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Incretins Mechanism Of Action

Incretin Mimetics (glp-1 Agonists)

Incretin Mimetics (glp-1 Agonists)

Tweet Incretin mimetics are a relatively new group of injectable drugs for treatment of type 2 diabetes. The drugs, also commonly known as glucagon-like peptide 1 (GLP-1) receptor agonists or GLP-1 analogues, are normally prescribed for patients who have not been able to control their condition with tablet medication. Drugs in this class In the UK, the following incretin mimetics are available for type 2 diabetic patients - (trade name first, generic name in brackets): Bydureon (Exenatide) - taken once weekly Byetta (Exenatide) - taken twice daily Lyxumia (lixisenatide) - taken once daily Trulicity (Dulaglutide) - taken once weekly Victoza (Liraglutide) - taken once daily Byetta and Bydureon are the same medical drug. The only difference is that Bydureon is long-lasting, requiring only one injection per week, whereas Byetta is taken twice-daily due to its much shorter-term effects. How do they work? They work by copying, or mimicking, the functions of the natural incretin hormones in your body that help lower post-meal blood sugar levels. These functions include: Stimulating the release of insulin by the pancreas after eating, even before blood sugars start to rise. Inhibiting the release of glucagon by the pancreas. Glucagon is a hormone that causes the liver to release its stored sugar into the bloodstream. Slowing glucose absorption into the bloodstream by reducing the speed at which the stomach empties after eating, thus making you feel more satisfied after a meal. These effects are in direct response to the presence of carbohydrate in the gut and therefore the chance of significant hypoglycemia occurring is unlikely, unless used in combination with other hypoglycemic drugs. Benefits of incretin mimetics By increasing insulin secretion and inhibiting glucagon releas Continue reading >>

Incretin Hormones And The Satiation Signal

Incretin Hormones And The Satiation Signal

Recent research has indicated that appetite-regulating hormones from the gut may have therapeutic potential. The incretin hormone, glucagon-like peptide-1 (GLP-1), appears to be involved in both peripheral and central pathways mediating satiation. Several studies have also indicated that GLP-1 levels and responses to meals may be altered in obese subjects. Clinical trial results have shown further that two GLP-1 receptor agonists (GLP-1 RAs), exenatide and liraglutide, which are approved for the treatment of hyperglycemia in patients with type 2 diabetes, also produce weight loss in overweight subjects without diabetes. Thus, GLP-1 RAs may provide a new option for pharmacological treatment of obesity. The incretin hormones are gut hormones that amplify nutrient-induced insulin secretion in response to meal intake. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are the two most important hormones and both are thought to contribute equally to the effect.1 GLP-1 is secreted from endocrine cells in the epithelium of the small intestine thatexpress the proglucagon gene, the so-called L cells. Unlike in the pancreas, the gene product, (pre)proglucagon, is processed here to release the two glucagon-like hormones, GLP-1 and GLP-2,2 whereas the glucagon sequence is buried in an N-terminal fragment of proglucagon called glicentin.3 GLP-1 binds to a single GLP-1 receptor4 and possesses several physiological effects that contribute to the regulation of glucose (Figure 1).4, 5, 6, 7 GIP is secreted from K cells in the proximal small bowel and binds to GIP receptors expressed by pancreatic islet β cells, as well as to receptors in adipose tissue and the brain.5 A large body of data indicate that GLP-1 has an important role in satiation signali 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 >>

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 >>

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 >>

Incretin Hormones As Immunomodulators Of Atherosclerosis

Incretin Hormones As Immunomodulators Of Atherosclerosis

Introduction Diabetes is global health problem with a prevalence of more than 285 million cases worldwide and an incidence that continues to increase. The vast majority of diabetic patients (~90–95%) suffer from type 2 diabetes (T2D), whereas type 1 diabetes (T1D), accounts for 5–10% and rare forms (i.e., genetic forms of diabetes, diabetes secondary to pancreatic diseases or surgery, as well as gestational diabetes) constitute the remaining subtypes (International Diabetes Federation, 2009). Cardiovascular complications represent the primary source of morbidity and mortality in diabetic subjects (Mazzone et al., 2008) and it is well known that diabetic milieu per se accelerates the course of atherosclerosis (Nogi et al., 2012). It is also well established that T2D is caused by a combination of insulin resistance in skeletal muscle, liver, and adipose tissues and impaired insulin secretion from the pancreatic islets (Stumvoll et al., 2005). Insulin resistance is the main feature of metabolic syndrome, which refers to the clustering of cardiovascular risk factors that include diabetes, obesity, dyslipidemia, and hypertension (Bajaj and Defronzo, 2003). In relation to insulin resistance, the mechanisms that can promote both atherogenesis and advanced plaque progression likely involve both systemic factors that promote these processes, particularly dyslipidemia, but also hypertension and a proinflammatory state as well as the effect of perturbed insulin signaling at the level of the intimal cells that participate in atherosclerosis (Bornfeldt and Tabas, 2011). There is extensive evidence indicating that insulin resistance increases the risk of coronary artery disease (CAD) even in the absence of hyperglycemia (DeFronzo, 2010). In vivo studies have provided data showing Continue reading >>

Treating Type Ii Diabetes - Pharmacology

Treating Type Ii Diabetes - Pharmacology

- [Voiceover] Type II diabetes receives a lot of attention in the laypress as a public health threat, as it affects about 10% of the global population, and is currently the eighth most common cause of death worldwide. As such, understanding how to treat type II diabetes is very important because if it's treated properly, one can avoid nearly all of the complications of type II diabetes and live a happy and healthy life. Now before we dive into the specific treatments, let's first discuss the glucose regulation pathway as it will help us to better understand the pharmacokinetics or the mechanisms of action for the different treatments of type II diabetes. Now in the center here is the blood glucose level, and as blood glucose levels increase, say after eating a meal, this is sensed by the pancreas, and the beta cells within the pancreas secrete insulin which acts on cells throughout the body to lower the blood glucose level. Then as blood glucose levels decrease, this is also sensed by the pancreas, and then the alpha cells secrete glucagon which acts to raise the blood glucose levels. And one of the mechanisms by which it does so is by promoting the conversion of glycogen to glucose in the liver which is then released into the blood stream. Now diabetes mellitus is a group of disorders that's caused by dysfunction of the insulin pathway resulting in an inability to lower blood glucose levels. And as you can see by this diagram, there are two main steps that must occur for this pathway to work properly. First, insulin must be secreted by the beta cells of the pancreas. Then second, the cells throughout the body must respond to insulin for it to have an effect. And this glucose regulation pathway can be thought of as similar to that of the temperature regulation in a buil 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 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

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 >>

Glucagon-like Peptide-1 Receptor Agonists For The Treatment Of Type 2 Diabetes Mellitus

Glucagon-like Peptide-1 Receptor Agonists For The Treatment Of Type 2 Diabetes Mellitus

INTRODUCTION Despite advances in options for the treatment of diabetes, optimal glycemic control is often not achieved. Hypoglycemia and weight gain associated with many antidiabetic medications may interfere with the implementation and long-term application of "intensive" therapies [1]. Current treatments have centered on increasing insulin availability (either through direct insulin administration or through agents that promote insulin secretion), improving sensitivity to insulin, delaying the delivery and absorption of carbohydrate from the gastrointestinal tract, or increasing urinary glucose excretion. Glucagon-like peptide-1 (GLP-1)-based therapies (eg, GLP-1 receptor agonists, dipeptidyl peptidase-4 [DPP-4] inhibitors) affect glucose control through several mechanisms, including enhancement of glucose-dependent insulin secretion, slowed gastric emptying, and reduction of postprandial glucagon and of food intake (table 1). These agents do not usually cause hypoglycemia in the absence of therapies that otherwise cause hypoglycemia. This topic will review the mechanism of action and therapeutic utility of GLP-1 receptor agonists for the treatment of type 2 diabetes mellitus. DPP-4 inhibitors are discussed separately. A general discussion of the initial management of blood glucose and the management of persistent hyperglycemia in adults with type 2 diabetes is also presented separately. (See "Dipeptidyl peptidase-4 (DPP-4) inhibitors for the treatment of type 2 diabetes mellitus" and "Initial management of blood glucose in adults with type 2 diabetes mellitus" and "Management of persistent hyperglycemia in type 2 diabetes mellitus".) GLUCAGON-LIKE PEPTIDE-1 Glucose homeostasis is dependent upon a complex interplay of multiple hormones: insulin and amylin, produced by Continue reading >>

Incretin Mimetics And Enhancers: Mechanisms Of Action

Incretin Mimetics And Enhancers: Mechanisms Of Action

The incretins are peptide hormones secreted from the gut in response to food. They increase the secretion of insulin. The incretin response is reduced in patients with type 2 diabetes, so drugs acting on incretins may improve glycaemic control. Incretins are metabolised by dipeptidyl peptidase, so selectively inhibiting this enzyme increases the concentration of circulating incretins. A similar effect results from giving an incretin analogue that cannot be cleaved by dipeptidyl peptidase. Physiology The incretins are peptide hormones. They are released into the circulation, in response to luminal nutrients, within minutes of eating. In humans, the major incretins are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 is secreted by the L cells in the ileum and colon, while GIP is secreted by the K cells in the duodenum. Both incretins have hormonal effects on multiple organs, notably the endocrine pancreas, the gut and the brain (Table 1). Their predominant role is regulation of energy homeostasis. They stimulate insulin secretion in a glucose-dependent manner, delay gastric emptying and suppress appetite. This combination of effects makes a significant contribution to glucose homeostasis, particularly the control of postprandial glucose. Subsequent studies have identified other actions including improvement in pancreatic β cell glucose sensitivity and, in animal studies, promotion of pancreatic β cell proliferation and reduction in β cell apoptosis. The circulating incretins act via specific G-protein-coupled receptors. There are clinically important differences in the tissue distribution of these receptors. The GLP-1 receptor is expressed in pancreatic islet a and β cells, heart, central nervous system, kidney, lung and g Continue reading >>

Incretin Mimetics And Dpp-iv Inhibitors: New Paradigms For The Treatment Of Type 2 Diabetes

Incretin Mimetics And Dpp-iv Inhibitors: New Paradigms For The Treatment Of Type 2 Diabetes

Abstract Incretin mimetics are a new class of pharmacological agents with multiple antihyperglycemic actions that mimic several of the actions of incretin hormones originating in the gut, such as glucagon-like peptide (GLP)-1. Dipeptidyl peptidase-IV (DPP-IV) inhibitors suppress the degradation of many peptides, including GLP-1, thereby extending their bioactivity. These agents seem to have multiple mechanisms of action for the treatment of type 2 diabetes mellitus (T2DM), including some or all the following: enhancement of glucose-dependent insulin secretion, suppression of inappropriately elevated glucagon secretion, slowing of gastric emptying, and decreased food intake. Exenatide (BYETTA®) is the first incretin mimetic approved for clinical use by the US Food and Drug Administration. In phase 3 clinical trials, exenatide reduced HbA1c by ∼1% and body weight by ∼2 kg in T2DM patients failing to achieve glycemic control with metformin and/or a sulfonylurea, with mild-to-moderate nausea the most common side effect. Several GLP-1 analogues and DPP-IV inhibitors are in late-stage clinical testing and may soon become available for treating T2DM patients. The use of these agents may provide an opportunity to bring about new improvements in diabetes care. 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 >>

Glucagon-like Peptide-1 (glp-1) Agonist - Incretin Mimetics

Glucagon-like Peptide-1 (glp-1) Agonist - Incretin Mimetics

The authors make no claims of the accuracy of the information contained herein; and these suggested doses and/or guidelines are not a substitute for clinical judgment. Neither GlobalRPh Inc. nor any other party involved in the preparation of this document shall be liable for any special, consequential, or exemplary damages resulting in whole or part from any user's use of or reliance upon this material. PLEASE READ THE DISCLAIMER CAREFULLY BEFORE ACCESSING OR USING THIS SITE. BY ACCESSING OR USING THIS SITE, YOU AGREE TO BE BOUND BY THE TERMS AND CONDITIONS SET FORTH IN THE DISCLAIMER. Products Albiglutide - TANZEUM™ inj. --> dulaglutide- TRULICITY ™ injection exenatide (Byetta ®) Liraglutide (Victoza®) Lixisenatide - Adlyxin™ injection --® Typical reductions in A1C values - Incretin Mimetics: 0.5 - 1.0%. Background Overview Secretagogues Insulin sensitizers Alpha-glucosidase inh Peptide analogs Drug UPDATES: TRULICITY ™ (dulaglutide) injection, for subcutaneous use [Drug information / PDF] Dosing: Click (+) next to Dosage and Administration section (drug info link) Initial U.S. Approval: 2014 Mechanism of Action: TRULICITY contains dulaglutide, which is a human GLP-1 receptor agonist with 90% amino acid sequence homology to endogenous human GLP-1 (7-37). Dulaglutide activates the GLP-1 receptor, a membrane-bound cell-surface receptor coupled to adenylyl cyclase in pancreatic beta cells. Dulaglutide increases intracellular cyclic AMP (cAMP) in beta cells leading to glucose-dependent insulin release. Dulaglutide also decreases glucagon secretion and slows gastric emptying. INDICATIONS AND USAGE: TRULICITY™ is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. 1.1 Limitations of Use TRULICITY is n Continue reading >>

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