereafter, mainly because they are cleared by the kidney and are enzymatically inactivated. Gut hormones activate neural circuits that communicate with peripheral organs, including the liver, muscle tissue, adipose tissue, and islets of Langerhans in the pancreas, to coordinate overall energy intake and assimilation (Figure 1). Incretin hormones (gastrointestinal hormones such as glucose-dependent insulinotropic polypeptide [GIP] and glucagon-like peptide-1 [GLP1] that cause an increase in the amount of insulin released from the β cells of the islets) augment the magnitude of meal-stimulated insulin secretion from islet β cells in a glucose-dependent manner (1). Incretin action facilitates the uptake of glucose by muscle tissue and the liver while simultaneously suppressing glucagon secretion by the α cells of the islets, leading to reduced endogenous production of glucose from hepatic sources. Figure 1 Actions of selected peptides on key tissues important for the control of glucose homeostasis. Both GLP1 and GIP promote insulin biosynthesis, insulin secretion, and islet β cell survival. GLP1 exerts additional actions important for regulation of glucose homeostasis, including inhibition of glucagon secretion and gastric emptying, and induction of satiety Continue reading >>

The Dpp-4 Inhibitor: Lowers Blood Glucose By Working On The Gut

The Dpp-4 Inhibitor: Lowers Blood Glucose By Working On The Gut

DPP-4 Januvia (sitagliptin phosphate), from Merck and Co., was the first DPP-4 inhibitor to be approved by the U.S. Food and Drug Administration in October 2006. Several more DPP-4 inhibitors should become available in the next few years. So what's all the fuss about the DPP-4 inhibitor category of medications that lower blood glucose? They work in an entirely different way than most other diabetes medications. They inhibit an enzyme in the gut that breaks down the hormones that help to lower your blood glucose. How It Works DPP-4 (dipeptidyl peptidase IV) is an enzyme that's responsible for inactivating hormones in your gut called incretins. These helpful incretin hormones cause your pancreas to produce more insulin and your liver to stop producing glucose. By depressing or inhibiting the DPP-4 enzyme that inactivates incretins, DPP-4 inhibitors promote higher levels of incretins to keep your blood glucose in the normal range, especially after meals. DPP-4 inhibitors are designed for people with type 2 diabetes to use in conjunction with a healthful meal plan and sufficient physical activity to control their blood glucose levels, especially when glucose levels soar following meals. They work in the presence of food or in response to a meal. "I see many people with diabetes who aren't able to get good control because of high postmeal blood glucose," says Joel Rosenberg, M.D., a cardiac surgeon in upstate New York. "Januvia is a great option for people who are having trouble with postmeal high glucose levels." However, DPP-4 inhibitors don't reduce overall blood glucose levels as well as some other oral medications that are in the same price range. What You Should Know About DPP-4 Inhibitors Side Effects: Januvia appears to have few significant side effects. A small perc Continue reading >>

Blood Sugar Regulation

Blood Sugar Regulation

Ball-and-stick model of a glucose molecule Blood sugar regulation is the process by which the levels of blood sugar, primarily glucose, are maintained by the body within a narrow range. This tight regulation is referred to as glucose homeostasis. Insulin, which lowers blood sugar, and glucagon, which raises it, are the most well known of the hormones involved, but more recent discoveries of other glucoregulatory hormones have expanded the understanding of this process.[1] Mechanisms[edit] Blood sugar regulation the flatline is the level needed the sine wave the fluctuations. Blood sugar levels are regulated by negative feedback in order to keep the body in balance. The levels of glucose in the blood are monitored by many tissues, but the cells in the pancreatic islets are among the most well understood and important. Glucagon[edit] If the blood glucose level falls to dangerous levels (as during very heavy exercise or lack of food for extended periods), the alpha cells of the pancreas release glucagon, a hormone whose effects on liver cells act to increase blood glucose levels. They convert glycogen into glucose (this process is called glycogenolysis). The glucose is released into the bloodstream, increasing blood sugar. Hypoglycemia, the state of having low blood sugar, is treated by restoring the blood glucose level to normal by the ingestion or administration of dextrose or carbohydrate foods. It is often self-diagnosed and self-medicated orally by the ingestion of balanced meals. In more severe circumstances, it is treated by injection or infusion of glucagon. Insulin[edit] When levels of blood sugar rise, whether as a result of glycogen conversion, or from digestion of a meal, a different hormone is released from beta cells found in the Islets of Langerhans in the p Continue reading >>

Incretin

Incretin

GLP-1 and DPP-4 inhibitors Incretins are a group of metabolic hormones that stimulate a decrease in blood glucose levels. Incretins are released after eating and augment the secretion of insulin released from pancreatic beta cells of the islets of Langerhans by a blood glucose-dependent mechanism. They also slow the rate of absorption of nutrients into the blood stream by reducing gastric emptying and may directly reduce food intake. They also inhibit glucagon release from the alpha cells of the islets of Langerhans. The two main candidate molecules that fulfill criteria for an incretin are the intestinal peptides glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (also known as: glucose-dependent insulinotropic polypeptide or GIP). Both GLP-1 and GIP are rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4); both GLP-1 and GIP are members of the glucagon peptide superfamily.[1][2][3] "Many factors stimulate insulin secretion, but the main one is blood glucose. Incretins, especially GIP and GLP-1 secreted, respectively, by K and L cells in the gut are also important" (Rang and Dale's Pharmacology (2015)). GLP-1 (7-36) amide is not very useful for treatment of type 2 diabetes mellitus, since it must be administered by continuous subcutaneous infusion. Several long-lasting analogs having insulinotropic activity have been developed, and three, exenatide (Byetta) and liraglutide (Victoza), plus exenatide extended-release (Bydureon), have been approved for use in the U.S. The main disadvantage of these GLP-1 analogs is they must be administered by subcutaneous injection. Another approach is to inhibit the enzyme that inactivates GLP-1 and GIP, DPP-4. Several DPP-4 inhibitors that can be taken orally as tablets have been developed. Once weekly dosage of Continue reading >>

Normal Regulation Of Blood Glucose

Normal Regulation Of Blood Glucose

The human body wants blood glucose (blood sugar) maintained in a very narrow range. Insulin and glucagon are the hormones which make this happen. Both insulin and glucagon are secreted from the pancreas, and thus are referred to as pancreatic endocrine hormones. The picture on the left shows the intimate relationship both insulin and glucagon have to each other. Note that the pancreas serves as the central player in this scheme. It is the production of insulin and glucagon by the pancreas which ultimately determines if a patient has diabetes, hypoglycemia, or some other sugar problem. In this Article Insulin Basics: How Insulin Helps Control Blood Glucose Levels Insulin and glucagon are hormones secreted by islet cells within the pancreas. They are both secreted in response to blood sugar levels, but in opposite fashion! Insulin is normally secreted by the beta cells (a type of islet cell) of the pancreas. The stimulus for insulin secretion is a HIGH blood glucose...it's as simple as that! Although there is always a low level of insulin secreted by the pancreas, the amount secreted into the blood increases as the blood glucose rises. Similarly, as blood glucose falls, the amount of insulin secreted by the pancreatic islets goes down. As can be seen in the picture, insulin has an effect on a number of cells, including muscle, red blood cells, and fat cells. In response to insulin, these cells absorb glucose out of the blood, having the net effect of lowering the high blood glucose levels into the normal range. Glucagon is secreted by the alpha cells of the pancreatic islets in much the same manner as insulin...except in the opposite direction. If blood glucose is high, then no glucagon is secreted. When blood glucose goes LOW, however, (such as between meals, and during Continue reading >>

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