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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Incretins such as glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are intestinal postprandial hormones that stimulate insulin release from the pancreas as long as circulating glucose concentrations are raised. In addition to their effect on insulin secretion and consequent glucose lowering, GIP and GLP-1, especially the latter, have a number of physiological effects such as inhibition of glucagon release, gastric emptying and food intake, as well as a tropic action on pancreatic B-cell mass. There is currently a pandemic of obesity and diabetes, and existing treatments are largely inadequate both in regard to efficacy as well as their ability to tackle important factors in the pathogenesis of type 2 diabetes (T2D). There is increasing evidence that current treatments do not address the issue of progressive B-cell failure in T2D. Since obesity is the engine that is driving the epidemic of diabetes, it is disappointing that most treatments that succeed in lowering plasma glucose are also associated with weight gain. It is now well established that intensively treated T2D has a better outcome than standard treatment. Consequently, achieving better control of diabetes with lower HbA1c is the goal of optimal treatment. Despite the use of usual therapeutic agents in T2D, often in high doses and as combinations, such as metformin, sulphonylurea, alpha-glycosidase inhibitors, thiazolidinediones and a number of animal and human insulin preparations, optimal control of glycaemia is not achieved. The use of incretins as therapeutic agents offers a new approach to the treatment of T2D.
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PMID:Incretins: pathophysiological and therapeutic implications of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1. 1837 45

Gastric inhibitory polypeptide (GIP) is an incretin and directly promotes fat accumulation in adipocytes. Inhibition of GIP signaling prevents onset of obesity and increases fat oxidation in peripheral tissues under high-fat diet (HFD), but the mechanism is unknown. In the present study, we investigated the effects of inhibition of GIP signaling on adiponectin levels after 3 weeks of HFD by comparing wild-type (WT) mice and GIP receptor-deficient (Gipr(-/-)) mice. In HFD-fed Gipr(-/-) mice, fat oxidation was significantly increased and adiponectin mRNA levels in white adipose tissue and plasma adiponectin levels were significantly increased compared to those in HFD-fed WT mice. In addition, the PPARalpha mRNA level was increased and the ACC mRNA level was decreased in skeletal muscle of HFD-fed Gipr(-/-) mice compared with those in HFD-fed WT mice. These results indicate that inhibition of GIP signaling increases adiponectin levels, resulting in increased fat oxidation in peripheral tissues under HFD.
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PMID:Inhibition of GIP signaling modulates adiponectin levels under high-fat diet in mice. 1872 1

This paper briefly reviews the concept of incretins and describes the biological effects of the two incretins identified so far: the glucose-dependent insulinotropic polypeptide (GIP); and the glucagon-like peptide-1 (GLP-1). GIP is released by the Kcells of the duodenum, while GLP-1 is released by the Lcells of the distal ileum, in response to nutrient absorption. GIP and GLP-1 stimulate insulin biosynthesis and insulin secretion in a glucose-dependent manner. In addition, they increase beta-cell mass. GIP has a specific effect on adipose tissue to facilitate the efficient disposal of absorbed fat and, thus, may be involved in the development of obesity. GLP-1 has specific effects on pancreatic alpha cells, the hypothalamus, and gastrointestinal and cardiovascular systems. By inhibiting glucagon secretion and delaying gastric-emptying, GLP-1 plays an important role in glucose homoeostasis and, by inhibiting food intake, prevents the increase in body weight. As the metabolic effects of GIP are blunted in type 2 diabetes, this peptide cannot be used as an efficient therapy for diabetes. In contrast, GLP-1 effects are preserved at high concentrations in type 2 diabetes, making this peptide of great interest for the treatment of diabetes, a topic that will be discussed in the second part of this review.
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PMID:The incretins: from the concept to their use in the treatment of type 2 diabetes. Part A: incretins: concept and physiological functions. 1903 24

Orlistat, an inhibitor of digestive lipases, is widely used for the treatment of obesity. Previous reports on the effect of orally ingested orlistat together with a meal on gastric emptying and secretion of gut peptides that modulate postprandial responses are controversial. We investigated the effect of ingested orlistat on gastric emptying and plasma responses of gut peptides in response to a solid mixed meal with a moderate energy load. In healthy subjects, gastric emptying was determined using scintigraphy and studies were performed without and with 120 mg of orlistat in pellet form in random order. Orlistat shortened t lag and t half and decreased the area under the gastric emptying curve. Orlistat significantly attenuated the secretion of glucose-dependent insulinotropic polypeptide (GIP) but did not alter the plasma responses of cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), pancreatic polypeptide (PP), and insulin. There was no peptide YY (PYY) response. Area under the curve of gastric emptying was positively correlated with integrated secretion of GIP (r=0.786) in orlistat and was negatively correlated with integrated plasma response of GLP-1 (r=-0.75) in control experiments, implying that inhibition of fat absorption modifies determinants of gastric emptying of a meal. Orlistat administered similar to its use in obesity treatment accelerates gastric emptying of a solid mixed meal with a moderate energy load and profoundly attenuates release of GIP without appreciably altering plasma responses of CCK, GLP-1, and PP. Since GIP is being implemented in the development of obesity, its role in weight control attained by orlistat awaits further investigation.
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PMID:Orlistat accelerates gastric emptying and attenuates GIP release in healthy subjects. 1910 8

Gastric inhibitory polypeptide (GIP) is a physiological gut peptide secreted from the intestinal K-cells with well documented insulin-releasing actions. However, the GIP receptor is widely distributed in peripheral organs, including the pancreas, gut, adipose tissue, heart, adrenal cortex and brain, suggesting that it may have other functions. The presence of functional GIP receptors on adipocytes and the key role played by GIP in lipid metabolism and fat deposition suggest a possible beneficial effect of compromised GIP action in obesity and insulin resistance. Several key observations in animal models of obesity-related diabetes with chemically or genetically mediated biological GIP deficiency support this concept. Thus, obese diabetic animals with compromised GIP action due to peptide-based GIP receptor antagonists, small molecular weight GIP receptor antagonists, vaccination against GIP, genetic knockout of GIP receptor or targeted K-cell destruction are protected against obesity and associated metabolic disturbances. In addition, by causing preferential oxidation of fat, blockade of GIP signalling clears triacylglycerol deposits from liver and muscle, thereby restoring mechanisms for suppression of hepatic glucose output and improving insulin sensitivity. Emerging evidence also suggests that rapid cure of diabetes in grossly obese patients undergoing bypass surgery is mediated, in part, by surgical removal of GIP-secreting K-cells in the upper small intestine.
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PMID:Evidence for beneficial effects of compromised gastric inhibitory polypeptide action in obesity-related diabetes and possible therapeutic implications. 1953 83

The incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), are produced predominantly by enteroendocrine cells and have multiple blood glucose-lowering effects. Recent years have seen a surge of interest in understanding the basic physiology and pathophysiology of incretins and in applying this knowledge to the treatment of diabetes and obesity. Considerable gains have been made in elucidating the mechanisms controlling incretin secretion, and there is growing evidence to suggest that incretins might be involved in the rapid reversal of diabetes observed in gastric bypass patients. Here, we review these recent advances and outline the multiple strategies being pursued to exploit the potential therapeutic benefits of GIP and GLP-1.
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PMID:Mining incretin hormone pathways for novel therapies. 1959 11

Glucose-dependent insulinotropic polypeptide (GIP or gastric inhibitory polypeptide) is a 42-amino-acid hormone, secreted from the enteroendocrine K cells, which has insulin-releasing and extrapancreatic glucoregulatory actions. However, the unfavourable pharmacokinetic profile and the weak biological effects of native GIP limit its effectiveness for the treatment of type 2 diabetes. To overcome this, longer-acting GIP agonists exhibiting enzymatic stability and enhanced bioactivity have been generated and successfully tested in animal models of diabetes. Thus, GIP receptor agonists offer one of the newest classes of potential antidiabetic drug. GIP is also known to play a role in lipid metabolism and fat deposition. Accordingly, both genetic and chemical ablation of GIP signalling in mice with obesity-diabetes can protect against, or even reverse many of the obesity-associated metabolic disturbances. Strong parallels exist with the beneficial metabolic effects of Roux-en-Y gastric bypass in obese, insulin-resistant humans that surgically ablates GIP-secreting K cells. The purpose of this article is to highlight the therapeutic potential of GIP-based therapeutics in the treatment of type 2 diabetes and obesity.
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PMID:Therapeutic potential for GIP receptor agonists and antagonists. 1974 67

Chemically modified starches (CMS) are RS4-type resistant starch, which shows a reduced availability, as well as high-amylose corn starch (HACS, RS2 type), compared with the corresponding unmodified starch. Previous studies have shown that RS4 increases fecal excretion of bile acids and reduces zinc and iron absorption in rats. The aim of this study was to investigate the effects of dietary RS4 supplementation on the development of diet-induced obesity in mice. Weight- and age-matched male C57BL/6J mice were fed for 24 wk on a high-fat diet containing unmodified starch, hydroxypropylated distarch phosphate (RS4), or HACS (RS2). Those fed the RS4 diet had significantly lower body weight and visceral fat weight than those fed either unmodified starch or the RS2 diet. Those fed the RS4 diet for 4 wk had a significantly higher hepatic fatty acid oxidation capacity and related gene expression and lower blood insulin than those fed either unmodified starch or the RS2 diet. Indirect calorimetry showed that the RS4 group exhibited higher energy expenditure and fat utilization compared with the RS2 group. When gavaged with fat (trioleate), RS4 stimulated a lower postprandial glucose-dependent insulinotropic polypeptide (GIP; incretin) response than RS2. Higher blood GIP levels induced by chronic GIP administration reduced fat utilization in high-fat diet-fed mice. In conclusion, dietary supplementation with RS4-type resistant starch attenuates high-fat diet-induced obesity more effectively than RS2 in C57BL/6J mice, which may be attributable to lower postprandial GIP and increased fat catabolism in the liver.
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PMID:RS4-type resistant starch prevents high-fat diet-induced obesity via increased hepatic fatty acid oxidation and decreased postprandial GIP in C57BL/6J mice. 2000 28

Consumption of a diet high in barley beta-glucan (BG) has been shown to prevent insulin resistance. To investigate the mechanism for the effects of barley BG, three groups of male 7-wk-old C57BL/6J mice were fed high-fat diets containing 0, 2, or 4% of barley BG for 12 wk. The 2% BG and 4% BG groups had significantly lower body weights compared with the 0% BG group. The 4% BG group demonstrated improved glucose tolerance and lower levels of insulin-resistance index and glucose-dependent insulinotropic polypeptide. Consumption of the BG diet decreased hepatic lipid content. Mice on the BG diet also demonstrated decreased fatty acid synthase and increased cholesterol 7alpha-hydroxylase gene expression levels. The BG diet promoted hepatic insulin signaling by decreasing serine phosphorylation of insulin receptor substrate 1 and activating Akt, and it decreased mRNA levels of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. In summary, consumption of BG reduced weight gain, decreased hepatic lipid accumulation, and improved insulin sensitivity in mice fed a high-fat diet. Insulin signaling enhanced due to the expression changes of glucose and lipid metabolism genes by BG consumption. Consumption of barley BG could be an effective strategy for preventing obesity, insulin resistance, and the metabolic syndrome.
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PMID:Consumption of barley beta-glucan ameliorates fatty liver and insulin resistance in mice fed a high-fat diet. 2011 96

Type 2 diabetes (T2DM) is a heterogeneous syndrome, characterized by beta-cell failure in the setting of obesity-related insulin resistance. T2DM has a progressive course and is associated with a high cardiovascular disease (CVD) risk, regardless of the treatment used. The incretin hormones glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) are secreted in the gut upon meal ingestion and lower blood glucose by glucose-dependent stimulation of insulin secretion and production. Exogenously administered GLP-1 lowers postprandial glucose excursions by inhibiting glucagon secretion and delaying gastric emptying, improves beta-cell function, and promotes satiety and weight loss. Native GLP-1 is degraded rapidly by the ubiquitous enzyme dipeptidyl-peptidase (DPP)-4. Thus, injectable DPP-4-resistant GLP-1 receptor agonists (GLP-1RA) and oral DPP-4 inhibitors have been developed. Exenatide is the first GLP-1RA that became available for the treatment of T2DM patients. Exenatide has unique characteristics, as to date it is the only agent that addresses the multiple defects of the T2DM phenotype, including hyperglycaemia, islet-cell dysfunction, alimentary obesity, insulin resistance, hypertension and dyslipidaemia. In animals, exenatide also increased beta-cell mass. Long-term prospective studies in high-risk populations should address the potentially disease modifying effect of exenatide and its effect on CVD risk, in addition to its safety and tolerability.
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PMID:Does glucagon-like peptide-1 receptor agonist therapy add value in the treatment of type 2 diabetes? Focus on exenatide. 2011 29


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