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)

Endothelial cells (EC) from diabetic BioBreeding (BB) rats have an impaired ability to produce NO. This deficiency is not due to a defect in the constitutive isoform of NO synthase in EC (ecNOS) or alterations in intracellular calcium, calmodulin, NADPH or arginine levels. Instead, ecNOS cannot produce sufficient NO because of a deficiency in tetrahydrobiopterin (BH(4)), a cofactor necessary for enzyme activity. EC from diabetic rats exhibited only 12% of the BH(4) levels found in EC from normal animals or diabetes-prone animals which did not develop disease. As a result, NO synthesis by EC of diabetic rats was only 18% of that for normal animals. Increasing BH(4) levels with sepiapterin increased NO production, suggesting that BH(4) deficiency is a metabolic basis for impaired endothelial NO synthesis in diabetic BB rats. This deficiency is due to decreased activity of GTP-cyclohydrolase I, the first and rate-limiting enzyme in the de novo biosynthesis of BH(4). GTP-cyclohydrolase activity was low because of a decreased expression of the protein in the diabetic cells.
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PMID:Impaired nitric oxide production in coronary endothelial cells of the spontaneously diabetic BB rat is due to tetrahydrobiopterin deficiency. 1086 Dec 47

Sustained hyperglycemia induces insulin resistance, but the mechanism is still incompletely understood. Glucosamine (GlcN) has been extensively used to model the role of the hexosamine synthesis pathway (HSP) in glucose-induced insulin resistance. 3T3-L1 adipocytes were preincubated for 18 h in media +/- 0.6 nmol/l insulin containing either low glucose (5 mmol/l), low glucose plus GlcN (0.1-2.5 mmol/l), or high glucose (25 mmol/l). Basal and acute insulin-stimulated (100 nmol/l) glucose transport was measured after re-equilibration in serum and insulin-free media. Preincubation with high glucose or GlcN (1-2.5 mmol/l) inhibited basal and acute insulin-stimulated glucose transport only if insulin was present during preincubation. However, only preincubation with GlcN plus insulin inhibited insulin-stimulated GLUT4 translocation. GLUT4 and GLUT1 protein expression were not affected. GlcN (2.5 mmol/l) increased cellular UDP-N-acetylhexosamines (UDP-HexNAc) by 400 and 900% without or with insulin, respectively. High glucose plus insulin increased UDP-HexNAc by 30%. GlcN depleted UDP-hexoses, whereas high glucose plus insulin increased them. Preincubation with 0.5 mmol/l GlcN plus insulin maximally increased UDP-HexNAc without affecting insulin-stimulated or basal glucose transport. GlcN plus insulin (but not high glucose plus insulin) caused marked GlcN dose-dependent accumulation of GlcN-6-phosphate, which correlated with insulin resistance of glucose transport (r = 0.935). GlcN plus insulin (but not high glucose plus insulin) decreased ATP (10-30%) and UTP (>50%). GTP was not measured, but GDP increased. Neither high glucose plus insulin nor GlcN plus insulin prevented acute insulin stimulation (approximately 20-fold) of insulin receptor substrate 1-associated phosphatidylinositol (PI)-3 kinase. We have come to the following conclusions. 1) Chronic exposure to high glucose or GlcN in the presence of low insulin caused insulin resistance of glucose transport by different mechanisms. 2) GlcN inhibited GLUT4 translocation, whereas high glucose impaired GLUT4 "intrinsic activity" or membrane intercalation. 3) Both agents may act distally to PI-3 kinase. 4) GlcN has metabolic effects not shared by high glucose. GlcN may not model HSP appropriately, at least in 3T3-L1 adipocytes.
Diabetes 2000 Jun
PMID:High glucose and glucosamine induce insulin resistance via different mechanisms in 3T3-L1 adipocytes. 1086 51

Glutamate dehydrogenase (GDH) is allosterically activated by the amino acid leucine to mediate protein stimulation of insulin secretion. Children with the hyperinsulinism/hyperammonemia (HI/HA) syndrome have symptomatic hypoglycemia plus persistent elevations of plasma ammonium. We have reported that HI/HA may be caused by dominant mutations of GDH that lie in a unique allosteric domain that is encoded within GDH exons 11 and 12. To examine the frequency of mutations in this domain, we screened genomic DNA from 48 unrelated cases with the HI/HA syndrome for exon 11 and 12 mutations in GDH. Twenty-five (52%) had mutations in these exons; 74% of the mutations were sporadic. Clinical manifestations included normal birth weight, late onset of hypoglycemia, diazoxide responsiveness, and protein-sensitive hypoglycemia. Enzymatic studies of lymphoblast GDH in seven of the mutations showed that all had reduced sensitivity to inhibition with GTP, consistent with an increase in enzyme activity. Mutations had little or no effect on enzyme responses to positive allosteric effectors, such as ADP or leucine. Based on the three-dimensional structure of GDH, the mutations may function by impairing the binding of an inhibitory GTP to a domain responsible for the allosteric and cooperativity properties of GDH.
Diabetes 2000 Apr
PMID:Molecular basis and characterization of the hyperinsulinism/hyperammonemia syndrome: predominance of mutations in exons 11 and 12 of the glutamate dehydrogenase gene. HI/HA Contributing Investigators. 1087 Dec 7

The changes in beta-adrenergic receptors and in adenylate cyclase (AC) activity were investigated in parotid glands from rats with acute diabetic mellitus (DM) induced by a single injection of streptozotocin (STZ, 80 mg/kg). The animals were divided into three groups: control rats, DM rats, and insulin-treated DM rats. Experiments were performed 7 days after the injection of STZ. Amylase and norepinephrine (NE) contents in parotid glands were markedly decreased in DM rats in comparison with control rats. The density of beta-adrenergic receptor decreased in DM rats, but its affinity for ligand was unaffected. The effect of GTP on isoprenaline (ISO)-stimulated adenylate cyclase (AC) activity significantly decreased in DM rats, but forskolin-stimulated AC activity was unaltered. In addition, diabetes induced the blunted response of AC activity to ISO. The changes in AC activity and in amylase content induced by diabetes were restored by insulin, but those in NE content and receptor density could not. These observations indicate that diabetes decreases NE and amylase contents, receptor density, and receptor-AC coupling in parotid gland, and that these changes would occur in the earlier stage of acute STZ-induced diabetic state.
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PMID:Beta-adrenergic receptors and adenylate cyclase activity in the parotid acinar cells from acute streptozotocin-induced diabetic rats. 1148 85

The stimulus-response coupling pathway for glucose-regulated insulin secretion has implicated a rise in cytosolic [Ca2+]i as a key factor to induce insulin exocytosis. However, it is unclear how elevated [Ca2+]i communicates with the pancreatic beta-cell's exocytotic apparatus. As Rab3A is a model protein involved in regulated exocytosis, we have focused on its role in regulating insulin exocytosis. By using a photoactivatable cross-linking synthetic peptide that mimics the effector domain of Rab3A and microsequence analysis, we found calmodulin to be a major Rab3A target effector protein in pancreatic beta-cells. Coimmunoprecipitation analysis from pancreatic islets confirmed a Rab3A-calmodulin interaction in vivo, and that it inversely correlated with insulin exocytosis. Calmodulin affected neither GTPase nor guanine nucleotide exchange activity of Rab3A. The calmodulin-Rab3A interaction was pH- and Ca2+-dependent, and it was preferential for GTP-bound Rab3A. However, Rab3A affinity for calmodulin was relatively low (Kd = 18-22 micromol/l at 10(-5) mol/l [Ca2+]) and competed by other calmodulin-binding proteins that had higher affinity (e.g., Ca2+/calmodulin-dependent protein kinase-2 [CaMK-2] [Kd = 300-400 nmol/l at 10(-5) mol/l [Ca2+]]). Moreover, the Ca2+ dependence of the calmodulin-Rab3A interaction (K0.5 = 15-18 micromol/l [Ca2+], maximal at 100 micromol/l [Ca2+]) was significantly lower compared with that of the calmodulin-CaMK-2 association (K0.5 = 40 micromol/l [Ca2+], maximal at 1 mmol/l [Ca2+]). The data suggested that a transient Rab3A-calmodulin interaction might represent a means of directing calmodulin to the cytoplasmic face of a beta-granule, where it can be subsequently transferred for activation of other beta-granule-associated calmodulin-binding proteins as local [Ca2+]i rises to promote insulin exocytosis.
Diabetes 2001 Sep
PMID:A low-affinity Ca2+-dependent association of calmodulin with the Rab3A effector domain inversely correlates with insulin exocytosis. 1152 68

In order to investigate whether there would be any association between abnormalities of either reg1 alpha or reg1 beta gene and diabetes mellitus in man, these two genes were analyzed in 42 patients with type 1 diabetes mellitus, 12 with fibrocalculous pancreatopathy, 37 with type 2 diabetes mellitus, and 22 normal controls, by PCR-SSCP analysis and nucleotide sequencing technique. Polymorphism in the reg1 alpha gene resulted in three mobility patterns in the PCR-SSCP analysis, due to nucleotide constituents at position -10 before exon 1 being either C/C, T/C or T/T. These three mobility patterns were observed in every group of subjects. The analysis of reg1 beta gene showed nucleotide substitutions in exon 4 in one patient, exon 5 in another patient with type 1 diabetes, and in exon 4 and intron 5 in one patient with fibrocalculous pancreatopathy. The nucleotide substitutions in exon 4 in the patient with type 1 diabetes and that with fibrocalculous pancreatopathy occurred at codons 103 and 84 while that in exon 5 in the patient with type 1 diabetes occurred at codon 141, changing the codons from CAT to CAC, GTG to GCG, and ACT to AAT and resulting in H103H silent, V84A and T141N missense mutations, respectively. In conclusion, using PCR-SSCP and nucleotide sequence analyses, we did not find any association between abnormalities of either reg1 alpha or reg1 beta gene with any type of diabetes studied.
Diabetes Res Clin Pract 2002 Feb
PMID:No abnormalities of reg1 alpha and reg1 beta gene associated with diabetes mellitus. 1179 76

The beta-cell mitochondria are known to generate metabolic coupling factors, or messengers, that mediate plasma membrane depolarization and the increase in cytosolic Ca(2+), the triggering event in glucose-stimulated insulin secretion. Accordingly, ATP closes nucleotide-sensitive K(+) channels necessary for the opening of voltage-gated Ca(2+) channels. ATP also exerts a permissive action on insulin exocytosis. In contrast, GTP directly stimulates the exocytotic process. cAMP is considered to have a dual function: on the one hand, it renders the beta-cell more responsive to glucose; on the other, it mediates the effect of glucagon and other hormones that potentiate insulin secretion. Mitochondrial shuttles contribute to the formation of pyridine nucleotides, which may also participate in insulin exocytosis. Among the metabolic factors generated by glucose, citrate-derived malonyl-CoA has been endorsed, but recent results have questioned its role. We have proposed that glutamate, which is also formed by mitochondrial metabolism, stimulates insulin exocytosis in conditions of permissive, clamped cytosolic Ca(2+) concentrations. The evidence for the implication of these and other putative messengers in metabolism-secretion coupling is discussed in this review.
Diabetes 2002 Feb
PMID:Beta-cell mitochondria and insulin secretion: messenger role of nucleotides and metabolites. 1181 56

We report crystal structures of the human enzyme phosphoenolpyruvate carboxykinase (PEPCK) with and without bound substrates. These structures are the first to be determined for a GTP-dependent PEPCK, and provide the first view of a novel GTP-binding site unique to the GTP-dependent PEPCK family. Three phenylalanine residues form the walls of the guanine-binding pocket on the enzyme's surface and, most surprisingly, one of the phenylalanine side-chains contributes to the enzyme's specificity for GTP. PEPCK catalyzes the rate-limiting step in the metabolic pathway that produces glucose from lactate and other precursors derived from the citric acid cycle. Because the gluconeogenic pathway contributes to the fasting hyperglycemia of type II diabetes, inhibitors of PEPCK may be useful in the treatment of diabetes.
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PMID:Crystal structure of human cytosolic phosphoenolpyruvate carboxykinase reveals a new GTP-binding site. 1185 36

Glutamate dehydrogenase (GDH) is important in normal glucose homeostasis. Mutations of GDH result in hyperinsulinism/hyperammonemia syndrome. Using PCR/single-strand conformation polymorphism analysis of the gene encoding GDH in 12 Japanese patients with persistent hyperinsulinemic hypoglycemia of infancy (PHHI), we found a mutation (Y266C) in one PHHI patient. This mutation was not found in any of the control or type 2 diabetic subjects. The activity of the mutant GDH (GDH266C), expressed in COS-7 cells, was constitutively elevated, and allosteric regulations by ADP and GTP were severely impaired. The effect of the unregulated increase in GDH activity on insulin secretion was examined by overexpressing GDH266C in an insulinoma cell line, MIN6. Although glutamine alone did not stimulate insulin secretion from control MIN6-lacZ, it remarkably stimulated insulin secretion from MIN6-GDH266C. This finding suggests that constitutively activated GDH enhances oxidation of glutamate, which is intracellularly converted from glutamine to alpha-ketoglutarate, a tricarboxylic acid cycle substrate, which thereby stimulates insulin secretion. Interestingly, insulin secretion is also exaggerated significantly at low glucose concentrations (2 and 5 mmol/l) but not at higher glucose concentrations (8--25 mmol/l). Our results directly illustrate the importance of GDH in the regulation of insulin secretion from pancreatic beta-cells.
Diabetes 2002 Mar
PMID:Unregulated elevation of glutamate dehydrogenase activity induces glutamine-stimulated insulin secretion: identification and characterization of a GLUD1 gene mutation and insulin secretion studies with MIN6 cells overexpressing the mutant glutamate dehydrogenase. 1187 71

The present studies were undertaken to determine the levels of stimulatory and inhibitory guanine nucleotide regulatory proteins (Gs and Gi respectively) and their relationship with adenylyl cyclase activity in aorta from 5-day streptozotocin-induced diabetic (STZ) rats. The levels of Gi alpha-2 as determined by immunoblotting techniques using AS/7 antibody were significantly decreased by about 60% in STZ as compared to control rats, whereas the levels of Gs alpha were not altered. In addition, the stimulatory effect of cholera toxin (CT) on GTP-sensitive adenylyl cyclase was not different in STZ as compared to control rats. On the other hand, the stimulatory effects of GTPgammaS, isoproterenol, glucagon, forskolin (FSK) and sodium fluoride on adenylyl cyclase were enhanced in STZ-rats. Furthermore, GTPgammaS inhibited FSK-stimulated adenylyl cyclase activity in a concentration-dependent manner (receptor independent functions of Gi) in control rats which was almost completely abolished in STZ rats. In addition, receptor-mediated inhibition of adenylyl cyclase by angiotensin II (AII), oxotremorine and atrial natriuretic peptide (ANP) was attenuated in STZ rats. These results suggest that the decreased expression of Gi alpha, but not of Gs alpha, may be responsible for the observed altered responsiveness of adenylyl cyclase to hormonal stimulation and inhibition in STZ-rats. It may thus be suggested that the decreased Gi activity may be one of the possible mechanisms responsible for the impaired vascular functions in diabetes.
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PMID:Alterations in g-protein-linked signal transduction in vascular smooth muscle in diabetes. 1190 Mar 77


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