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)

Energy stores and intermediates of carbohydrate metabolism were investigated in the freeze-clamped cerebral cortex of the fetus and fasted neonate born to a diabetic canine mother. Prior studies in these same pups demonstrated circulating hyperinsulinemia, depressed free fatty acid levels, and attenuated gluconeogenesis. Hepatic and muscle tissue also demonstrated augmented levels of glycogen, triglycerides, and amino acids. In the present investigation, cerebral tissue from these same pups of diabetic mothers also demonstrated enhanced fetal cerebral glucose and glycogen content. After 24 h of neonatal fasting, cerebral glycogen content declined to values lower than in control pups. Cerebral cortical levels of glucose-6-phosphate, fructose-6-phosphate, lactate, citrate, alpha-ketoglutarate, and malate were not altered, while oxaloacetate was higher at 3 and 9 h and fructose-1,6-diphosphate was higher at 9 and 24 h in the IDM pups. Adenine nucleotide levels and the energy charge were equivalent to those in control pups at each time interval. In contrast, cerebral cortical amino acids of the glutamate group were enhanced in the fetus or neonate of the diabetic mother. Cerebral cortical alanine was increased from 3 to 24 h while aspartate and glutamate were augmented in the fetus and fasted IDM newborn pup. Glutamine was increased at 6 and 24 h, while gamma-aminobutyrate was elevated in the fetus. Cerebral ammonia concentration was not altered. The augmented stores of cerebral carbohydrate and amino acid pools in the fetus and neonate after maternal canine diabetes may serve as oxidizable substrates for the brain during periods of attenuated systemic fuel availability.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1985 Feb
PMID:Enhanced cerebral substrate pools in the fetus and neonate of the diabetic canine mother. 285 42

To evaluate whether the gamma-aminobutyric acid (GABA)ergic system plays a role in the defective insulin secretion in human diabetes mellitus, 15 non-insulin-dependent diabetics with fasting hyperglycemia above 140 mg/dl were submitted to two consecutive i.v. glucose tolerance tests (IVGTT) (0.33 g/kg b.w.), in basal conditions and after pharmacologic activation of the GABA system with baclofen and sodium valproate. Baclofen, a synthetic analogue, was given to 8 diabetics in two divided doses of 10 mg each 8h and 1h before the post-treatment test; sodium valproate, a drug that increases endogenous GABA activity, was given orally (800 mg) 60 min before the performance of the post-treatment IVGTT. Neither treatment brought about significant changes in insulin, C-peptide, glucagon or growth hormone responses to i.v. glucose nor did they significantly change glucose disappearance rates. These results seem to indicate that GABA does not play a major role in the pathogenesis of defective insulin secretion in non-insulin-dependent diabetes mellitus.
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PMID:Impaired insulin secretion in human diabetes mellitus. Effect of pharmacological activation of gamma-aminobutyric acid system. 301 23

Stiff-man syndrome is a rare disorder of the central nervous system consisting of progressive, fluctuating muscle rigidity with painful spasms. It is occasionally associated with endocrine disorders, including insulin-dependent diabetes, and with epilepsy. We investigated the possible existence of autoimmunity against the nervous system in a patient with stiff-man syndrome associated with epilepsy and Type I diabetes mellitus. Levels of IgG, which had an oligoclonal pattern, were elevated in the cerebrospinal fluid. The serum and the cerebrospinal fluid produced an identical, intense staining of all gray-matter regions when used to stain brain sections according to an indirect light-microscopical immunocytochemical procedure. The staining patterns were identical to those produced by antibodies to glutamic acid decarboxylase (the enzyme responsible for the synthesis of gamma-aminobutyric acid). A band comigrating with glutamic acid decarboxylase in sodium dodecyl sulfate-polyacrylamide gels appeared to be the only nervous-tissue antigen recognized by cerebrospinal fluid antibodies, and the predominant antigen recognized by serum antibodies. These findings support the idea that an impairment of neuronal pathways that operate through gamma-aminobutyric acid is involved in the pathogenesis of stiff-man syndrome, and they raise the possibility of an autoimmune pathogenesis.
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PMID:Autoantibodies to glutamic acid decarboxylase in a patient with stiff-man syndrome, epilepsy, and type I diabetes mellitus. 328 Oct 11

This study examines the effect of muscimol, a high affinity, specific gamma-aminobutyric acid (GABA) agonist, on glucose-stimulated somatostatin and insulin release from the isolated, perfused rat pancreas. Perfusion with low glucose (50 mg/dl) conditions resulted in basal somatostatin release of 46 +/- 4 pg/ml. Basal insulin release was less than 20 microU/ml. High glucose (300 mg/dl) conditions stimulated somatostatin and insulin release. Steady-state levels of somatostatin and insulin release under high glucose conditions were 425 +/- 12 pg/ml and 419 +/- 18 microU/ml, respectively. Perfusion with medium containing 1 microM muscimol inhibited glucose-stimulated somatostatin release by 38%, whereas the course of glucose-stimulated insulin release was unaffected. Tentative conclusions from this study are (1) that GABA is potentially a modulator of islet somatostatin but not insulin release, and (2) the fact that somatostatin, an inhibitor of insulin, can be suppressed 38% without coincidental increase in insulin release seems to indicate that, under high glucose conditions, somatostatin is without a significant paracrine effect on the beta-cells.
Diabetes 1981 Feb
PMID:Effect of muscimol on glucose-stimulated somatostatin and insulin release from the isolated, perfused rat pancreas. 611 May 97

Diabetes-prone NOD mice of both sexes and at different ages were compared to control mice with regard to the level of pancreatic expression of certain autoantigens: antigens for islet cell antibodies (ICA antigens) and glutamic acid decarboxylase (GAD) 67 kDa. ICA antigens were compared by immunofluorescence using serial dilutions of ICA positive human sera so that differences of fluorescence intensity were due only to differences in amounts of antigen. Pancreatic GAD67 mRNAs were compared by polymerase chain reaction followed by Southern hybridization with 32P-probes and densitometry of autoradiographic bands. GAD67 product and gamma-aminobutyric acid (GABA) were compared by immunoperoxidase staining. As compared to BALB/c, C57BL6, Swiss, or F1 mice, NOD mice displayed higher ICA antigen levels (P < 0.01) both before and after insulitis onset (at 7 days, 15 days, 1 month, 2 months). ICA antigens were scarcely detectable by the first day of life, and increased with age from 7 days to 2 months (P < 0.01; n = 10 for each strain and at each age). Both before and after insulitis onset (4 days, 7 days, 15 days, 1 month, 2 months), amounts of GAD67 mRNAs were higher (P < 0.01) in NOD mice than in BALB/c mice (n = 8 for each age in each strain). This was already noted in foetuses on Day 18 of gestation (n = 8). After birth, amounts of GAD67 mRNAs increased up to 1 month (P < 0.04) and then decreased in older mice. The staining intensity of pancreatic sections with antisera against either GAD67 or GABA was higher (P < 0.04) in islets from NOD mice than in those from control mice. Whatever the age, no significant difference was noted between female and male NOD mice with regard to ICA antigens or GAD67. The expression of ICA antigens and GAD67 was intermediate in NOD x BALB/c F1 mice when compared to parental strains. We conclude that whatever the age, NOD mice strongly express ICA antigens and GAD67. This peculiarity was detectable very early, in embryos for GAD67 but after birth for ICA antigens. The timing of antigen expression may underlie the development of diabetes. The antigen overexpression might affect early completion of self-tolerance and, during later life, might also contribute to amplification of the anti-beta cell autoimmune response due to the existence of more targets for effector mechanisms.
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PMID:Pancreatic expression of antigens for islet cell antibodies in non-obese diabetic mice. 749 44

Glutamic acid decarboxylase (GAD) is the enzyme responsible for the synthesis of gamma-aminobutyric acid (GABA). GAD has been identified as a 64-kDa antigen expressed in pancreatic beta-cells, to which autoantibodies are generated prior to the onset of type 1 (insulin-dependent) diabetes mellitus. GAD may therefore be an initiating factor in beta-cell destruction. We administered baclofen, a GABA-B receptor agonist, to non-obese diabetic (NOD) mice in an attempt to down-regulate GAD expression and thereby reduce the incidence of diabetes. Twenty-four female NOD mice were given baclofen in their drinking water at a final dose of 50 mg/kg body weight daily from weaning to 30 weeks of age. Twenty-four sex- and litter-matched mice were used as controls. At 30 weeks there was no difference in the incidence of diabetes in the treated group compared with the controls. However, there was a significant delay in the onset of diabetes in the treated group (P < 0.001, parallelism test). The degree of insulitis and the GAD activity in the pancreas per mg of protein were unchanged by baclofen treatment with respect to controls. These results suggest that baclofen may be effective in delaying diabetes onset in NOD mice by stimulating GABA activity, as this neurotransmitter, localised in the islets, may modulate insulin secretion and the antigen expression associated with it.
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PMID:Baclofen, a gamma-aminobutyric acid-b receptor agonist, delays diabetes onset in the non-obese diabetic mouse. 761 19

Glutamic acid decarboxylase (GAD) catalyzes the biosynthesis of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). GAD has been suggested as an autoantigen in insulin-dependent diabetes mellitus and stiff-man syndrome. Recently, three forms of membrane-associated GAD (MGAD) have been characterized in porcine brain, but the subcellular localization and function of these proteins are unknown. We present evidence that GAD activity is associated with synaptic vesicles from porcine brain. These vesicles contain a 60 kDa protein recognized by serum from patients with insulin-dependent diabetes mellitus, probably MGADII, as shown by subcellular fractionation and immunoblotting. These results raise the possibility that the association of MGADII with synaptic vesicles may be crucial for its role as an autoantigen in insulin-dependent diabetes mellitus.
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PMID:Synaptic vesicle-associated glutamate decarboxylase: identification and relationship to insulin-dependent diabetes mellitus. 771 21

Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the CNS, taking part in processes which are now relatively well understood but also in processes which are remarkable progress has been achieved. The most thoroughly studied field of GABA operation is its role of inhibitory neurotransmitter realized through the mediation of GABA-A and GABA-B receptors. There are at least 40 per cent of synaptic inhibitory events in the CNS in which the neurotransmitter action of GABA is involved. The action of GABA on GABA-A receptor, a Cl- channel, is influenced by benzodiazepines, barbiturates and other substances, suggesting that some neurological and psychiatric diseases are connected with the function of GABA-A receptor. In addition to synaptic inhibition, GABA has several metabolic regulatory functions. GABA is produced not only in neurons but also in beta cells of the pancreas and in tubular cells of the kidney cortex. Its role in these parenchymatous cells is not sufficiently understood. Similarly as GABA, glutamic acid decarboxylase (GAD), an enzyme catalysing GABA formation from glutamate, has also been intensively studied. GAD structure, its function in various parts of the CNS and in some parenchymatous cells, and the regulation of GAD activity are still in the focus of interest. Recently GAD has been demonstrated to act as autoantigen in the rare neurological disease "stiff man syndrome" (SMS) and in insulin-dependent diabetes mellitus (IDDM). In the presented paper a short review of GABA functions, GAD properties and of the antigenic feature of GAD are given. (Fig. 7, Ref. 41.)
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PMID:[Gamma-aminobutyric acid and glutamate decarboxylase]. 800 82

Three patients with hemiballism-hemichorea caused by non-ketotic hyperglycaemia are presented, two of whom had hyperosmolar non-ketotic hyperglycaemic syndrome. In two of the three patients, the hyperkinesia was the initial presenting symptom of their diabetes mellitus. The hypersensitivity of the postmenopausal dopamine receptor, decreased gamma-aminobutyric acid in the brain in non-ketotic hyperglycaemia, coexisting lacunar infarct in the basal ganglion, and pre-existing metabolic dysfunction in the basal ganglion may all have played a part in the pathogenesis of this movement disorder.
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PMID:Hemiballism-hemichorea and non-ketotic hyperglycaemia. 800 61

To elucidate possible alteration of gamma-aminobutyric acid (GABA) in the diabetic retina, the distribution and determination of GABA was analyzed in streptozotocin-induced diabetic and normal rats after electroretinogram (ERG) recording. Immunoreactivity of GABA was found in the inner nuclear layer, inner plexiform layer, and ganglion cell layer in normal and diabetic rats. In the inner nuclear layer, strong immunoreactivity of GABA was found in amacrine-like cells. In diabetic retinas, GABA immunoreactivity was higher than in normal retinas. The contents of GABA increased began 1 week after occurrence of diabetes mellitus, attained a maximum at 2 months, and maintained this amount for 5 months. The latencies of oscillatory potentials of ERG were prolonged beginning 1 month after occurrence. These results suggest that increase of GABA in the amacrine cells of diabetic retinas may be related with the abnormality of oscillatory potentials.
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PMID:[Alteration of gamma-aminobutyric acid in streptozotocin-induced diabetic rat retina]. 819 14


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