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)

Ketotic, insulin-requiring diabetes mellitus and a severe peripheral neuropathy developed in a previously healthy 25-year-old man several days after he attempted suicide with rat poison containing N-3-pyridylmethyl N'-p-nitrophenyl urea. Study of islet-cell function ten months after ingestion showed a reduced disappearance rate of intravenous glucose and depressed C-peptide response to intravenous glucose when compared with a normal control but no impairment of glucagon release after intravenous arginine stimulation. Nerve conduction studies demonstrated severe sensory and mild motor neuropathy. Quadriceps capillary basement membrane thickness was in the diabetic range. Because at least 15 similar occurrences have been reported to the manufacturer, this agent appears to be diabetogenic in man, probably causing beta-cell destruction. Niacinamide, which can prevent glucose intolerance in both streptozocin- and alloxan-treated animals and prevents death in rats given this rodenticide, may be a useful antidote.
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PMID:Diabetes mellitus following rodenticide ingestion in man. 20 29

The success rate of pancreas transplantation allows us to study in more detail the potential beneficial effects of normoglycemia on secondary complications in diabetes mellitus. We report a prospective follow-up (mean 26 mo) of metabolic control, neuropathy, retinopathy, and peripheral microcirculation in 31 patients with type I (insulin-dependent) diabetes (mean age 33 +/- 1 yr; mean duration of diabetes 21 +/- 1 yr) after combined kidney and segmental pancreas grafting. All patients had normal HbA1 levels. Glucose tolerance (GT), insulin, C-peptide, and glucagon were normal in 22 patients, and impaired oral GT with reduced insulin secretory capacity was seen in 9 patients. During follow-up, there was no deterioration of GT and insulin release. Vascular risk factors, e.g., hypertension, cholesterol, and triglycerides, decreased after grafting. Autonomic neuropathy improved clinically, and R-R variation increased significantly in 3 of 18 patients. Peripheral neuropathy improved clinically in 46% of patients and did not deteriorate in the others. Motor nerve conduction velocity increased greater than 20% in 8, less than 20% in 12, and was unchanged in 8 of 28 recipients. Most of the patients (n = 30) had pretransplant laser treatment of their advanced retinopathy. Posttransplant visual acuity improved at least more than one line in 56%, stabilized in 32%, and deteriorated in 12% of patients. Patients with functioning grafts for greater than 1 yr had no further deterioration of visual acuity. Vitreous hemorrhage frequency and severity dropped markedly from pretransplant (from 69 to 24%) 10 mo after grafting. Retinal morphology remained stable in all eyes except two.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Fate of late complications in type I diabetic patients after successful pancreas-kidney transplantation. 264 53

Exocrine pancreatic insufficiency has been observed in some diabetics with peripheral neuropathy and diarrhea. Several mechanisms may be responsible for this insufficiency: (1) pancreatic atrophy, (2) disruption of the cholinergic enteropancreatic reflexes, or (3) elevated serum levels of peptides such as glucagon and pancreatic polypeptide which are known to inhibit pancreatic exocrine secretion. To clarify the mechanism(s) involved in this exocrine pancreatic impairment, we studied 10 diabetics with diarrhea and peripheral neuropathy. Their results were compared to those of eight normal volunteers. Each subject underwent a standardized pancreatic function study which assessed nonstimulated secretion, the response to intrajejunal infusion of a mixture of amino acids, and the output following intravenous administration of secretin and cholecystokinin (CCK). In separate studies, the effect of a background infusion of bethanechol and secretin on the pancreatic response to CCK was assessed in six patients and six normal controls. Compared to normals, all diabetics exhibited a significant reduction in both enzyme and bicarbonate secretion to all stimuli. This reduction was not corrected by administering bethanechol. Plasma glucagon and pancreatic polypeptide levels in diabetics were not significantly higher than those in controls. We conclude that diabetics with diarrhea and peripheral neuropathy exhibit impairment of their exocrine pancreatic secretion and possible mechanisms for this are discussed.
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PMID:Impaired exocrine pancreatic function in diabetics with diarrhea and peripheral neuropathy. 289 72

A young, diabetic woman suffering from fainting spells, vomiting, and diarrhea is described. Extensive investigations showed total cardiac denervation, orthostatic hypotension, and disturbances in the the pupillary and sudomotor functions, as well as impairment of glucagon secretion during hypoglycemia. These disturbances were found to be caused by autonomic neuropathy. No signs of peripheral neuropathy could be detected. To the best of our knowledge this is the second case of total cardiac denervation due to diabetic neuropathy described in the literature.
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PMID:Cardiac denervation and other multisystem manifestations caused by isolated autonomic neuropathy in a young diabetic patient. 743 22

In order to evaluate clinical presentation and to determinate classification criteria of type 1 diabetes in the elderly, we carried out a study in 258 diabetic patients more than 60 years old of which 100 used insulin by failure to oral hypoglycemic agents (OHA). The prevalence of ischemic cardiovascular disease was 36%, peripheral vascular disease 34% and stroke 30%. Non-proliferative retinopathy 47%, nephropathy 16% and peripheral neuropathy 37%. Cardiovascular risk factors as obesity (36%), hypertension (33%) and hypercholesterolemia (12%) were evaluated. The average duration of diabetes was 20 years. Post-glucagon C-Peptide, HLA-DR antigens and islet cell antibodies (ICA), were measured in 75 older diabetic patients on treatment of which 24 used insulin, 11 diet and 40 OHA. Older patients on treatment with insulin had longer duration of disease, less obesity, low level basal of C-Peptide and a low response to post glucagon C-Peptide (0.94 +/- 0.5 pmol/ml) compared with patients on diet (1.8 +/- 0.9 pmol/ml) and OHA (1.8 +/- 0.8 pmol/ml). Older diabetics on insulin therapy had a greater frequency of HLA-DR3 (42%) and HLA-DR4 (21%) than other older diabetics. The ICA was negative in most patients. This study shows the high prevalence of macrovascular and microvascular disease in elderly patients with diabetes mellitus and that the most reliable parameter in classifying type 1 (insulin-dependent) diabetes is the measurement of basal and post-glucagon C-Peptide. HLA-DR specific markers can be used with this parameter because their expression is partly shared. This approach appears useful in the older diabetic patients to help classify diabetes and its management.
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PMID:[Diabetes mellitus in the elderly: a study on its clinical presentation, C-peptide reserve, and immunogenetic markers of insulin dependence]. 848 59

Optimal blood glucose levels and normal insulin sensitivity are aims in the treatment of insulin-dependent diabetes mellitus (IDDM). Insulin sensitivity and insulin reserve are closely interrelated. It is essential to know more about both of these parameters at clinical diagnosis, because their preservation may delay the occurrence of diabetes-related complications. B-cell function is likely to be retained for a longer period in patients with adult onset of the disease compared with children. In this study, intensive insulin treatment was initiated in newly diagnosed adult patients to determine if it preserved endogenous insulin secretion longer than conventional therapy. Forty-nine patients with newly diagnosed diabetes were carefully categorized as having IDDM according to clinical and serological criteria. They were randomized to an intensive (I group) or conventional (C group) insulin therapy and evaluated for 5 years. Every 6 months, a check-up included glucagon-stimulated C-peptide (GSCP), hyperglycemic glucose clamp with arginine bolus, euglycemic-hyperinsulinemic clamp, and screening for microalbuminuria, retinopathy, and neuropathy. At the end of the study, hemoglobin A1c (HbA1c) was 6.3% +/- 1.9% in the I patients and 8.1% +/- 2.1% in the C patients (P < .001). Blood glucose concentrations less than 3.5 mmol/L were more frequent in the I group than in the C group (P < .05). Insulin sensitivity (M/I) and GSCP were higher in intensively treated patients after 5 years (M/I, I group 40 +/- 10 nmol x kg(-1) x min(-1) x pmol/L1 v C group 21 +/- 11, P < .005; GSCP, I group 0.6 +/- 0.2 nmol/L v C group 0.19 +/- 0.11, P < .005). The prevalence of peripheral neuropathy was significantly lower in the I group at the end of the study. In conclusion, intensive therapy is more effective in the preservation of insulin action and reserve. In our patients, no case of severe hypoglycemia was observed, indicating that intensive therapy was safe in these patients.
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PMID:Intensive therapy in adult insulin-dependent diabetes mellitus is associated with improved insulin sensitivity and reserve: a randomized, controlled, prospective study over 5 years in newly diagnosed patients. 896 84

Persistent humoral autoimmunity to the enzyme glutamic acid decarboxylase (GAD) has been described in a substantial proportion of patients with insulin-dependent diabetes mellitus (IDDM) of long duration. The source of the stimulus for this autoimmune reactivity is still unknown. Because the GAD 65 isoform is mainly expressed in pancreatic beta-cells and in the nervous system we investigated in the present study of the largest number of well characterized patients with longstanding IDDM (n = 105; median duration: 21 years; range: 10-46 years) the presence of autoantibodies to GAD 65 and their relationship to a residual C-peptide response or peripheral and autonomic neuropathy. Additionally we studied the HLA-DR status relative to GAD 65 antibodies in 86 out of the 105 individuals. One hundred healthy control subjects and 100 recent onset IDDM patients were also studied for GAD 65 antibodies. GAD 65 antibodies were detected in a radioligand-binding-assay with recombinant human GAD 65 and were present in 32% of the long-term diabetic patients, 82% of the recent onset IDDM patients and in 3% of the healthy control subjects. A preserved C-peptide response to i.v. glucagon (Hendriksen criteria) was observed in 23% of the long-term IDDM patients. Autonomic neuropathy and peripheral neuropathy was identified using criteria based on both symptoms and formal testing giving a frequency of 67% vs 79%. The HLA specific DR 4/X was observed in 47% and HLA-DR 3/X in 22% of the long-term IDDM patients. Patients who were heterozygous for DR3/DR4 were found in 23% of the cases. GAD 65 antibodies were significantly less frequent in the long-term IDDM patients compared to recent onset IDDM (p < 0.001), and diabetes duration showed a significant negative correlation with GAD 65 antibody index levels (r = 0.22, p < 0.01). Interestingly, GAD 65 antibodies were not significantly correlated either with residual beta-cell function or neuropathy and no particular HLA-DR status was associated with persistent GAD 65 antibodies. In conclusion neither residual beta-cell function nor diabetic neuropathy or a certain HLA-DR specificity are exclusively associated with persistent autoimmunity directed to GAD 65 in longstanding IDDM. The stimulus for the persistent humoral immune response and its significance for the disease process and its complications remain to be established.
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PMID:Persistent GAD 65 antibodies in longstanding IDDM are not associated with residual beta-cell function, neuropathy or HLA-DR status. 940 79

The insulinotropic hormone glucagon-like peptide-1 (7-36)-amide (GLP-1) has potent effects on glucose-dependent insulin secretion, insulin gene expression, and pancreatic islet cell formation and is presently in clinical trials as a therapy for type 2 diabetes mellitus. We report on the effects of GLP-1 and two of its long-acting analogs, exendin-4 and exendin-4 WOT, on neuronal proliferation and differentiation, and on the metabolism of two neuronal proteins in the rat pheochromocytoma (PC12) cell line, which has been shown to express the GLP-1 receptor. We observed that GLP-1 and exendin-4 induced neurite outgrowth in a manner similar to nerve growth factor (NGF), which was reversed by coincubation with the selective GLP-1 receptor antagonist exendin (9-39). Furthermore, exendin-4 could promote NGF-initiated differentiation and may rescue degenerating cells after NGF-mediated withdrawal. These effects were induced in the absence of cellular dysfunction and toxicity as quantitatively measured by 3-(4,5-cimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide and lactate dehydrogenase assays, respectively. Our findings suggest that such peptides may be used in reversing or halting the neurodegenerative process observed in neurodegenerative diseases, such as the peripheral neuropathy associated with type 2 diabetes mellitus and Alzheimer's and Parkinson's diseases. Due to its novel twin action, GLP-1 and exendin-4 have therapeutic potential for the treatment of diabetic peripheral neuropathy and these central nervous system disorders.
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PMID:A novel neurotrophic property of glucagon-like peptide 1: a promoter of nerve growth factor-mediated differentiation in PC12 cells. 1186 4

Pyridoxine (vitamin B6) intoxicated rodents develop a peripheral neuropathy characterized by sensory nerve conduction deficits associated with disturbances of nerve fiber geometry and axonal atrophy. To investigate the possibility that glucagon-like peptide-1 (7-36)-amide (GLP-1) receptor agonism may influence axonal structure and function through neuroprotection neurotrophic support, effects of GLP-1 and its long acting analog, Exendin-4 (Ex4) treatment on pyridoxine-induced peripheral neuropathy were examined in rats using behavioral and morphometric techniques. GLP-1 is an endogenous insulinotropic peptide secreted from the gut in response to the presence of food. GLP-1 receptors (GLP-1R) are coupled to the cAMP second messenger pathway, and are expressed widely throughout neural tissues of humans and rodents. Recent studies have established that GLP-1 and Ex4, have multiple synergistic effects on glucose-dependent insulin secretion pathways of pancreatic beta-cells and on neural plasticity. Data reported here suggest that clinically relevant doses of GLP-1 and Ex4 may offer some protection against the sensory peripheral neuropathy induced by pyridoxine. Our findings suggest a potential role for these peptides in the treatment of neuropathies, including that associated with type II diabetes mellitus.
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PMID:Evidence of GLP-1-mediated neuroprotection in an animal model of pyridoxine-induced peripheral sensory neuropathy. 1712 67

Glucagon-like peptide 1 (GLP-1) is a relatively recently discovered molecule originating in the so-called L-cells of the intestine. The peptide has insulinotrophic properties and it is this characteristic that has predominantly been investigated. This has led to the use of the GLP-1-like peptide exendin-4 (EX-4), which has a much longer plasma half-life than GLP-1 itself, being used in the treatment of type II diabetes. The mode of action of this effect appears to be a reduction in pancreatic apoptosis, an increase in beta cell proliferation or both. Thus, the effects of GLP-1 receptor stimulation are not based upon insulin replacement but an apparent repair of the pancreas. Similar data suggest that the same effects may occur in other peripheral tissues. More recently, the roles of GLP-1 and EX-4 have been studied in nervous tissue. As in the periphery, both peptides appear to promote cellular growth and reduce apoptosis. In models of Alzheimer's disease, Parkinson's disease and peripheral neuropathy, stimulation of the GLP-1 receptor has proved to be highly beneficial. In the case of Parkinson's disease this effect is evident after the neurotoxic lesion is established, suggesting real potential for therapeutic use. In the present review we examine the current status of the GLP-1 receptor and its potential as a therapeutic target.
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PMID:Glucagon-like peptide 1 receptor stimulation as a means of neuroprotection. 2012


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