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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The incretin effect (i.e. the difference between the insulin response after oral and i.v. glucose) is reduced in type 2 diabetes although GIP secretion is normal or exaggerated. This suggests an insensitivity of the diabetic B-cell to GIP. However, it could also indicate the lack of another not yet defined "incretin". 2. While CCK is a potent incretin in rats and dogs, physiological concentrations of this hormone do not stimulate insulin secretion in man in presence of elevated blood levels of glucose or phenylalanine in the physiological range. It also does not interact with GIP. 3. Glucagon-like peptide I (7-36) is a potent glucose-dependent stimulator of insulin secretion in animals and man. Preliminary data suggest release after oral glucose despite localization of the GLPI containing cells predominantly in the ileum and colon. More data are needed before GLPI (7-36) can be regarded as a physiological incretin and its role in type 2 diabetes assessed.
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PMID:Entero-insular axis and diabetes mellitus. 149 Jun 80

The effects of an intravenous infusion of porcine GIP on beta-cell secretion in patients with untreated type 2 diabetes mellitus have been studied. The subjects were studied on two separate days. After a 10 h overnight fast and a further 120 min basal period they were given an intravenous infusion of porcine GIP (2 pmol.kg-1.min-1) or control solution in random order from 120-140 min. Frequent plasma glucose, insulin, C-peptide and GIP measurements were made throughout and the study was continued until 200 min. Plasma glucose levels were similar throughout both tests. During the GIP infusion there was an early significant rise in insulin concentration from 0.058 +/- 0.006 nmol/l to 0.106 +/- 0.007 nmol/l (P less than 0.01) within 6 min of commencing the GIP infusion and insulin levels reached a peak of 0.131 +/- 0.011 nmol/l at 10 min (P less than 0.01). Insulin levels remained significantly elevated during the rest of the GIP infusion (P less than 0.01-0.001) and returned to basal values 20 min post infusion. No change in basal insulin values was seen during the control infusion. C-peptide levels were similarly raised during the GIP infusion and the increase was significant just 4 min after commencing the GIP infusion (P less than 0.05). GIP levels increased from 16 +/- 3 pmol/l prior to the infusion to a peak of 286 +/- 24 pmol/l 20 min later. At 4 min when a significant beta-cell response was observed GIP levels were well within the physiological range.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Glucose dependent insulinotropic polypeptide (GIP) infused intravenously is insulinotropic in the fasting state in type 2 (non-insulin dependent) diabetes mellitus. 264 5

A physiological role for GIP as an insulinotropic hormone involved in the enteroinsular axis has been established and ingestion of glucose, fatty acids and certain amino acids will produce an increase in circulating IR-GIP levels. The insulinotropic action of GIP is glucose concentration dependent in normal animals. A role for GIP in NIDDM is equivocal although several studies have demonstrated elevated serum levels. Animal models have indicated a disturbance of GIP receptor function associated with hyperinsulinaemia, i.e. lowering of the minimum glucose concentration at which GIP is insulinotropic.
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PMID:Enteroinsular axis. 307 97

Mexican Americans, a group at high risk for type II diabetes mellitus, have higher postprandial insulin and glucose levels when compared to non-Hispanic whites. A rapid rate of gastric emptying contributes to an increased rate of nutrient absorption and subsequent greater elevation of postprandial glucose and insulin levels. A more rapid rate of gastric emptying and hyperinsulinemia have been observed in patients with recently diagnosed type II diabetes mellitus. In this study, we examined whether Mexican Americans have a more rapid rate of gastric emptying than non-Hispanic whites. Gastric emptying studies were performed on 32 nondiabetic Mexican Americans and on 31 nondiabetic non-Hispanic whites. The rate of gastric emptying following a liquid glucose meal was measured. Serum insulin, plasma glucose, and GIP levels were measured in fasting and postprandial blood samples collected at 15-min intervals for 2 hr. Adjusting for age, body mass index, and gender, the gastric half-emptying time of a glucose meal was significantly (P < 0.05) more rapid for the Mexican American subjects (56.5 +/- 3.4 min) compared to the non-Hispanic white subjects (66.4 +/- 3.5 min). Nondiabetic Mexican Americans empty a liquid glucose meal more rapidly from their stomachs than nondiabetic non-Hispanic whites. Rapid gastric emptying is associated with hyperinsulinemia as a normal physiologic response to increased nutrient availability. The rapid gastric emptying observed in nondiabetic Mexican Americans is associated with hyperinsulinemia and could be a contributing factor for the increased risk of obesity and type II diabetes in this population.
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PMID:Gastric emptying in Mexican Americans compared to non-Hispanic whites. 789 57

Basic research on the cellular mechanisms that control the expression of the gene encoding glucagon has led to the discovery of proglucagon, which is processed alternatively by tissue-specific proteolysis to produce glucagon in the pancreatic alpha cells and a GLP-1 in the intestines. GLP-1 hormone is released into the circulation from intestinal L cells in response to meals and is the most potent incretin hormone known; GLP-1 and GIP appear to account for most, if not all, of the intestinal incretin effect in the augmentation of glucose-stimulated insulin secretion. Analyses of the mechanisms of action of GLP-1 and of glucose on isolated cultured rat beta cells using patch-clamp techniques to record ion channel activities has led to the glucose competence concept in which the combined glucose-signaling and GLP-1/cAMP-signaling pathways are required to affect depolarization of beta cells and to thereby stimulate insulin secretion. It is hypothesized that, among other possible target channels, the K-ATP channel is key first event in GLP-1/glucose-mediated activation of the beta cell secretory response. It is proposed that at least one factor contributing to the pathogenesis of NIDDM is a desensitization of the GLP-1 receptor on beta cells induced by the hypersecretion of GLP-1. Because of the discoveries that GLP-1 stimulates both secretion and production of insulin, and that the actions of GLP-1 are entirely glucose-dependent, GLP-1 may provide unique advantages over the sulfonylurea drugs in the treatment of NIDDM.
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PMID:The incretin notion and its relevance to diabetes. 812 72

The literature with respect to GIP is flooded with conflicting data especially with respect to its role in type 2 diabetes mellitus, obesity, type 1 diabetes mellitus and chronic pancreatitis. This review describes possible reasons for the discrepancies which include species variation of GIP, heterogeneity of molecules with different immunoreactivity and bioactivity, deterioration of immunoreactivity of standard and sample on prolonged storage and the effect of the preceding intake of type and quantity of food. The problems can be resolved by raising antibodies to synthetic human GIP and its fragments, the chemical characterization of and the raising of antibodies to immunoreactive GIP 8000, the correct storage of samples and the standard preparation of subjects prior to experimental procedures.
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PMID:Conflicting gastric inhibitory polypeptide data: possible causes. 847 32

Gastric inhibitory polypeptide (tGIP) and truncated glucagon like peptide-1 (GLP-1) are potent gastrointestinal insulinotropic factors (incretin), are most released after a meal or ingestion of glucose in man and animals. To investigate whether sulfonylurea (SU) affects the secretion of incretin, the modulation of plasma GIP and tGLP-1 levels following glucose ingestion in non-insulin-dependent diabetic type 2 patients with or without SU therapy was studied. A 75-G oral glucose tolerance test (OGTT) was carried out on 9 healthy subjects (controls) and 18 patients with non-obese type 2, 9 of whom were treated by diet alone (NIDDM-diet) and the other 9 with SU (glibenclamide 2.5 mg or gliclazide 40 mg) once a day (NIDDM-SU). Plasma GIP was measured by radioimmunoassay (RIA) with R65 antibody, and GLP-1 was measured by RIA with N-terminal-directed antiserum R1043 (GLP-1NT) and C-terminal-directed antiserum R2337 (GLP-1CT). Following OGTT, plasma glucose, GIP, GLP-1NT, and GLP-1CT in type 2 patients increased more markedly than in controls, despite the lower response of insulin. However, there were no significant differences in plasma levels of these peptides between the NIDDM-diet and NIDDM-SU groups. Therefore, it is unlikely that SU is involved in the high response of GIP and GLP-1s to OGTT in type 2 patients.
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PMID:Response of truncated glucagon-like peptide-1 and gastric inhibitory polypeptide to glucose ingestion in non-insulin dependent diabetes mellitus. Effect of sulfonylurea therapy. 859 Jul 85

A definitive assessment of the relative roles of insulin resistance and insulin deficiency in the etiology of NIDDM is hampered by several problems. 1) Due to better methodology, data on insulin resistance are generally more accurate and consistent than data on insulin deficiency. 2) In source data, case-control studies are prone to selection bias, while epidemiological associations, whether cross-sectional or longitudinal, are liable to misinterpretation. 3) Insulin secretion and action are physiologically interconnected at multiple levels, so that an initial defect in either is likely to lead with time to a deficit in the companion function. The fact that both insulin resistance and impaired insulin release have been found to precede and predict NIDDM in prospective studies may be in part a reflection of just such relatedness. 4) Direct genetic analysis is effective in rarer forms of glucose intolerance (MODY, mitochondrial mutations, etc.) but encounters serious difficulties with typical late-onset NIDDM. Despite these uncertainties, the weight of current evidence supports the view that insulin resistance is very important in the etiology of typical NIDDM for the following reasons: 1) it is found in the majority of patients with the manifest disease; 2) it is only partially reversible by any form of treatment (117); 3) it can be traced back through earlier stages of IGT and high-risk conditions; and 4) it predicts subsequent development of the disease with remarkable consistency in both prediabetic and normoglycemic states. Of conceptual importance is also the fact that the key cellular mechanisms of skeletal muscle insulin resistance (defective stimulation of glucose transport, phosphorylation, and storage into glycogen) have been confirmed in NIDDM subjects by a variety of in vivo techniques [ranging from catheter balance (118) to multiple tracer kinetics (119) to 13C nuclear magnetic resonance spectroscopy (120)], and have been detected also in normoglycemic NIDDM offspring (121). If insulin resistance is a characteristic finding in many cases of NIDDM, insulin-sensitive NIDDM does exist. On the other hand, given the tight homeostatic control of plasma glucose levels in humans, beta-cell dysfunction, relative or absolute, is a sine qua non for the development of diabetes. If insulin deficiency must be present whereas insulin resistance may be present, is this proof that the former is etiologically primary to the latter? If so, do we have convincing evidence that the primacy of insulin deficiency is genetic in nature? The answer to both questions is negative on several accounts. The defect in insulin secretion in overt NIDDM is functionally severe but anatomically modest: beta-cell mass is reduced by 20-40% in patients with long-standing NIDDM (122). Moreover, the insulin secretory deficit is progressively worse with more severe hyperglycemia (123) and recovers considerably upon improving glycemic control (124). These observations indicate that part of the insulin deficiency is acquired (through glucose toxicity, lipotoxicity, or both). In addition, although insulin deficiency is necessary for diabetes, it may not always be sufficient to cause NIDDM. In fact, subtle defects in the beta-cell response to glucose may be widespread in the population (108, 125) and only cause frank hyperglycemia when obesity/insulin resistance stress the secretory machinery. Conceivably, there could be beta-cell dysfunction without NIDDM just as there is insulin resistance without diabetes. Incidentally, any defect in insulin secretion, whether in normoglycemic or hyperglycemic persons, could be due to other factors than primary beta-cell dysfunction: amyloid deposits in the pancreas (126), changes in insulin secretagogues (amylin, GLP-1, GIP, galanin) (127-130), early intrauterine malnutrition (131). Finally, the predictive power of early changes in insulin secretion for the development of typical NIDDM is generally lower than that of insulin
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PMID:Insulin resistance versus insulin deficiency in non-insulin-dependent diabetes mellitus: problems and prospects. 971 76

Diets enriched in monounsaturated fatty acids (MUFA)s have been shown to benefit glycemic control. Furthermore, MUFAs specifically stimulate secretion of the antidiabetic hormone, Glucagon-like peptide-1 (GLP-1) in vitro. To determine whether the MUFA-induced benefit in glycemic tolerance in vivo is due to increased GLP-1 release, lean Zucker rats were pair-fed a synthetic diet containing 5% fat derived from either olive oil (OO; 74% MUFA) or coconut oil (CO; 87% saturated fatty acids; SFA) for 2 weeks. Food intake and body weight gain were similar for both groups over the feeding period. The OO group had improved glycemic tolerance compared with the CO group in both oral and duodenal glucose tolerance tests [area under curve (AUC) 121 +/- 61 vs. 290 +/- 24 mM.120 min, P < 0.05; and 112 +/- 28 vs. 266 +/- 65 mM.120 min, P < 0.05, respectively]. This was accompanied by increased secretion of gut glucagon-like immunoreactivity (gGLI; an index of GLP-1 levels) in the OO rats compared with the CO rats (402 +/- 96 vs. 229 +/- 33 pg/ml at t = 10 min, P < 0.05). Tissue levels of GLP-1 and plasma insulin and glucagon levels were not different between the two groups. To determine the total contribution of GLP-1 to the enhanced glycemic tolerance in OO rats, the GLP-1 receptor antagonist exendin(9-39) (Ex(9-39)) was infused 3 min before a duodenal glucose tolerance test. Ex(9-39) abolished the benefit in glycemic tolerance conferred by OO feeding (OO+Ex(9-39) vs. CO+Ex(9-39), P = NS), and resulted in a deterioration of glycemic tolerance in the OO+Ex(9-39) group when compared with the OO controls (AUC 331 +/- 21 vs. 112 +/- 28 mM.120 min, P < 0.05). To probe the mechanism by which the OO diet enhanced GLP-1 secretion, a GLP-1-secreting L cell line was incubated for 24 h with either 100 microM oleic acid (MUFA) or 100 microM palmitic acid (SFA) and subsequently challenged with GIP, a known stimulator of the L cell. Preexposure to oleic acid but not to palmitic acid significantly increased GIP-induced GLP-1 secretion when compared with controls (55 +/- 12% vs. 34 +/- 9%, P < 0.01). These results demonstrate that the benefit in glycemic tolerance obtained with MUFA diets occurs in association with increased GLP-1 secretion, through a mechanism of enhanced L cell sensitivity. These results suggest that diet therapy with MUFAs may be useful for the treatment of patients with impaired glucose tolerance and/or type 2 diabetes through increased GLP-1 secretion.
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PMID:Monounsaturated fatty acid diets improve glycemic tolerance through increased secretion of glucagon-like peptide-1. 1118 30

Incretin hormones are insulinotropic hormones from the intestinal mucosa, which after being released in response to ingestion of a meal, enhance insulin secretion in excess of that elicited by the absorbed nutrients (glucose. amino acids etc) themselves. To day it is well established that the most important incretin hormones are glucose-dependent insulinotropic polypeptide (GIP, previously known as gastric inhibitory polypeptide) and glucagon-like peptide-1 (GLP-1) from the upper and lower small intestinal mucosa, respectively. It has been shown that interference with the incretin function causes glucose intolerance and it has also been shown that the incretin function is greatly impaired in type 2 diabetes mellitus. The reason for this seems to be twofold: an impaired secretion of GLP-1 and a severely impaired insulinotropic effect of GIP in these patients. In agreement with this, administration of the active incretin, GLP-1, to patients with type 2 diabetes may nearly normalise their fasting and postprandial hyperglycaemia. In addition to its insulinotropic effects, GLP-1 has been shown to stimulate the formation of new beta cells in rodents, partly by enhanced beta cell proliferation and partly by enhancing differentiation of duct progenitor cells to mature beta cells. GLP-1 also inhibits glucagon secretion, inhibits gastric emptying and reduces appetite and food intake. During the last years, therefore, several most promising attempts have been made to develop GLP-1 into a clinically useful therapeutic agent for the treatment of type 2 diabetes.
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PMID:Incretin hormones--an update. 1171 84


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