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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Lithium is the best available marker of proximal tubular reabsorption of fluid. The first part of the present thesis reviews the background for the use of the lithium clearance (CLi) method. Micropuncture studies on proximal reabsorption of lithium, showed that CLi is a reasonably correct measure of end-proximal fluid delivery rate, even during osmotic diuresis. During severe salt restriction, distal reabsorption of lithium renders the CLi method inappropriate in animals, but this problem does probably not occur in humans. The major current issue is whether a quantitatively significant reabsorption of lithium occurs in the loop of Henle. Available evidence is in accord with the interpretation that it does not occur. The interpretation of results form CLi studies depends to a surprising degree on the investigators beliefs about renal physiology. In the evaluation of proximal tubular function, the relevant parameter is the absolute proximal reabsorption rate of fluid and sodium. In the evaluation of integrated distal tubular reabsorption of sodium, the relevant parameter is the fractional distal reabsorption rate of sodium. The fractional CLi does not give meaningful information, and calculated absolute distal reabsorption rate of sodium is inherently not suited to detect modest changes in distal reabsorption leading to large changes in sodium excretion. Results from the use of the CLi method in relation to diabetes are reviewed in the second section. Even in IDDM patients with early diabetic nephropathy, the proximal reabsorption rate is elevated, resulting in a normal CLi despite glomerular hyperfiltration. Overnight euglycemia did not change GFR in IDDM patients, but during maintained euglycemia, GFR was normalized. A few hours of hyperglycemia prevented the decline in GFR, whereas CLi was unchanged. Thus hyperglycemia produced changes in renal function similar to those observed previously, but the time-course of the effect of euglycemia on kidney function is delayed. Plasma levels of atrial natriuretic peptide, renin and glucagon were not importantly affected by plasma glucose. In NIDDM patients CLi was normal, despite slight hyperfiltration, although this observation must be confirmed in a study with larger sample size. Prompted by the clinical observation of a marked decline in the GFR induced by carbonic anhydrase inhibitors, we studied the renal effects of acetazolamide in a controlled study.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Lithium clearance in the evaluation of segmental renal tubular reabsorption of sodium and water in diabetes mellitus. 818 64

Potentiation of glucose-induced insulin secretion by intestinal factors has been described for many years. Today, two major peptides with potent insulinotropic action have been recognized: gastric inhibitory peptide and truncated forms of glucagon-like peptide I, GLP-I(7-37) or the related GLP-I(7-36)amide. These hormones have specific beta-cell receptors that are coupled to production of cAMP and activation of cAMP-dependent protein kinase. Elevation in intracellular cAMP levels is required to mediate the glucoincretin effect of these hormones: the potentiation of insulin secretion in the presence of stimulatory concentrations of glucose. In addition, circulating glucoincretins maintain basal levels of cAMP, which are necessary to keep beta-cells in a glucose-competent state. Interactions between glucoincretin signaling and glucose-induced insulin secretion may result from the phosphorylation of key elements of the glucose signaling pathway by cAMP-dependent protein kinase. These include the ATP-dependent K+ channel, the Ca++ channel, or elements of the secretory machinery itself. In NIDDM, the glucoincretin effect is reduced. However, basal or stimulated gastric inhibitory peptide and glucagon-like peptide I levels are normal or even elevated, suggesting that signals induced by these hormones on the beta-cells are probably altered. At pharmacological doses, infusion of glucagon-like peptide I but not gastric inhibitory peptide, can ameliorate postprandial insulin secretory response in NIDDM patients. Agonists of the glucagon-like peptide I receptor have been proposed as new therapeutic agents in NIDDM.
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PMID:Glucagon-like peptide-I and the control of insulin secretion in the normal state and in NIDDM. 834 31

To elucidate the mechanism of impaired pancreatic A cell function in hypoglycemia in diabetics, the effect of long-term strict glycemic regulations on hypoglycemia-induced glucagon secretion was studied. Firstly, the effect of plasma insulin concentrations on suppressing A cell was studied in healthy volunteers by injecting insulin at doses of 0.1 U/kg and 0.3 U/kg. With 0.3 U/kg of insulin, the rate of fall in glycemia and the nadir of blood glucose were made similar to those with 0.1 U/kg of insulin by glucose infusion with artificial endocrine pancreas. Plasma glucagon response after 0.3 U/kg of insulin was significantly suppressed as compared to that after 0.1 U/kg of insulin, demonstrating that not only hypoglycemic stimulus but also plasma insulin concentration were important determinants responsible for glucagon secretion in insulin-induced hypoglycemia. Secondly, effect of strict glycemic control was studied. Short-acting insulin at a dose of 0.1 U/kg was injected in an intravenous bolus form into 12 insulin-dependent (IDDM) and 9 non-insulin-dependent (NIDDM) diabetics before and 1-3 months after strict glycemic control with multiple insulin injections therapy. Before strict glycemic regulations in IDDM, no significant rise in plasma glucagon concentrations was observed during the insulin-induced hypoglycemia. In NIDDM, a rise in plasma glucagon concentrations was observed, though the response was delayed. After strict glycemic regulations, in patients with residual endogenous insulin secretion, the glucagon response to hypoglycemia improved considerably in IDDM and normalized in NIDDM. In IDDM and NIDDM, improvement in glucagon response to hypoglycemia related positively to daily urinary secretion rate of C-peptide.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Improvement in blunted glucagon response to insulin-induced hypoglycemia by strict glycemic control in diabetics. 837 72

Non-insulin-dependent diabetes mellitus (NIDDM, type 2 diabetes) is a disorder of glucose homeostasis characterized by hyperglycaemia, peripheral insulin resistance, impaired hepatic glucose metabolism, and diminished glucose-dependent secretion of insulin from pancreatic beta-cells. Glucagon-like-peptide-1(7-37) (GLP-1) is an intestinally derived hormone that may be useful for the treatment of NIDDM because it acts in vivo to increase the level of circulating insulin, and thus lower the concentration of blood glucose. This therapeutic effect may result from the ability of GLP-1 to compensate for a defect in the glucose signalling pathway that regulates insulin secretion from beta-cells. In support of this concept we report here that GLP-1 confers glucose sensitivity to glucose-resistant beta-cells, a phenomenon we term glucose competence. Induction of glucose competence by GLP-1 results from its synergistic interaction with glucose to inhibit metabolically regulated potassium channels that are also targeted for inhibition by sulphonylurea drugs commonly used in the treatment of NIDDM. Glucose competence allows membrane depolarization, the generation of action potentials, and Ca2+ influx, events that are known to trigger insulin secretion.
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PMID:Pancreatic beta-cells are rendered glucose-competent by the insulinotropic hormone glucagon-like peptide-1(7-37). 838 Dec 11

Glucagon-like peptide-1 is a fragment of proglucagon secreted by intestinal L-cells. It has potent glucose-dependent insulin secretory effects and also suppresses gastric acid secretion in the stomach. The biological actions of GLP-1 are mediated by the GLP-1 receptor, the structure of which has recently been determined. Defects in insulin secretion are a common feature of NIDDM and as such the GLP-1 receptor is a candidate for contributing to the development of this clinically and genetically heterogeneous disorder. As a first step in determining the role of the GLP-1 receptor in the development of NIDDM, we have isolated the human GLP-1 receptor gene and mapped it to chromosome 6, band p21.1, using the technique of fluorescence in situ hybridization. We also identified a simple tandem repeat DNA polymorphism in the human GLP-1 receptor gene of the form (TG)n. This DNA polymorphism has 14 alleles and a heterozygosity of > 0.8. We have used this DNA polymorphism to localize the GLP-1 receptor gene within the genetic map of the short arm of chromosome 6. This DNA polymorphism will facilitate genetic studies of the contribution of the GLP-1 receptor gene to impaired beta-cell function and NIDDM.
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PMID:Human glucagon-like peptide-1 receptor gene. Localization to chromosome band 6p21 by fluorescence in situ hybridization and linkage of a highly polymorphic simple tandem repeat DNA polymorphism to other markers on chromosome 6. 839 11

The classification of adults with diabetes mellitus can be invalidated by patients who initially present as NIDDM but who later become frankly insulin dependent. In some of these, the pathogenesis could be similar to that in IDDM, namely autoimmune destruction of the pancreatic beta-cells. We studied 102 patients > 35 yr of age at diabetes onset who had initially been nonketotic and non-insulin-dependent for > or = 6 mo. They were classified according to glucagon-stimulated C-peptide levels into an insulin-deficient group (n = 33) and a non-insulin-deficient group (n = 69). We measured antibodies to GAD, islet cell cytoplasm, thyroid antigens, and gastric parietal cells in both groups. Anti-GAD was significantly higher in the insulin deficient group, 76% (25 of 33), than in the non-insulin deficient group, 12% (8 of 69), and this difference was substantially greater than that shown for ICAs. Thus, in a proportion of adults who present with NIDDM, a slowly evolving autoimmune insulitis can be revealed by testing for anti-GAD. This could have important connotations not only for early intervention, but also for the correct classification of diabetes.
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PMID:Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with a non-insulin-dependent onset of disease. 842 74

The study objective was to determine the dose-response relationships between postprandial blood glucose, insulin, and glucagon responses and the amount of starch ingested in non-insulin-dependent diabetic (NIDDM) subjects. Three test meals were served in random order with a 7-day interval. Mixed meals of 23, 46, and 69 g (raw weight) parboiled white rice containing approximately 20, 40, and 60 g available carbohydrate were served cooked with 167 g meat sauce on 3 separate days. Patients ingested the meals after a 12-hour fast. Clear-cut dose-response relationships between the amount of starch ingested and postprandial peak blood glucose values (R = .99), glucose response areas (R = .99), and insulin response areas (R = .98) were found. Glucose response areas to meals of 20, 40, and 60 g carbohydrate as white rice differed significantly (P < .05) at 139 +/- 58, 285 +/- 86, and 453 +/- 113 mmol/L x 280 min, respectively. Insulin response areas to meals of 23 g rice (11.382 +/- 2,220 pmol/L x 240 min) were significantly lower compared with response areas to 46 g rice (18.138 +/- 3,522 pmol/L x 240 min) and 69 g rice (21.312 +/- 2,970 pmol/L x 240 min), with the latter two values being similar. Glucagon response areas showed an inverse pattern to glucose response areas, reaching 3,450 +/- 823, 2,715 +/- 651, and 2,168 +/- 553 pmol/L x 240 min, but differences did not reach statistical significance.
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PMID:Dose-dependency of the glycemic response to starch-rich meals in non-insulin-dependent diabetic subjects: studies with varying amounts of white rice. 847 18

NIDDM is the result of concomitant defects in both insulin secretion and insulin action. Although plasma insulin concentration in NIDDM patients may be normal or even increased as compared to normal individuals, insulin secretion is always impaired when related to ambient hyperglycemia. Moreover, the loss of first-phase insulin secretion is always present and it occurs at the very early stage of the disease. The defect in the early release of insulin may have quite an impact in post-prandial glucose homeostasis, due to inadequate suppression of hepatic glucose production. Therefore, insulin releasers should be able; 1. to increase total insulin secretory capacity, and 2. to restore physiologic profile of insulin secretion. However, this is rarely achieved with the current therapeutical tools. Sulfonylureas may exert some suppressive action on the liver and may maintain a portal-peripheral venous insulin gradient. Metformin may improve insulin sensitivity but has no effect on the beta-cell. Exogenous insulin exerts an inhibitory effect on hepatic glucose production but it does not maintain the physiologic gradient, neither can it mimic first-phase insulin secretion. Therefore, more appropriate tools must be sought. Prompt stimulation of insulin secretion can be elicited by alpha 2-adrenoreceptor antagonists, but their clinical use is still under evaluation. New sulfonylureas are under development, though some of them may exert a better peripheral action than more potent stimulation of the beta-cell. Special interest has been focused on incretin peptides. Infusion of glucagon-like peptide 1 (GLP-1) in NIDDM patients improves glucose tolerance through enhancement of acute release of insulin, suppression of glucagon secretion, and improvement of peripheral glucose utilization.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:What therapy do our NIDDM patients need? Insulin releasers. 852 9

Most of diabetics have no symptoms and chemical analyses may be sole way to diagnose the disease itself and its complications. Chemical analyses are also important to assess the propriety of glycemic control during every possible treatment of diabetes. Some markers for long-term glycemic control other than glucose concentration may be also used as a screening methods for glucose intolerance. HbA1c is established for long term as a marker for glycemic control but still large interlaboratory variation is present. Fructosamine is measured by a simpler procedure but many deoxidizing materials in serum especially superoxide may interfere with the reaction. Glycated albumin should be more reliable than fructosamine but a standard method of measurement has not been established yet. The decrease in serum 1,5-anhydro-D-glucitol(1,5-AG) is very sensitive to urinary glucose excretion and may be useful as a marker of glycemic control and diagnosis of diabetes. Discrimination of Type I(IDDM) from Type II(NIDDM) in Japanese diabetic patients is sometimes very difficult and evidences of autoimmunity by anti-glutamic acid decarboxylase(GAD) antibody and of exhaustion of insulin secretion by C-peptide measurement 6min after combined infusion of 1mg of glucagon and 20ml of 50% glucose are the few methods to diagnose. Early diagnosis of diabetic complication is another important point of clinico-chemical determinations. Usually, each diabetic complication progresses in parallel. Micro-measurement of urinary transferrin is one of the most sensitive methods likewise urinary microalbumin measurement. Future measurement of advanced glycation end product (AGE) may also tell us if patients are suffering from diabetic complications or if one is suffering from diabetes or not.
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PMID:[Recent progress in diagnoses of diabetes and its complications]. 856 34


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