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Incretins Function

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 >>

The Pathophysiologic Role Of Incretins

The Pathophysiologic Role Of Incretins

Many patients with type 2 diabetes mellitus (T2DM) are unable to achieve adequate glycemic control. Of the approximately 19 million individuals with T2DM in the United States, only about a third achieve the hemoglobin A1c (HbA1c0 goal set forth by the American Diabetes Association (HbA1c <7% [6% if it can be achieved safely]). The incretin mimetics are a new class of medications available for treating patients with T2DM. They mimic the action of incretins, which are peptide hormones that originate in the gastrointestinal tract. The two major incretins in humans are glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). These hormones are released during nutrient absorption, augmenting insulin secretion. However, incretins are susceptible to degradation by dipeptidyl peptidase IV (DPP-IV). Dipeptidyl peptidase IV inhibitors suppress the degradation of incretins, thus extending the activity of GLP-1 and GIP. The glycemic profiles of patients after administration of incretin mimetics and DPP-IV inhibitors show improvement in postprandial glucose levels and ultimately in HbA1c. Therefore, incretin mimetics and DPP-IV inhibitors may play a clinically significant role in the treatment of patients with T2DM. Despite lifestyle changes and pharmacologic interventions, many individuals with type 2 diabetes mellitus (T2DM) fail to achieve adequate glycemic control. This failure is noticed most often among patients undergoing long-term management.1-3 Of the approximately 19 million individuals affected with T2DM in the United States, only about a third achieve the hemoglobin A1c (HbA1c) goal previously set forth by the American Diabetes Association (HbA1c<7% [6% if it can be safely achieved]).2,4,5 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 >>

The Role Of Insulin And Incretins In Neuroinflammation And Neurodegeneration | Spielman | Immunoendocrinology

The Role Of Insulin And Incretins In Neuroinflammation And Neurodegeneration | Spielman | Immunoendocrinology

The Role of Insulin and Incretins in Neuroinflammation and Neurodegeneration Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotrophic polypeptide (GIP) are incretin hormones secreted from intestinal cells in response to incoming nutrients. The release of these incretins triggers the production and secretion of insulin from pancreatic cells, which upregulates the transport of glucose from the blood stream into the muscles, liver and adipose tissue for storage; therefore, insulin and incretins are vital to maintaining energy homeostasis within the body. Recently, it has been recognized that the activity of these hormones is not limited to the periphery, but extends to the central nervous system (CNS) as well. Within the CNS, insulin and incretins function as components of the anti-apoptotic and growth-regulating signaling cascades. Moreover, anti-inflammatory and neuroprotective roles for these hormones in the CNS have also been demonstrated. Specific discoveries have been made suggesting that insulin, GLP-1 and GIP may inhibit pathological processes in several CNS diseases, such as Alzheimers disease, Parkinsons disease, and schizophrenia. Hallschmid M, Schultes B. Central nervous insulin resistance: A promising target in the treatment of metabolic and cognitive disorders? Diabetologia 2009; 52:2264-2269. Fawcett DW. Histological observations on the relation of insulin to the deposition of glycogen in adipose tissue. Endocrinology 1948; 42:454-467. Leonards JR, Landau BR, Craig JW, Martin FI, Miller M, Barry FM. Regulation of blood glucose concentration: Hepatic action of insulin. Am J Physiol 1961; 201:47-54. Iwasaki Y, Nishiyama M, Taguchi T, Asai M, Yoshida M, Kambayashi M, et al. Insulin exhibits short-term anti-inflammatory but long-term proinflammator Continue reading >>

Incretin System In The Pathogenesis Of Type 2 Diabetes And The Role Of Incretin Based Therapies In The Management Of Type 2 Diabetes

Incretin System In The Pathogenesis Of Type 2 Diabetes And The Role Of Incretin Based Therapies In The Management Of Type 2 Diabetes

Incretin System in the Pathogenesis of Type 2 Diabetes and the Role of Incretin Based Therapies in the Management of Type 2 Diabetes 1. Introduction Discovery of incretin hormones and their role on glucose metabolism and pathogenesis of type 2 diabetes mellitus (T2 DM) are current interests of diabetology. Incretin hormones are secreted from intestinal endocrine cells in response to food ingestion and potentiate pancreatic insulin secretion when compared with iv glucose administration. Since malfunction of incretin hormones has been found to have role in T2 DM pathogenesis, incretin based therapies have been developed. Incretin effect, incretine hormones, functions, their role in pathogenesis of T2 DM and management of T2 DM with incretin-based drugs are discussed in this chapter. 2. Incretin effect, incretin hormones, secretion and functions 2.1. The incretin effect Pancreas secrete insulin in response to the food content in the gastrointestinal lumen. Endocrine pancreas senses food ingestion via incretin hormones, nerve inputs and substrates to secrete insulin. This chain of secretion which starts with food ingestion and result with insulin secretion by endocrine pancreas is called enteroinsulinar axis [1, 2]. The first definition of incretin effect depend on the fact that, much more insulin secretion is induced by oral glucose than with iv glucose administration. So two-to three fold augmented insulin response to oral glucose compared with iv glucose is known as the incretin effect [3]. A duodenal exctract has been found to reduce glucosuria first in early 20th century before the discovery of this phenomenon. The elements of the incretin effect were recognised much more before their insulinotropic effects. Glucagon like insulinotropic peptide (GIP) is the first, whic 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 >>

Role Of Incretin Hormones, Glp-1 Mimetics, Dpp-iv Inhibitors In Diabetes (transcript)

Role Of Incretin Hormones, Glp-1 Mimetics, Dpp-iv Inhibitors In Diabetes (transcript)

Dr. Wysham: Incretin hormones were initially discovered in the 1960s. They were discovered after an observation that insulin release related to an oral ingestion of glucose was greater than that when the same amount of glucose was administered intravenously. As you can see in this slide, there is a marked increase in insulin response related to the meal in normal individuals on the left panel; however, the individuals with type 2 diabetes have a delayed response and they do not respond as much to the oral glucose as the normal individuals. [1] In the case of the normal individuals, it appears as if 70% of the insulin secretion that is secreted in response to a meal is due to an incretin response. Furthermore, as you can see from this slide, glucagon levels are abnormally regulated in patients with type 2 diabetes. Focusing on the bottom part of the slide, you can see that in normal individuals, glucagon levels are suppressed after the ingestion of a meal; however, in patients with type 2 diabetes, glucagon levels are actually increased. [2] And as I indicated earlier, there is no medication among the traditional medications that can address these abnormal glucagon dynamics, in which glucagon does result in an increase in glucose levels after meals. Medscape: What are some of the tissue-specific effects of these new GLP-1 therapies in patients with type 2 diabetes? Dr. Wysham: GLP-1 is the major incretin hormone. As you can see on this slide, it has many effects related to glucose regulation, as well as others that are unrelated to glucose regulations such as those on the heart and the brain. [3] Focusing on those [effects] that are specific for glucose regulation, the effects of GLP-1 have [an] impact on the pancreas -- on the a cells, they suppress glucagon secretion. Continue reading >>

Review Pharmacology, Physiology, And Mechanisms Of Incretin Hormone Action

Review Pharmacology, Physiology, And Mechanisms Of Incretin Hormone Action

Incretin peptides, principally GLP-1 and GIP, regulate islet hormone secretion, glucose concentrations, lipid metabolism, gut motility, appetite and body weight, and immune function, providing a scientific basis for utilizing incretin-based therapies in the treatment of type 2 diabetes. Activation of GLP-1 and GIP receptors also leads to nonglycemic effects in multiple tissues, through direct actions on tissues expressing incretin receptors and indirect mechanisms mediated through neuronal and endocrine pathways. Here we contrast the pharmacology and physiology of incretin hormones and review recent advances in mechanisms coupling incretin receptor signaling to pleiotropic metabolic actions in preclinical studies. We discuss whether mechanisms identified in preclinical studies have potential translational relevance for the treatment of human disease and highlight controversies and uncertainties in incretin biology that require resolution in future studies. Continue reading >>

Incretin Secretion: Direct Mechanisms

Incretin Secretion: Direct Mechanisms

The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are secreted from gastro-intestinal K- and L-cells, respectively, and play an important role in post-prandial blood glucose regulation. They do this by direct stimulation of the pancreatic β-cell, accounting for some 25-70% of postprandial insulin secretion in healthy subjects. In patients with type 2 diabetes (T2D, however, this effect is greatly reduced or lost due to a combination of severely impaired or eliminated insulinotrophic effect of GIP and reduced meal stimulated GLP-1 secretion. This suggests that the therapeutic potential of GIP for the treatment for T2D is limited, whereas GLP-1 based treatments have been on the market since 2005. Research is now pursuing novel approaches to utilize the effects of GLP-1 for T2D treatment. A combinatorial approach by which the activity of the major enzyme responsible for incretin degradation (dipeptidyl peptidase-4) is inhibited (drugs are already on the market) while the secretion of endogenous GLP-1 secretion is stimulated at the same time may prove particularly rewarding. In this section we review current knowledge on the mechanisms for direct activation of GIP and GLP-1 secretion. Direct mechanisms of incretin secretion The endocrine K- and L-cells are located in the intestinal epithelium and are morphologically described as cone-shaped cells with apical cytoplasmic processes equipped with microvilli extending into the gut lumen. While this suggested that the incretin producing cells might be able to directly sense nutrients, it was only after the development of the GLP-1 producing cell lines GLUTag, STC-1 and NCI-H716 that evidence supporting this assumption was provided and the underlying pathways began to be Continue reading >>

Physiology Of Incretins (gip And Glp-1) And Abnormalities In Type 2 Diabetes - Em|consulte

Physiology Of Incretins (gip And Glp-1) And Abnormalities In Type 2 Diabetes - Em|consulte

Physiology of incretins (GIP and GLP-1) and abnormalities in type 2 diabetes Physiologie des incrtines (GLP1 et GIP) et anomalies des incrtines dans le diabte de type 2 aService de Diabtologie et dEndocrinologie et INSERM CIC9504, Hpital Saint-Louis, 101, avenue Claude Vellefaux, 75010 Paris, France bINSERM U 872, Centre de Recherche des Cordeliers, 15, rue de lcole de mdecine, 75270 Paris Cedex 06, France cInstitut Cochin, Universit Paris Descartes, CNRS (UMR 8104), Paris, France, Inserm, U567, Paris, France Incretin hormones are defined as intestinal hormones released in response to nutrient ingestion, which potentiate the glucose-induced insulin response. In humans, the incretin effect is mainly caused by two peptide hormones, glucose-dependent insulin releasing polypeptide (GIP), and glucagon-like peptide-1 (GLP-1). GIP is secreted by K cells from the upper small intestine while GLP-1 is mainly produced in the enteroendocrine L cells located in the distal intestine. Their effect is mediated through their binding with specific receptors, though part of their biological action may also involve neural modulation. GIP and GLP-1 are both rapidly degraded into inactive metabolites by the enzyme dipeptidyl-peptidase-IV (DPP-IV). In addition to its effects on insulin secretion, GLP-1 exerts other significant actions, including stimulation of insulin biosynthesis, inhibition of glucagon secretion, inhibition of gastric emptying and acid secretion, reduction of food intake, and trophic effects on the pancreas. As the insulinotropic action of GLP-1 is preserved in type 2 diabetic patients, this peptide was likely to be developed as a therapeutic agent for this disease. The full text of this article is available in PDF format. Les incrtines sont des hormones intestinales libre Continue reading >>

The Incretin Approach For Diabetes Treatment

The Incretin Approach For Diabetes Treatment

Glucagon-like peptide (GLP)-1 is a gut hormone that stimulates insulin secretion, gene expression, and β-cell growth. Together with the related hormone glucose-dependent insulinotropic polypeptide (GIP), it is responsible for the incretin effect, the augmentation of insulin secretion after oral as opposed to intravenous administration of glucose. Type 2 diabetic patients typically have little or no incretin-mediated augmentation of insulin secretion. This is due to decreased secretion of GLP-1 and loss of the insulinotropic effects of GIP. GLP-1, however, retains insulinotropic effects, and the hormone effectively improves metabolism in patients with type 2 diabetes. Continuous subcutaneous administration greatly improved glucose profiles and lowered body weight and HbA1c levels. Further, free fatty acid levels were lowered, insulin resistance was improved, and β-cell performance was greatly improved. The natural peptide is rapidly degraded by the enzyme dipeptidyl peptidase IV (DPP IV), but resistant analogs as well as inhibitors of DPP IV are now under development, and both approaches have shown remarkable efficacy in experimental and clinical studies. THE INCRETIN EFFECT IN TYPE 2 DIABETES It is now recognized that inadequate secretion of insulin may be a very early element in the development of type 2 diabetes and that its progression is due to declining β-cell function (1–3). The β-cell defect is partly due to loss of β-cells, but the loss, which may amount to 50% in advanced type 2 diabetes (4), does not seem to parallel the dysfunction. This raises the possibility that the dysfunction could at least be partly due to dysregulation. Thus, dysfunction of the autonomic innervation of the islets could be responsible, perhaps particularly with respect to the ear 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 >>

The Role Of Incretin On Diabetes Mellitus.

The Role Of Incretin On Diabetes Mellitus.

The role of incretin on diabetes mellitus. Department of Internal Medicine, Hasanuddin University, Jl. Perintis Kemerdekaan no. 11, Makasar, Indonesia. [email protected] Beta cell dysfunction in type-2 diabetes mellitus holds an important role not just on its pathogenesis, but also on the progression of the disease. Until now, diabetes treatment cannot restore the reduced function of pancreatic beta cell. McIntyre et al stated that there is a factor from the intestine which stimulates insulin secretion as a response on glucose.This factor is known as incretin. It is a hormone which is released by the intestine due to ingested food especially those which contain carbohydrate and fat. Currently, there are 2 types of incretin hormones which have been identified, i.e.Glucose dependent insulinotropic polypeptide (GIP) and Glucagon like peptide-1 (GLP-1). These two hormones act by triggering insulin release immediately after food ingestion, inhibiting glucagon secretion, delaying stomach emptying, and suppressing hunger sensation. Several in vitro studies have demonstrated that these two incretin hormones may increase the proliferation of pancreatic beta cell.There is a decrease of GIP function and GLP-1 amount in type-2 diabetes mellitus; thus the attempt to increase both incretin hormones - in this case by using GLP-1 agonist and DPP-IV inhibitor - is one of treatment modalities to control the glucose blood level, either as a monotherapy or a combination therapy. Currently, there are two approaches of incretin utilization as one of type-2 diabetes mellitus treatment, which is the utilization of incretin mimetic/agonist and DPP-IV inhibitor. Continue reading >>

Incretins And Preservation Of Endothelial Function

Incretins And Preservation Of Endothelial Function

Incretins and Preservation of Endothelial Function Author(s): Juraj Koska . Phoenix Veteran Affairs Healthcare System, 650 E Indian School Rd, CS111E, Phoenix, AZ 85012, USA. Journal Name: Cardiovascular & Hematological Agents in Medicinal Chemistry The endothelium is critical for multiple processes occurring on both sides of the vascular wall includingregulation of blood flow, maintenance of blood fluidity and control of inflammation. Endothelial dysfunction is an earlyevent in the pathogenesis of atherosclerosis and appears to be a critical determinant of cardiovascular events. It isfrequently detected in the early stages of type 2 diabetes and even in pre-diabetes conditions. Risk factors for endothelialdysfunction are numerous and include among others fasting and postprandial hyperglycemia and hyperlipidemia,hypertension, obesity, insulin resistance and inflammation. Many of these conditions can be improved by syntheticglucagon like peptide 1 (GLP-1) mimetics or inhibitors of the main GLP-1 degrading enzyme dipeptidyl peptidase 4(DPP-4). Acute increases in GLP-1 activity abolish endothelial dysfunction induced by high-fat meals or byhyperglycemia. In vitro and preliminary clinical studies also indicate that GLP-1 or GLP-1 agonists can improveendothelial function by direct action on endothelium. GLP-1 or GLP-1 mimetic effects appear to extend to both conduitarteries and the microvasculature, and may depend on activation of endothelial GLP-1 receptors and downstream nitricoxide production. Additional studies are necessary to confirm improvement of endothelial function after prolongedtreatment with incretin based medications as well as the cardiovascular benefit of these agents. Keywords: Cardiovascular risk, DPP-4 inhibitors, endothelium, eNOS, GLP-1 analogs, GLP-1, 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 >>

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