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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The remission phase of Type 1 diabetes mellitus is associated with substantial recovery of beta-cell function and with marked improvement of endogenous insulin responses to meals in the early months after diagnosis, accompanied by little or no improvement in the insulin response to parenteral glucose, suggesting that the incretin function may be important in glycaemic regulation in this phase of diabetes. Preservation of the insulin response to parenteral glucagon-like peptide-1 (GLP-1), contrasting with lack of stimulation of insulin secretion by the other known incretin gastric inhibitory polypeptide (GIP), prompted studies with exogenous GLP-1 in recent-onset Type 1 diabetes. These studies showed substantial reduction of glycaemic excursions after ingestion of mixed nutrients during intravenous infusion of GLP-1 without administration of insulin, in subjects with a range of endogenous secretion of insulin in response to meals as demonstrated by blood levels of the insulin-connecting peptide (CP). These effects were independent of stimulation of blood levels of CP and were reproduced in volunteers with no endogenous release of CP in response to meals. The glycaemic effects were associated with inhibition of abnormal rises of blood levels of glucagon, and with suppression of endogenous release of human pancreatic polypeptide (HPP), by GLP-1. It was hypothesized that a major component of the glycaemic effect is attributable to the known action of GLP-1 to inhibit gastric emptying and to inhibit glucagon secretion. Studies of the effects of GLP-1 agonists (GLP-1 and exendin-4) given together with established insulin doses before a meal supported the hypothesis. The more prolonged actions of exendin-4 were accompanied by greater and more prolonged reduction of glycaemic effects of ingestion of meals in volunteers with CP-negative Type 1 diabetes mellitus, during intensive insulin therapy, in whom delay of gastric emptying was confirmed by studies of blood levels of acetaminophen ingested with the meals. Side effect-free doses of exendin-4 given together with insulin in volunteers with CP-negative Type 1 diabetes receiving continuing intensive insulin therapy demonstrated the capacity of this combination therapy to normalize blood glucose levels after ingestion of meals that were consistent with the dietary program of the volunteers, without apparent increased risk of hypoglycaemia within a normal between-meals interval. It is suggested that further and more prolonged studies of the use of long-acting GLP-1 agonists as congeners with insulin in Type 1 diabetes mellitus are indicated.
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PMID:Glycaemic effects of incretins in Type 1 diabetes mellitus: a concise review, with emphasis on studies in humans. 1578 Apr 34

Glucagon-like peptide 1 (GLP-1) has been proposed to act as an incretin hormone due to its ability to enhance glucose-stimulated insulin secretion. Because GLP-1 also decelerates gastric emptying, it physiologically reduces rather than augments postprandial insulin secretory responses. Therefore, we aimed to antagonize the deceleration of gastric emptying by GLP-1 to study its effects on insulin secretion after a meal. Nine healthy male volunteers (age 25 +/- 4 years, BMI 25.0 +/- 4.9 kg/m2) were studied with an infusion of GLP-1 (0.8 pmol.kg(-1).min(-1) from -30 to 240 min) or placebo. On separate occasions, the prokinetic drugs metoclopramide (10 mg), domperidone (10 mg), cisapride (10 mg, all at -30 min per oral), or erythromycin (200 mg intravenously from -30 to -15 min) were administered in addition to GLP-1. A liquid test meal (50 g sucrose and 8% mixed amino acids in 400 ml) was administered at 0 min. Capillary and venous blood samples were drawn for the determination of glucose (glucose oxidase), insulin, C-peptide, GLP-1, glucagon, gastric inhibitory polypeptide (GIP), and pancreatic polypeptide (specific immunoassays). Gastric emptying was assessed by the phenol red dilution technique. Statistical analyses were performed using repeated-measures ANOVA and Duncan's post hoc test. GLP-1 significantly decelerated the velocity of gastric emptying (P < 0.001). This was completely counterbalanced by erythromycin, whereas the other prokinetic drugs used had no effect. Postprandial glucose concentrations were lowered by GLP-1 (P < 0.001 vs. placebo), but this effect was partially reversed by erythromycin (P < 0.05). Insulin secretory responses to the meal were lower during GLP-1 administration (P < 0.05 vs. placebo). However, when erythromycin was added to GLP-1, insulin concentrations were similar to those in placebo experiments. The suppression of meal-related increments in glucagon secretion by GLP-1 was reversed by erythromycin (P < 0.001). The time course of GIP secretion was delayed during GLP-1 administration (P < 0.05), but when erythromycin was added, the pattern was similar to placebo experiments. GLP-1 administration led to a reduction in pancreatic polypeptide plasma concentrations (P < 0.05). In contrast, pancreatic polypeptide levels were markedly increased by erythromycin (P < 0.001). Intravenous erythromycin counteracts the deceleration of gastric emptying caused by GLP-1, probably by interacting with the parasympathetic nervous system (pancreatic polypeptide responses). Despite augmented rises in insulin secretion, the glucose-lowering effect of GLP-1 is markedly reduced when the deceleration of gastric emptying is antagonized, illustrating the importance of this facet of the multiple antidiabetic actions of GLP-1.
Diabetes 2005 Jul
PMID:Erythromycin antagonizes the deceleration of gastric emptying by glucagon-like peptide 1 and unmasks its insulinotropic effect in healthy subjects. 1598 24

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.
Diabetes 2005 Aug
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

Orally ingested glucose leads to a much higher insulin response than intravenous glucose leading to identical postprandial plasma glucose excursions. This phenomenon, termed ''incretin effect'' comprises up to 60% of the postprandial insulin secretion and is diminished in type 2 diabetes. The gastrointestinal hormones glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) promote the incretin effect. Type 2 diabetes is characterized by an incretin defect: while GIP does not stimulate insulin secretion, GLP-1 action is still preserved under supraphysiological concentrations. GLP-1 stimulates insulin secretion only under hyperglycaemic conditions, therefore it does not cause hypoglycaemia. Furthermore, GLP-1 inhibits glucagon secretion and delays gastric emptying. In vitro and animal data demonstrated that GLP-1 increases beta cell mass by stimulating islet cell neogenesis and by inhibiting apoptosis of islets. The improvement of beta cell function can be indirectly observed from the increased insulin secretory capacity of humans receiving GLP-1. In contrast to GIP, GLP-1 may represent an attractive therapeutic method for type 2 diabetes due to its multiple effects also including the simulation of satiety in the central nervous system by acting as transmitter or by crossing the blood brain barrier. Native GLP-1 is degraded rapidly upon intravenous or subcutaneous administration and is therefore not feasible for routine therapy. Long-acting GLP-1 analogs (e.g. Liraglutide) and exendin-4 (Exenatide, Byetta) that are resistant to degradation, called ''incretin mimetics'' are approved (Exenatide, Byetta) or in clinical trials. DPP-4-inhibitors (e.g. Vildagliptin), Sitagliptin and Saxagliptin) that inhibit the enzyme DPP-4 responsible for incretin degradation are also under study.
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PMID:Therapies for the treatment of type 2 diabetes mellitus based on incretin action. 1668 37

Glucose homeostasis is accomplished through intricate, and arguably, elegant interactions among several organs and hormones. Historically, glucose homeostasis has been viewed somewhat narrowly--insulin from pancreatic beta cells regulated glucose disposal, while glucagon from pancreatic alpha [corrected] cells regulated glucose appearance during fasting states. But more recent characterization and understanding of the role of incretin hormones from the gut--notably, glucagon-like peptide 1 and gastric inhibitory polypeptide--and amylin from pancreatic beta cells has led to a more complete model of glucose homeostasis. Furthermore, availability of pharmacologic agents to replace, mimic, or enhance the actions of these hormones allows application of this more complete model of glucose homeostasis to the treatment of type 1 and type 2 diabetes. This article provides an overview of the role of the pancreatic hormone amylin in glucose homeostasis and of Pramlintide, a analogue of native amylin, recently approved as adjunct therapy to insulin in people with type 1 and type 2 diabetes.
Diabetes Educ
PMID:The physiology of amylin and insulin: maintaining the balance between glucose secretion and glucose uptake. 1675 50

The incretin hormones gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are released in response to nutrient ingestion and potentiate glucose-stimulated insulin secretion from pancreatic beta cells. The augmentation of postprandial insulin secretion by such gastrointestinal hormones is called the incretin effect. The incretin effect is almost completely absent in patients with type 2 diabetes. This is due to 1) an approximate 15% reduction in postprandial GLP-1 secretion and 2) a near total loss of insulinotropic activity of GIP. This review article summarizes clinical studies on abnormalities in the secretion and insulinotropic effects of GIP and GLP-1 in patients with type 2 diabetes as well as in individuals at high risk. A significant proportion of first-degree relatives are characterized by a reduced insulinotropic response to exogenous GIP. Nevertheless, this phenomenon does not predispose to a more rapid deterioration in glucose tolerance or conversion to impaired glucose tolerance or diabetes. Therefore, although there are hints of early abnormalities in incretin secretion and action in prediabetic populations, it has not been proven that such phenomena are central to the pathogenesis of type 2 diabetes.
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PMID:Incretins and the development of type 2 diabetes. 1689 71

The actions of the structurally related proglucagon-derived peptides (PGDPs)-glucagon, glucagon-like peptide (GLP)-1 and GLP-2-are focused on complementary aspects of energy homeostasis. Glucagon opposes insulin action, regulates hepatic glucose production, and is a primary hormonal defense against hypoglycemia. Conversely, attenuation of glucagon action markedly improves experimental diabetes, hence glucagon antagonists may prove useful for the treatment of type 2 diabetes. GLP-1 controls blood glucose through regulation of glucose-dependent insulin secretion, inhibition of glucagon secretion and gastric emptying, and reduction of food intake. GLP-1-receptor activation also augments insulin biosynthesis, restores beta-cell sensitivity to glucose, increases beta-cell proliferation, and reduces apoptosis, leading to expansion of the beta-cell mass. Administration of GLP-1 is highly effective in reducing blood glucose in subjects with type 2 diabetes but native GLP-1 is rapidly degraded by dipeptidyl peptidase IV. A GLP-1-receptor agonist, exendin 4, has recently been approved for the treatment of type 2 diabetes in the US. Dipeptidyl-peptidase-IV inhibitors, currently in phase III clinical trials, stabilize the postprandial levels of GLP-1 and gastric inhibitory polypeptide and lower blood glucose in diabetic patients via inhibition of glucagon secretion and enhancement of glucose-stimulated insulin secretion. GLP-2 acts proximally to control energy intake by enhancing nutrient absorption and attenuating mucosal injury and is currently in phase III clinical trials for the treatment of short bowel syndrome. Thus the modulation of proglucagon-derived peptides has therapeutic potential for the treatment of diabetes and intestinal disease.
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PMID:Biologic actions and therapeutic potential of the proglucagon-derived peptides. 1692 63

Contradictory reports of gastric inhibitory polypeptide (GIP) responses in diabetes have been published by different workers using different radioimmunoassay systems. The present study was undertaken to assess GIP responses in type 2 diabetes using three antibodies (S100, GP01 and GP24). Seven untreated diabetics and seven healthy control subjects had a standard 50 g oral glucose tolerance test. An alcohol extract of plasma of each sample was assayed using these three different antibodies. Using S100, GIP responses in the diabetic group were significantly lower at 30' (P<0.025) and at 120' (P<0.01) and the integrated incremental GIP responses also were significantly lower in the diabetic group (P< 0.025). Using GP01, GIP responses in the diabetic group were significantly lower only 120' (P<0.05) but there was no significant difference in the integrated incremental GIP responses. Using GP24, there was no significant difference between the diabetic and control groups at any time intervals or in the integrated incremental responses. However, three to sixfold higher levels of GIP were recorded when using GP24 as compared with the other two antibody systems which gave similar absolute values. Structurally abnormal variable cross-reacting 5000 dalton (5 kDa) and 8 kDa GIP forms or still unidentified structurally GIP related peptides associated with type 2 diabetes might be responsible for these conflicting results.
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PMID:Gastric inhibitory polypeptide (GIP) responses in type 2 diabetes using three different antibodies. 1759 Jun 99

The gut hormone gastric inhibitory polypeptide (GIP) plays a key role in glucose homeostasis and lipid metabolism. This study investigated the effects of administration of a stable and specific GIP receptor antagonist, (Pro(3))GIP, in mice previously fed a high-fat diet for 160 days to induce obesity and related diabetes. Daily intraperitoneal injection of (Pro(3))GIP over 50 days significantly decreased body weight compared with saline-treated controls, with a modest increase in locomotor activity but no change of high-fat diet intake. Plasma glucose, glycated hemoglobin, and pancreatic insulin were restored to levels of chow-fed mice, and circulating triglyceride and cholesterol were significantly decreased. (Pro(3))GIP treatment also significantly decreased circulating glucagon and corticosterone, but concentrations of GLP-1, GIP, resistin, and adiponectin were unchanged. Adipose tissue mass, adipocyte hypertrophy, and deposition of triglyceride in liver and muscle were significantly decreased. These changes were accompanied by significant improvement of insulin sensitivity, meal tolerance, and normalization of glucose tolerance in (Pro(3))GIP-treated high-fat-fed mice. (Pro(3))GIP concentrations peaked rapidly and remained elevated 24 h after injection. These data indicate that GIP receptor antagonism using (Pro(3))GIP provides an effective means of countering obesity and related diabetes induced by consumption of a high-fat, energy-rich diet.
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PMID:GIP receptor antagonism reverses obesity, insulin resistance, and associated metabolic disturbances induced in mice by prolonged consumption of high-fat diet. 1784 29

The association of obesity with type 2 diabetes mellitus has been recognized for years. In type 2 diabetes, there is a possibility that an important part of the impaired insulin secretion is due to the gastric inhibitory polypeptide (GIP) hormone. This study investigated changes that occur in the pancreatic GIP receptors' (GIP-Rs) expression and in GIP secretion in obese and type 2 diabetic rats and its relation to plasma glucose and insulin levels during oral glucose tolerance test (OGTT) compared to control rats. During the first 20 min of the OGTT, both the obese and the diabetic rats had a significant increase in the glucose excursion and a significant decrease in early-insulin secretion compared to the control group, with more prominent changes in the diabetic group. The obese rats had a significant increase in fasting GIP level and in the incremental change of GIP from 0 to 20 min (GIP Delta 0-20: 60.1 + or - 6.66 pmol/l) compared to that of the control (33.96 + or - 4.69 pmol/l) and the diabetic (29.34 + or - 2.62 pmol/l) group, which were not significantly different from each other. However, there was a significant decrease in GIP-Rs expression in both the obese (88.07 + or - 10.36 microg/ml) and diabetic (87.51 + or - 4.72 microg/ml) groups compared to the control group (120.35 + or - 8.06 microg/ml). During the second hour of the OGTT, plasma GIP was decreasing in all groups, however, the obese group had a significant hyperinsulinemia compared to the other two groups. Moreover, the diabetic group had a significantly lower plasma insulin level until the 90 min interval and thereafter it showed a non-significant difference compared to the control group. In conclusion, both obese and diabetic rats had an impaired early-phase insulinotropic effect of GIP due to impaired gene expression of GIP-Rs which could be a potential target to prevent transition of obesity to diabetes and to improve insulin secretion in the latter.
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PMID:Impairment of the insulinotropic effect of gastric inhibitory polypeptide (GIP) in obese and diabetic rats is related to the down-regulation of its pancreatic receptors. 1806 45


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