Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A case of pseudohypoparathyroidism has been investigated. Indirect evidence allows to eliminate a defect of renal 1 alpha-hydroxylase as the determining factor of this condition. Similarly, the increased size of the mean surface area of the cross-section of periosteocytic lacunae, as determined on decalcified sections of bone obtained by transiliac biopsy, shows the osteocytes to be sensitive to the endogenous PTH, discarding cAMP response to PTH in bone as a prerequisite for PTH action on bone. The authors conclude from these data and from previous experiments that the defect of parathyroid function in this condition probably relates to the existence of an abnormal PTH molecule and/or metabolism and/or interaction with the receptors sites. The endocrine function was studied as well. Prediabetes was demonstrated, as well as primary latent hypothyroidism (TRH test). Prolactin release could not be stimulated by TRH, levodopa, metoclopramide, chlorpromazine and insulin hypoglycemia. The latter produced a normal release of ACTH (as ascertained by plasma cortisol levels) and GH, and possibly a sluggish response of glucagon and gastrin. There was a deficiency of urinary concentration upon restriction of fluid intake. This was only partially corrected by ADH administration.
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PMID:[Physio-pathology of pseudohypoparathyroidism (author's transl)]. 22 97

Changes in cortisol, growth hormone, and glucagon levels observed in diabetes mellitus appear to be secondary to insulin deficiency, and can be related to the severity of insulinopenia with its attendant metabolic sequelae. Similarly, disturbances in plasma concentrations of catecholamines in diabetes also appear to be secondary to insulin deficiency, although a primary disturbance in adrenergic function or receptors at the cellular level cannot be excluded. As "inappropriate" compensatory responses, these hormones may aggravate the diabetic syndrome, but their dysfunction is not the cause of diabetes and cannot be used to identify prediabetes. To date, the primary hormonal disturbance in insulin-dependent diabetes remains defective insulin secretion.
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PMID:The contribution of hyperglycemic hormones to the pathogenesis of diabetes mellitus. 91 Jul 69

To determine whether abnormalities in glucagon secretion might precede the onset of hyperglycemia in diabetes mellitus, 32 prediabetic Pima (American) Indians, 27 normal Pima Indians and 34 normal Caucasians received an infusion of arginine monochloride (5 mg/kg/min for 40 minutes) with measurement of glucose, insulin, and glucagon. [Prediabetes is the period between conception and the development of diabetes. In most studies the term is used to characterize patients who on genetic grounds are believed to be at high risk of developing the disease, including the normoglycemic monozygotic co-twin of a diabetic or the normoglycemic offspring of two diabetic parents. The latter definition is used in the present study recognizing that in the final analysis the true prediabetic can be identified only in retrospect after the development of diabetes.] The three groups had similar mean fasting glucagon levels. During arginine infusion, the prediabetic Indians reached a mean maximum glucagon level of 315 +/- 14 pg/ml (mean +/- 1 SEM) compared with 294 +/- 20 pg/ml in the normal Indians and 292 +/- 25 pg/ml in the normal Caucasians. The calculated mean areas above baseline under the glucagon curves were 5704 +/- 324 pg-min/ml in the prediabetics, 5189 +/- 446 pg-min/ml in the normal Indians, and 4239 +/- 613 pg/min/ml in the normal Caucasians. The differences among the groups in these variables were not statistically significant. Thus, arginine induced hyperglucagonemia could not be identified as a characteristic of the prediabetic state in Pima Indians.
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PMID:Normal glucagon response to arginine infusion in "prediabetic" Pima Indians. 95 Mar 63

Non-insulin-dependent diabetes mellitus is a complex metabolic disorder that involves numerous biochemical abnormalities, a heterogenous clinical picture, and a polygenic hereditary component. The pathophysiologic state involves increased basal hepatic glucose production, decreased insulin-mediated glucose utilization in target tissues, and altered pancreatic function with decreased beta cell function and enhanced glucagon secretion. Prospective studies indicate that insulin resistance and hyperinsulinemia exist in the prediabetic state at a time when glucose tolerance is normal. When hyperglycemia supervenes, both insulin secretion and insulin-mediated glucose utilization are further compromised, mediated in part by sustained hyperglycemia itself. Insulin resistance may occur at any level in the biologic action of insulin, from initial binding to cell surface receptors to the phosphorylation cascade that is initiated by autophosphorylation of the insulin receptor. Receptors isolated from patients with non-insulin-dependent diabetes mellitus have compromised autophosphorylation-kinase activity when isolated from adipocytes, liver, erythrocytes, and skeletal muscle. The magnitude of the decrease in insulin receptor kinase activity is correlated with the degree of fasting hyperglycemia. However, the defect in insulin receptor kinase activity is normalized after weight reduction or other measures that reduce hyperglycemia, indicating the secondary nature of the defect. Clarification of the mechanisms underlying insulin resistance in non-insulin-dependent diabetes mellitus will lead to new treatment modalities for this disease.
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PMID:Insulin resistance and non-insulin-dependent diabetes mellitus: cellular and molecular mechanisms. 790 Jun 97

Acute insulin responses to glucose (AIRG), glucagon (AIRGln), and arginine (AIRArg) were evaluated prospectively in nine subjects positive for islet-cell antibodies (ICAs) who later progressed to type I diabetes or impaired glucose tolerance (IGT) (progressors), 64 ICA-positive subjects at risk who did not develop type I diabetes, 365 ICA-negative relatives of diabetic patients who also remained free of the disease, and 89 control subjects. Seven progressors already had a low AIRG at entry into the study, and the other two became low responders 3 to 9 months before diabetes or IGT, with a progressive decline of AIRG over serial intravenous (IV) glucose tolerance tests. At entry into the study, the group of progressors displayed lower AIRG, AIRGln, and AIRArg than the other three groups (P<.001). However, AIRArg was less altered than AIRG. During the course of the prediabetic phase, there was a progressive decline in AIRG and AIRGln analyzed as a function either of time (P<.006) or of basal glycemia (P<.05), ie, two different ways of estimating worsening of the disease process. Conversely, there was no significant decrease in AIRArg with time or with increasing basal glycemia, so that AIRArg was not totally blunted in these prediabetic subjects even a few months before the onset of diabetes. The persistence of a substantial response to arginine, ie, higher than the fifth control percentile, even at a late stage, was confirmed in five of nine diabetic patients tested either at onset of the disease or during non-insulin-receiving remission. Whereas AIRG deteriorates during prediabetes, AIRArg appears to be less altered with time and increased basal glycemia, remaining substantial even at the onset of the disease. This reinforces the supposition that the prediabetic state may be associated with a glucose-specific beta-cell functional abnormality in addition to a decreasing beta-cell mass.
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PMID:Differential beta-cell response to glucose, glucagon, and arginine during progression to type I (insulin-dependent) diabetes mellitus. 860 36

The effect of the insulinotropic gut hormone glucagon-like-peptide-1 (GLP-1) was studied on the residual insulin capacity of prediabetic nonobese diabetic (NOD) mice, a model of insulin-dependent diabetes mellitus (type 1). This was done using isolated pancreas perfusion and dynamic islet perifusion. Prediabetes was defined by insulitis and fasting normoglycemia. Insulitis occurred in 100% of NOD mice beyond the age of 12 weeks. K values in the intravenous glucose tolerance test were reduced in 20-week-old NOD mice compared with age matched non-diabetes-prone NOR (nonobese resistant) mice (2.4 +/- 1.1 vs 3.8 +/- 1.5% min-1, P < 0.05). Prediabetic NOD pancreases were characterized by a complete loss of the glucose-induced first-phase insulin release. In perifused NOD islets GLP-1, at concentrations already effective in normal islets, left the insulin release unaltered. However, a significant rise of glucose-dependent insulin secretion occurred for GLP-1 concentrations > 0.1 nM. This was obtained with both techniques, dynamic islet perifusion and isolated pancreas perfusion, indicating a direct effect of GLP-1 on the beta-cell. Analysis of glucose-insulin dose-response curves revealed a marked improvement of glucose sensitivity of the NOD endocrine pancreas in the presence of GLP-1 (half-maximal insulin output without GLP-1 15.2 mM and with GLP-1 9.4 mM, P < 0.002). We conclude that GLP-1 can successfully reverse the glucose sensing defect of islets affected by insulitis.
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PMID:Glucagon-like-peptide-1 (7-36) amide improves glucose sensitivity in beta-cells of NOD mice. 877 80

So far, a wealth of data originating from in vitro or animal experiments has been collected supporting the concept that the gut hormone, glucagon-like peptide-1 (GLP-1) may serve as a model molecule for the design of a new drug for the treatment of diabetes mellitus. This is supported by observations that GLP-1 has potent insulinotropic action in patients with non-insulin-dependent diabetes mellitus (NIDDM). It enhances beta-cell sensitivity to glucose stimulated insulin secretion. GLP-1 may also have a role in the treatment of impaired glucose tolerance, where the beta-cell is already insensitive to changes in plasma glucose concentrations. It may, as has previously been shown in animal models of 'prediabetes', delay the progressive decline in glucose tolerance to NIDDM. The glucose-dependent action of this peptide is an important feature in the treatment of NIDDM as it will protect against hypoglycaemic reactions, the most serious acute side-effect of antidiabetic therapy. Glucose utilization may be enhanced which would improve metabolic control in both NIDDM and IDDM. A glucagon lowering effect will further enhance metabolic control. This article reviews current experiences of the effects of GLP-1 in human studies. It points out the outcomes and limitations of previous trials and discusses future directions for the investigation of its potential use as a new agent in diabetes treatment.
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PMID:Human studies with glucagon-like-peptide-1: potential of the gut hormone for clinical use. 891 78

Vildagliptin is a potent selective inhibitor of dipeptidyl peptidase-4 (DPP-4) that improves glycaemic control by increasing islet alpha-cell and beta-cell responsiveness to glucose. In patients with type 2 diabetes mellitus (T2DM), vildagliptin improves beta-cell function, measured as insulin secretory rate relative to glucose level, and reduces glucagon secretion and endogenous glucose production in the postprandial period, resulting in reduced glucose levels. In clinical trials in T2DM, vildagliptin 100 mg/day monotherapy is effective in reducing haemoglobin A1c (HbA1c) across the spectrum of hyperglycaemia and has maintained efficacy over long-term treatment with neutral effects on body weight and lipids. Vildagliptin is associated with a low risk of hypoglycaemia, and has an adverse event profile comparable to placebo, including a reduced rate of gastrointestinal adverse effects compared with metformin and a reduced rate of oedema compared with rosiglitazone. As add-on combination therapy, vildagliptin produces significant further reductions in HbA1c in patients receiving metformin, pioglitazone, glimepiride and insulin, and has been found to reduce frequency of hypoglycaemia as an add-on to insulin. Preliminary findings indicate that the improved islet cell function underlying the efficacy of vildagliptin in T2DM is also observed in patients with impaired glucose tolerance, with vildagliptin treatment resulting in reduced glycaemic excursions. The overall profile of vildagliptin and the preliminary evidence of beneficial effects in the prediabetic state suggest that DPP-4 inhibition could be an effective strategy to prevent or delay progression from the prediabetic state to overt T2DM.
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PMID:The DPP-4 inhibitor vildagliptin: robust glycaemic control in type 2 diabetes and beyond. 1787 45

The rapid and often relentless progression of type 2 diabetes suggests that high-risk patients should be provided with an equally aggressive strategy to protect their remaining beta-cell function and endogenous insulin secretion. Management of patients with prediabetes should incorporate both lifestyle and pharmacologic intervention. Although no specific recommendations are published for the management of prediabetes, one can assume that preservation of pancreatic beta-cell function, improvement in peripheral insulin resistance and pancreatic insulin secretion, reducing pancreatic alpha-cell secretion of glucagon, preventing long- and short-term diabetes-related complications, and assisting patients to loose weight are beneficial. Aggressive, timely, and physiologic management of prediabetes should be advocated.
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PMID:Preventing type 2 diabetes. 1892 23

Ultrastructural observations reveal a continuous interstitial matrix connection between the endocrine and exocrine pancreas, which is lost due to fibrosis in rodent models and humans with type 2 diabetes mellitus (T2DM). Widening of the islet-exocrine interface appears to result in loss of desmosomes and adherens junctions between islet and acinar cells and is associated with hypercellularity consisting of pericytes and inflammatory cells in T2DM pancreatic tissue. Organized fibrillar collagen was closely associated with pericytes, which are known to differentiate into myofibroblasts-pancreatic stellate cells. Of importance, some pericyte cellular processes traverse both the connecting islet-exocrine interface and the endoacinar interstitium of the exocrine pancreas. Loss of cellular paracrine communication and extracellular matrix remodeling fibrosis in young animal models and humans may result in a dysfunctional insulino-acinar-ductal-incretin gut hormone axis, resulting in pancreatic insufficiency and glucagon-like peptide deficiency, which are known to exist in prediabetes and overt T2DM in humans.
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PMID:Attenuation of endocrine-exocrine pancreatic communication in type 2 diabetes: pancreatic extracellular matrix ultrastructural abnormalities. 1904 May 93


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