UMLS:C0011860 - FACTA Search

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Query: UMLS:C0011860 (type 2 diabetes)
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Glucose-dependent insulinotropic polypeptide (gastric inhibitory polypeptide [GIP]) is an important incretin hormone secreted by endocrine K-cells in response to nutrient ingestion. In this study, we investigated the effects of chemical ablation of GIP receptor (GIP-R) action on aspects of obesity-related diabetes using a stable and specific GIP-R antagonist, (Pro3)GIP. Young adult ob/ob mice received once-daily intraperitoneal injections of saline vehicle or (Pro3)GIP over an 11-day period. Nonfasting plasma glucose levels and the overall glycemic excursion (area under the curve) to a glucose load were significantly reduced (1.6-fold; P < 0.05) in (Pro3)GIP-treated mice compared with controls. GIP-R ablation also significantly lowered overall plasma glucose (1.4-fold; P < 0.05) and insulin (1.5-fold; P < 0.05) responses to feeding. These changes were associated with significantly enhanced (1.6-fold; P < 0.05) insulin sensitivity in the (Pro3)GIP-treated group. Daily injection of (Pro3)GIP reduced pancreatic insulin content (1.3-fold; P < 0.05) and partially corrected the obesity-related islet hypertrophy and beta-cell hyperplasia of ob/ob mice. These comprehensive beneficial effects of (Pro3)GIP were reversed 9 days after cessation of treatment and were independent of food intake and body weight, which were unchanged. These studies highlight a role for GIP in obesity-related glucose intolerance and emphasize the potential of specific GIP-R antagonists as a new class of drugs for the alleviation of insulin resistance and treatment of type 2 diabetes.
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PMID:Chemical ablation of gastric inhibitory polypeptide receptor action by daily (Pro3)GIP administration improves glucose tolerance and ameliorates insulin resistance and abnormalities of islet structure in obesity-related diabetes. 1604 12

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 a candidate as a therapeutic agent for this disease. A number of pharmacological strategies have been developed to provide continuous delivery of GLP-1 and to prevent degradation of GLP-1, including continuous administration of GLP-1, DPP-IV inhibitors and DPP-IV resistant GLP-1 analogues. Recent results of the most clinically advanced incretin mimetics confirmed their efficacy to improve glycemic control in type 2 diabetic patients. Further results are expected to confirm the efficacy/safety profile of these compounds, and to find their place in the therapeutic strategy of type 2 diabetes.
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PMID:Biological actions of the incretins GIP and GLP-1 and therapeutic perspectives in patients with type 2 diabetes. 1614 14

Among the products of enteroendocrine cells are the incretins glucagon-like peptide-1 (GLP-1, secreted by L cells) and glucose-dependent insulinotropic peptide (GIP, secreted by K cells). These are key modulators of insulin secretion, glucose homeostasis, and gastric emptying. Because of the rapid early rise of GLP-1 in plasma after oral glucose, we wished to definitively establish the absence or presence of L cells, as well as the relative distribution of the incretin cell types in human duodenum. We confirmed the presence of proglucagon and pro-GIP genes, their products, and glucosensory molecules by tissue immunohistochemistry and RT-PCR of laser-captured, single duodenal cells. We also assayed plasma glucose, incretin, and insulin levels in subjects with normal glucose tolerance and type 2 diabetes for 120 min after they ingested 75 g of glucose. Subjects with normal glucose tolerance (n=14) had as many L cells (15+/-1), expressed per 1,000 gut epithelial cells, as K cells (13+/-1), with some containing both hormones (L/K cells, 5+/-1). In type 2 diabetes, the number of L and L/K cells was increased (26+/-2; P<0.001 and 9+/-1; P < 0.001, respectively). Both L and K cells contained glucokinase and glucose transporter-1, -2, and -3. Newly diagnosed type 2 diabetic subjects had increased plasma GLP-1 levels between 20 and 80 min, concurrently with rising plasma insulin levels. Significant coexpression of the main incretin peptides occurs in human duodenum. L and K cells are present in equal numbers. New onset type 2 diabetes is associated with a shift to the L phenotype.
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PMID:Human duodenal enteroendocrine cells: source of both incretin peptides, GLP-1 and GIP. 1621 66

This chapter describes a physiological and profound effect of amylin to inhibit meal-related glucagon secretion. Glucagon is processed from a large precursor, proglucagon, in a tissue-specific manner in pancreatic alpha-cells. In addition to amino acid nutrient stimuli, glucagon is also secreted in response to stressful stimuli, such as hypoglycemia and hypovolemia. Glucagon primarily acts on liver to initiate glycogenolysis and gluconeogenesis, resulting in a rapid increase in endogenous production of glucose. With longer stimulation, glucagon action at the liver results in a glucose-sparing activation of free fatty acid oxidation and production of ketones. During hypoglycemia, glucagon secretion is clearly a protective feed-back, defending the organism against damaging effects of low glucose in brain and nerves (neuroglycopenia). Amino acid-stimulated glucagon secretion during meals has a different purpose: amino acids stimulate insulin secretion, which mobilizes amino acid transporters and effects their storage in peripheral tissues. At the same time, insulin obligatorily recruits GLUT4 glucose transporters in muscle and fat. The hypoglycemic potential of such GLUT4 mobilization is averted only by the simultaneous liberation of endogenous glucose in response to feedforward (anticipatory) glucagon secretion. The effect of amylin and its agonists to inhibit amino acid-stimulated glucagon secretion is both potent (EC50 = 18 pM) and profound (approximately 70% inhibition). This glucagonostatic action appears to be extrinsic to the pancreatic islet, occurring in intact animals and in patients, but not in isolated islets or isolated perfused pancreas preparations. On the other hand, the effect of hypoglycemia to stimulate glucagon secretion, which is intrinsic to the islet and occurs in isolated preparations, is not affected by amylin or its agonists. The physiological interpretation of these actions fits with the general concept, illustrated in Fig. 1, that amylin and insulin secreted in response to meals shut down endogenous production as a source of glucose, in favor of that derived from the meal. Amylin and insulin secreted in response to nutrients already absorbed act as a feedback switch for glucose sourcing. The insulinotropic (incretin) gut peptides, GLP-1 and GIP, secreted in response to yet-to-be-absorbed intraluminal nutrients, amplify beta-cell secretion and thereby activate the glucose sourcing switch in a feedforward manner. Hypoglycemia-stimulated glucagon secretion and nutrient (amino acid)-stimulated glucagon secretion are two clearly different processes, differently affected by amylin. The balance of glucose fluxes is disturbed in diabetic states, partly as a result of inappropriate glucagon secretion. Although glucose production due to glucagon secreted in response to hypoglycemia is normal or even reduced in diabetic patients, the secretion of glucagon (and production of endogenous glucose) in response to protein meals is typically exaggerated. Absence of appropriate beta-cell suppression of alpha-cell secretion has been invoked as a mechanism that explains exaggerated glucagon responses, especially prevalent in patients with deficient beta-cell secretion (type 1 diabetes and insulinopenic type 2 diabetes). A proposed benefit of insulin replacement therapy is the reduction of absolute or relative hyperglucagonemia. High glucagon is said to be necessary for ketosis in severe forms of diabetes. A further benefit of reversing hyperglucagonemia is reduction of the excessive endogenous glucose production that contributes to fasting and postprandial hyperglycemia in diabetes. The idea that amylin is a part of the beta-cell drive that normally limits glucagon secretion after meals fits with the observation that glucagon secretion is exaggerated in amylin-deficient states (diabetes characterized by beta-cell failure). This proposal is further supported by the observation that postprandial glucagon suppression is restored following amylin replacement therapy in such states. These observations argue for a therapeutic case for amylin replacement in patients in whom excess glucagon action contributes to fasting and postprandial hyperglycemia and ketosis. The selectivity of amylin's glucagonostatic effect (wherein it is restricted to meal-related glucagon secretion, while preserving glucagon secretion and glucagon action during hypoglycemia) may confer additional benefits; the patient population amenable to amylin replacement therapy is likely to also be receiving insulin replacement therapy, and is thereby susceptible to insulin-induced hypoglycemia. Most explorations of the biology of amylin have used the endogenous hormone in the cognate species (typically rat amylin in rat studies). Clinical studies have typically employed the amylinomimetic agent pramlintide. Studies of amylinomimetic effects on glucagon secretion include effects of rat amylin in anesthetized non-diabetic rats (Jodka et al., 2000; Parkes et al., 1999; Young et al., 1995), effects of rat amylin in isolated perfused rat pancreas (Silvestre et al., 1999), effects of pramlintide in anesthetized non-diabetic rats (Gedulin et al., 1997b,c,d, 1998), effects of pramlintide in patients with type l diabetes (Fineman et al., 1997a,b,c,d, 1998a; Holst, 1997; Nyholm et al., 1996, 1997a,b,c; Orskov et al., 1999; Thompson and Kolterman, 1997), and effects in patients with type 2 diabetes (Fineman et al., 1998b). In addition, effects of amylin antagonists have been observed in isolated preparations (Silvestre et al., 1996), and effects of antagonists or neutralizing antibody have been determined in whole-animal preparations (Gedulin et al., 1997a,e,f).
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PMID:Inhibition of glucagon secretion. 1649 45

GLP-1 and GIP are insulin-releasing 'incretin' hormones inactivated following degradation by dipeptidyl peptidase IV. Incretin hormone analogues resistant to degradation by DPP IV, as well as, inhibitors of DPP IV are in development as novel treatments for type 2 diabetes. The biguanide metformin is an oral agent commonly prescribed to treat type 2 diabetes. Antidiabetic actions of metformin involve the reduction of hepatic glucose production and/or insulin resistance. Recent reports indicate that metformin may have the additional property of inhibiting DPP IV activity. Here we examine the effects of metformin on plasma DPP IV activity of normal and ob/ob diabetic mice. DPP IV activity present in mouse plasma was concentration-dependently inhibited by metformin generating IC(50) values of 38 microM for normal mice and 29 microM for ob/ob mice. In vivo metformin lowered plasma DPP IV activity in ob/ob mice, and improved glucose-lowering and insulin-releasing effects of exogenous GLP-1 administration. This was associated with increased circulating concentrations of active GLP-1(7-36)amide. In contrast metformin had minor effects on in vitro GLP-1-stimulated insulin release from clonal beta cells. Long-term (12 day) oral metformin administration to ob/ob mice resulted in lower DPP IV activity but had no effect on basal glucose and insulin levels. These findings indicate that metformin decreases the plasma DPP IV activity, limiting the inactivation of exogenously administered GLP-1 and improving glycaemic control.
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PMID:Inhibition of dipeptidyl peptidase-IV activity by metformin enhances the antidiabetic effects of glucagon-like peptide-1. 1694 66

Dipeptidyl peptidase IV (DPP4) deactivates glucose-regulating hormones such as GLP-1 and GIP, thus, DPP4 inhibition has become a useful therapy for type 2 diabetes. Optimization of the high-throughput screening lead 6 led to the discovery of 25 (ABT-341), a highly potent, selective, and orally bioavailable DPP4 inhibitor. When dosed orally, 25 dose-dependently reduced glucose excursion in ZDF rats. Amide 25 is safe in a battery of in vitro and in vivo tests and may represent a new therapeutic agent for the treatment of type 2 diabetes.
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PMID:Discovery of ((4R,5S)-5-amino-4-(2,4,5- trifluorophenyl)cyclohex-1-enyl)-(3- (trifluoromethyl)-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone (ABT-341), a highly potent, selective, orally efficacious, and safe dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. 1706 63

Oral administration of glucose stimulates insulin secretion to a greater extent than does glucose administered as an isoglycaemic intravenous glucose infusion. This phenomenon is called the incretin effect and is caused by the two incretin hormones GIP and GLP-1. In patients with type 2 diabetes, the incretin effect is impaired. The mechanisms of the impaired incretin effect have been found to involve reduced secretion of GLP-1 and a severely impaired effect of GIP. It is currently unknown whether these defects are consequences of the diabetic state or primary pathogenetic factors.
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PMID:[Effect of incretin hormones GIP and GLP-1 for the pathogenesis of type 2 diabetes mellitus]. 1755 92

Dipeptidyl peptidase IV (DPP IV) is the primary inactivator of glucoregulatory incretin hormones. This has lead to development of DPP IV inhibitors as a new class of agents for the treatment of type 2 diabetes. Recent reports indicate that other antidiabetic drugs, such as metformin, may also have inhibitory effects on DPP IV activity. In this investigation we show that high concentrations of several antidiabetic drug classes, namely thiazolidinediones, sulphonylureas, meglitinides and morphilinoguanides can inhibit DPP IV. The strongest inhibitor nateglinide, the insulin-releasing meglitinide was effective at low therapeutically relevant concentrations as low as 25 micromol/l. Nateglinide also prevented the degradation of glucagon-like peptide-1 (GLP-1) by DPP IV in a time and concentration-dependent manner. In vitro nateglinide and GLP-1 effects on insulin release were additive. In vivo nateglinide improved the glucose-lowering and insulin-releasing activity of GLP-1 in obese-diabetic ob/ob mice. This was accompanied by significantly enhanced circulating concentrations of active GLP-1(7-36)amide and lower levels of DPP IV activity. Nateglinide similarly benefited the glucose and insulin responses to feeding in ob/ob mice and such actions were abolished by co-administration of exendin(9-39) and (Pro(3))GIP to block incretin hormone action. These data indicate that the use of nateglinide as a prandial insulin-releasing agent may partly rely on inhibition of GLP-1 degradation as well as beta-cell K(ATP) channel inhibition.
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PMID:Effects of antidiabetic drugs on dipeptidyl peptidase IV activity: nateglinide is an inhibitor of DPP IV and augments the antidiabetic activity of glucagon-like peptide-1. 1757 70

The two incretin hormones GLP-1 (Glucagon-Like Peptide-1) and GIP (Glucose-dependent Insulinotropic Peptide) are released by the gut in response to nutrient ingestion. Both of them potentiate glucose-induced insulin response, enhance insulin biosynthesis and, at least in rodents, preserve beta-cell mass through reduction of apoptosis and stimulation of beta-cell proliferation. In addition to its insulinotropic action, GLP-1 (but not GIP) suppresses glucagon secretion, delays gastric emptying and promotes satiety. Since in type 2 diabetes, the secretion of GLP-1 is dramatically reduced whereas its effects are retained, a number of pharmacological strategies aiming at restoring the incretin activity of this peptide have been explored. Because GLP-1 is rapidly degraded by the ubiquitous enzyme, dipeptidyl peptidase-IV (DPP-IV) and has a very short-lived action, DPP-IV resistant mimetics have been designed. Several randomized placebo-controlled studies with DPP-IV resistant GLP-1 analogues confirmed their efficacy to improve glycemic control in type 2 diabetic patients. The first one, exenatide, has been approved by the Food and Drug Administration (FDA) in 2005 for the treatment of type 2 diabetes. Longer-acting mimetics requiring only one injection per day or even per week are currently assessed in phase 3 trials. Another successful approach has been the development of orally active DPP-IV inhibitors which reversibly and selectively block the enzymatic activity. Many small-molecule DPP-IV inhibitors, called gliptins, have been shown to be effective as antihyperglycemic agents and, up to now, devoid of major adverse events. The first drug of this new therapeutic class having received FDA approval, sitagliptin, is now available for the treatment of type 2 diabetes in U.S. However, the efficacy/safety profile of these compounds and their positioning in the therapeutic algorithm of type 2 diabetes remains to be defined.
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PMID:[The incretin effect: a new therapeutic target in type 2 diabetes]. 1795 29

Incretins are hormones produced in the intestine that are released in response to oral intake of nutrients, above all carbohydrates. They are powerful secretors that increase insulin release. The two most important incretin hormones are GIP (glucose-dependent insulinotropic peptide; also known as gastric inhibitory peptide) and GLP-1 (glucagon-like peptide-1). GLP-1 not only stimulates insulin secretion but also reduces glucagon release, slows gastric emptying, improves insulin sensitivity and increases satiety. Other nutrients may also stimulate insulin secretion: oleic acid and serum protein. Currently a new therapeutic armamentarium focused on the role of incretins is being developed to improve the treatment of type 2 diabetes mellitus (DM 2).
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PMID:[GLP-1. Generalities and incretin-nutrient interaction]. 1798 96

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