Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is increasing realization that gastric inhibitory polypeptide (GIP) has actions outside of the pancreas and gastrointestinal tract. Most significant is the presence of functional GIP receptors on adipocytes and the appreciation that GIP, secreted strongly in response to fat ingestion, plays a role in the translation of excessive amounts of dietary fat into adipocyte tissue stores. Such effects open up the possibility of exploiting GIP receptor antagonism for the treatment of obesity and insulin resistance. This is borne out by studies in high-fat-fed mice or ob/ob mice with either genetic knockout of GIP receptor or chemical ablation of GIP action using the GIP receptor antagonist, (Pro3)GIP. By causing preferential oxidation of fat, blockade of GIP signalling clears triglyceride deposits from liver and muscle, thereby respectively restoring mechanisms for suppression of hepatic glucose output and cellular glucose uptake. Further studies are needed to determine the applicability of this research to human obesity-diabetes. However, proof of concept is provided by emerging evidence that rapid cure of diabetes in grossly obese subjects undergoing Roux-en-Y bypass surgery is mediated in part by surgical bypass of GIP-secreting K-cells in the upper small intestine.
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PMID:Dorothy Hodgkin Lecture 2008. Gastric inhibitory polypeptide (GIP) revisited: a new therapeutic target for obesity-diabetes? 1851 8

Recent research suggests that long-term ablation of gastric inhibitory polypeptide (GIP) receptor signalling can reverse or prevent many of the metabolic abnormalities associated with dietary and genetically induced obesity-diabetes. The present study was designed to assess the sub-chronic effects of passive or active immunisation against GIP in ob/ob mice. Initial acute administration of GIP antibody together with oral glucose in ob/ob mice significantly increased the glycaemic excursion compared to controls (p<0.05). This was associated with a significant reduction (p<0.05) in the overall glucose-mediated insulin response. However, sub-chronic passive GIP immunisation was not associated with any changes in body weight, food intake or metabolic control. In contrast, active immunisation against GIP for 56 days in young ob/ob mice resulted in significantly (p<0.05) reduced circulating plasma glucose concentrations on day 56 compared to controls. There was a tendency for decreased circulating insulin in GIP immunised mice. The glycaemic response to intraperitoneal glucose was correspondingly improved (p<0.05) in mice immunised against GIP. Glucose-stimulated insulin levels were not significantly different from controls. Furthermore, insulin sensitivity was similar in mice immunised against GIP and respective controls. Overall, the results reveal that active, as opposed to passive, immunisation against GIP improves blood glucose control ob/ob mice.
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PMID:Active immunisation against gastric inhibitory polypeptide (GIP) improves blood glucose control in an animal model of obesity-diabetes. 1893 25

The incretin hormones gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) augment postprandial glucose-mediated insulin release from pancreatic beta-cells. The Goto-Kakizaki (GK) rat is a widely used, lean rodent model of Type 2 diabetes; however, little is known regarding the incretin secretion profile to different nutrients in these rats. We have recently shown that lymph is a sensitive medium to measure incretin secretion in rodents and probably the preferred compartment for GLP-1 monitoring. To characterize the meal-induced incretin profile, we compared lymphatic incretin concentrations in the GK and Wistar rat after enteral macronutrient administration. After cannulation of the major mesenteric lymphatic duct and duodenum, each animal received an intraduodenal bolus of either a fat emulsion, dextrin, a mixed meal, or saline. Lymph was collected for 3 h and analyzed for triglyceride, glucose, GLP-1, and GIP content. There was no statistical difference in GIP or GLP-1 secretion after a lipid bolus between GK and Wistar rats. Dextrin and a mixed meal both increased incretin concentration area under the curve, however, significantly less in GK rats compared with Wistar rats (dextrin GIP: 707 +/- 106 vs. 1,373 +/- 114 pg ml(-1) h, respectively, P < 0.001; dextrin GLP-1: 82.7 +/- 24.3 vs. 208.3 +/- 26.3 pM/h, respectively, P = 0.001). After administration of a carbohydrate-containing meal, GK rats were unable to mount as robust a response of both GIP and GLP-1 compared with Wistar rats, a phenomenon not seen after a lipid meal. We propose a similar, glucose-mediated incretin secretion pathway defect of both K and L cells in GK rats.
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PMID:Nutrient-driven incretin secretion into intestinal lymph is different between diabetic Goto-Kakizaki rats and Wistar rats. 1905 62

The incretin effect, that is, the postprandial augmentation of insulin secretion by gastrointestinal hormones, mediates approximately 50-70% of the overall insulin responses after a mixed meal or glucose ingestion in healthy subjects. In patients with type 2 diabetes, the incretin effect is markedly reduced, and this has been attributed to defects in the secretion and insulinotropic action of the two main incretin hormones, namely gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). It has been speculated that a reduced incretin effect might precede the onset of hyperglycaemia in patients with type 2 diabetes. However, the secretion and action of GIP and GLP-1 is relatively unaltered in normal glucose-tolerant individuals at high risk for type 2 diabetes (e.g., first-degree relatives) and a diminished incretin effect is also detectable in other types of diabetes, thereby arguing against such reasoning. This article will describe the defects in the incretin system in patients with type 2 diabetes, summarise their relevance in the development of hyperglycaemia and discuss the potential individual roles of GIP and GLP-1 in the pathogenesis of type 2 diabetes.
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PMID:The contribution of incretin hormones to the pathogenesis of type 2 diabetes. 1974 61

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

DPP-4 (dipeptidyl peptidase-4) degrades the incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (gastric inhibitory polypeptide), decreasing their stimulatory effects on beta-cell insulin secretion. In patients with Type 2 diabetes, meal-related GLP-1 secretion is reduced. DPP-4 inhibitors (alogliptin, saxagliptin, sitagliptin and vildagliptin) correct the GLP-1 deficiency by blocking this degradation, prolonging the incretin effect and enhancing glucose homoeostasis. DPP-4 is a member of a family of ubiquitous atypical serine proteases with many physiological functions beyond incretin degradation, including effects on the endocrine and immune systems. The role of DPP-4 on the immune system relates to its extra-enzymatic activities. The intracytosolic enzymes DPP-8 and DPP-9 are recently discovered DPP-4 family members. Although specific functions of DPP-8 and DPP-9 are unclear, a potential for adverse effects associated with DPP-8 and DPP-9 inhibition by non-selective DPP inhibitors has been posed based on a single adverse preclinical study. However, the preponderance of data suggests that such DPP-8 and DPP-9 enzyme inhibition is probably without clinical consequence. This review examines the structure and function of the DPP-4 family, associated DPP-4 inhibitor selectivity and the implications of DPP-4 inhibition in the treatment of Type 2 diabetes.
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PMID:Inhibitor selectivity in the clinical application of dipeptidyl peptidase-4 inhibition. 1978 Jul 19

The incretin hormones gastric inhibitory polypeptide and especially glucagon-like peptide (GLP) have an important physiological function in augmenting postprandial insulin secretion. Since GLP-1 may play a role in the pathophysiology and treatment of type 2 diabetes, assessment of meal-related GLP-1 secretory responses in type 2 diabetic patients vs healthy individuals is of great interest. A common view states that GLP-1 secretion in patients with type 2 diabetes is deficient and that this applies to a lesser degree in individuals with impaired glucose tolerance. Such a deficiency is the rationale for replacing endogenous incretins with GLP-1 receptor agonists or re-normalising active GLP-1 concentrations with dipeptidyl peptidase-4 inhibitors. This review summarises the literature on this topic, including a meta-analysis of published studies on GLP-1 secretion in individuals with and without diabetes after oral glucose and mixed meals. Our analysis does not support the contention of a generalised defect in nutrient-related GLP-1 secretory responses in type 2 diabetes patients. Rather, factors are identified that may determine individual incretin secretory responses and explain some of the variations in published findings of group differences in GLP-1 responses to nutrient intake.
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PMID:Secretion of glucagon-like peptide-1 (GLP-1) in type 2 diabetes: what is up, what is down? 2087 75

In the 1970s, glucose-dependent insulinotropic polypeptide (GIP, formerly gastric inhibitory polypeptide), a 42-amino acid peptide hormone, was discovered through a search for enterogastrones and subsequently identified as an incretin, or an insulinotropic hormone secreted in response to intraluminal nutrients. Independent of the discovery of GIP, the K-cell was identified in small intestine by characteristic ultrastructural features. Subsequently, it was realized that K-cells are the predominant source of circulating GIP. The density of K-cells may increase under conditions including high-fat diet and obesity, and generally correlates with plasma GIP levels. In addition to GIP, K-cells secrete xenin, a peptide with as of yet poorly understood physiological functions, and GIP is often colocalized with the other incretin hormone glucagon-like peptide-1 (GLP-1). Differential posttranslational processing of proGIP produces 30 and 42 amino acid versions of GIP. Its secretion is elicited by intraluminal nutrients, especially carbohydrate and fat, through the action of SGLT1, GPR40, GPR120, and GPR119. There is also evidence of regulation of GIP secretion via neural pathways and somatostatin. Intracellular signaling mechanisms of GIP secretion are still elusive but include activation of adenylyl cyclase, protein kinase A (PKA), and protein kinase C (PKC). GIP has extrapancreatic actions on adipogenesis, neural progenitor cell proliferation, and bone metabolism. However, the clinical or physiological relevance of these extrapancreatic actions remain to be defined in humans. The application of GIP as a glucose-lowering drug is limited due to reduced efficacy in humans with type 2 diabetes and its potential obesogenic effects demonstrated by rodent studies. There is some evidence to suggest that a reduction in GIP production or action may be a strategy to reduce obesity. The meal-dependent nature of GIP release makes K-cells a potential target for genetically engineered production of satiety factors or glucose-lowering agents, for example, insulin. Transgenic mice engineered to produce insulin from intestinal K-cells are resistant to diabetes induced by a beta-cell toxin. Collectively, K-cells and GIP play important roles in health and disease, and both may be targets for novel therapies.
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PMID:K-cells and glucose-dependent insulinotropic polypeptide in health and disease. 2109 98

Saxagliptin is a novel dipeptidyl peptidase-4 inhibitor (DPP-4 inhibitor) for the treatment of type 2 diabetes, with a duration profile for once daily dosing. It is highly selective for DPP-4 in comparison to other enzymes of the dipeptidyl peptidase family. DPP-4 inhibitors elevate plasma concentrations of the incretin hormones glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP). This effect results in a glucose-dependent stimulation of insulin secretion and an inhibition of glucagon secretion without an intrinsic risk for hypoglycemia. In comparison to sulfonylureas and thiazolidinediones that promote weight gain, DPP-4 inhibitors are weight neutral. Saxagliptin has been approved by the FDA for the US and by the EMEA for Europe in 2009. Clinical trials showed a dose-dependent inhibition of DPP-4 by saxagliptin in doses ranging from 2.5 to 100 mg daily without serious side effects. Type 2 diabetic patients receiving 5 mg to 10 mg saxagliptin once daily had a significant lowering of HbA(1c) and glycemic parameters along with good tolerability and safety. Saxagliptin has demonstrated a good efficacy for glycemic parameters in various patient populations either in monotherapy or in combination with metformin and other oral antidiabetic drugs as well as a favorable cardiovascular profile. With its high selectivity for DPP-4 and its clinical and cardiovascular profile, saxagliptin is an attractive novel DPP-4 inhibitor.
Diabetes Metab Syndr Obes 2010 May 10
PMID:New treatments in the management of type 2 diabetes: a critical appraisal of saxagliptin. 2143 82

To compare the effects of miglitol [an alpha-glucosidase inhibitor (AGI) absorbed in the intestine] and voglibose (an AGI not absorbed) on plasma glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) levels, 26 and 24 Japanese type 2 diabetic patients were randomly assigned to receive miglitol or voglibose, respectively. After 12-week administration of both drugs, during 2-h meal tolerance test, plasma glucose, serum insulin and total GIP were significantly decreased and active GLP-1 was significantly increased. Miglitol group showed a significantly lower total GIP level than voglibose group. Miglitol, but not voglibose, significantly reduced body weight (BW). In all participants, the relative change in BW was positively correlated with that of insulin significantly and of GIP with a weak tendency, but not of GLP-1. In conclusion, both drugs can enhance postprandial GLP-1 responses and reduce GIP responses. The significant BW reduction by miglitol might be attributable to its strong GIP-reducing efficacy.
Diabetes Obes Metab 2012 Mar
PMID:Comparisons of the effects of 12-week administration of miglitol and voglibose on the responses of plasma incretins after a mixed meal in Japanese type 2 diabetic patients. 2205 Nov 62


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