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)

The relationship between the GOT/GPT ratio in nonviral liver disorders and underlying physical condition and life-style were evaluated. The subjects were 12,808 male railway company workers who underwent an annual health checkup. Nonviral liver disorders were defined as elevated transaminases (GOT > 76 IU/liter or GPT > 86 IU/liter, while negative for hepatitis B and C markers (282 cases). Controls were 9,783 males with normal findings for GOT, GPT, and y-GTP. By logistic regression analysis, GOT-dominant liver disorders were significantly related to alcohol consumption, hypertriglyceridemia, and diabetes mellitus. They were still significant on multivariate analysis. GPT-dominant liver disorders were significantly related to obesity, less exercise, hypercholesterolemia, and hypertriglyceridemia. Obesity and hypercholesterolemia were significant on multivariate analysis. In conclusion, the relationship between hypertriglyceridemia or diabetes mellitus and GOT-dominant disorders, which was not explained empirically, could indicate another pathogenesis for nonviral liver disorders, such as underlying insulin resistance.
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PMID:Various S-GOT/S-GPT ratios in nonviral liver disorders and related physical conditions and life-style. 1191 40

Several novel genes that are upregulated in diabetic kidneys have been identified. Recently, transforming growth factor beta driven secreted proteins, i.e., connective tissue growth factor and gremlin (bone morphogenetic protein 2), have been identified, and their expression has been correlated with the tissue changes seen in diabetic nephropathy in the adult population. However, there are very few studies reported in the literature that describe the gene expression in the diabetic state during embryonic and neonatal life. It is well known that exposure to glucose or its epimer, i.e., mannose, induces marked dysmorphogenesis of the embryonic metanephros in an organ culture system. These changes are associated with ATP depletion and marked apoptosis, suggesting an oxidant stress in the induction of dysmorphogenesis of the embryonic metanephros. In view of the glucose-induced changes in the fetal metanephros, a diabetic state was induced by the administration of streptozotocin during pregnancy, and newborn mouse kidneys were processed for suppression subtractive hybridization-PCR. In addition, a diabetic state was induced in newborn diabetic mice, and after 1 week their kidneys were harvested and subjected to representational difference analysis of cDNA. Four novel genes with upregulated mRNA expression were identified. They included: (1) a translocase inner mitochondrial membrane 44 that is involved in the ATP-dependent import of preproteins from the cytosol into the mitochondrial matrix; (2) a kidney-specific aldo-keto reductase that utilizes NADPH and NADH as cofactors in the reduction of aromatic aldehydes and aldohexoses; (3) Rap1b, a Ras-related small GTP-binding protein that behaves as a GTPase and cycles between GTP-bound (active) and GDP-bound (inactive) states associated with conformational change, and (4) a fusion protein of ubiquitin polypeptide and ribosomal protein L40 (UbA(52) or ubiquitin/60) that is intimately involved in the ubiquitin-dependent proteasome pathway related to the accelerated degradation of proteins under various stress conditions, such as those seen in patients with cancer and diabetes mellitus.
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PMID:Renal gene expression in embryonic and newborn diabetic mice. 1193 60

The secondary signals emanating from increased glucose metabolism, which lead to specific increases in proinsulin biosynthesis translation, remain elusive. It is known that signals for glucose-stimulated insulin secretion and proinsulin biosynthesis diverge downstream of glycolysis. Consequently, the mitochondrial products ATP, Krebs cycle intermediates, glutamate, and acetoacetate were investigated as candidate stimulus-coupling signals specific for glucose-induced proinsulin biosynthesis in rat islets. Decreasing ATP levels by oxidative phosphorylation inhibitors showed comparable effects on proinsulin biosynthesis and total protein synthesis. Although it is a cofactor, ATP is unlikely to be a metabolic stimulus-coupling signal specific for glucose-induced proinsulin biosynthesis. Neither glutamic acid methyl ester nor acetoacetic acid methyl ester showed a specific effect on glucose-stimulated proinsulin biosynthesis. Interestingly, among Krebs cycle intermediates, only succinic acid monomethyl ester specifically stimulated proinsulin biosynthesis. Malonic acid methyl ester, an inhibitor of succinate dehydrogenase, also specifically increased glucose-induced proinsulin biosynthesis without affecting islet ATP levels or insulin secretion. Glucose caused a 40% increase in islet intracellular succinate levels, but malonic acid methyl ester showed no further effect, probably due to efficient conversion of succinate to succinyl-CoA. In this regard, a GTP-dependent succinyl-CoA synthetase activity was found in cytosolic fractions of pancreatic islets. Thus, succinate and/or succinyl-CoA appear to be preferential metabolic stimulus-coupling factors for glucose-induced proinsulin biosynthesis translation.
Diabetes 2002 Aug
PMID:Succinate is a preferential metabolic stimulus-coupling signal for glucose-induced proinsulin biosynthesis translation. 1214 63

Statins significantly reduce cardiovascular-related morbidity and mortality in patients with and without coronary artery disease. The potential of this drug class has yet to be fully explored. Accumulating evidence from basic research and clinical trials indicates that statins have pleiotropic effects that may largely account for the clinical benefits observed. Potential beneficial effects of these agents include enhancement of nitric oxide production in vasculature and the kidney. Statins have been shown to stabilize unstable plaques, improve vascular relaxation, and promote new vessel formation. Clinical trials and animal studies have shown that these agents reduce cardiovascular disease (CVD) risks and events, progression of nephropathy, development of diabetes, and fracture rates; these are benefits that go beyond lipid lowering alone. Potential beneficial effects are due to the positive impact on vascular and glomerular nitric oxide (NO) production and attenuation of vascular inflammation. Effects on bone, including fracture reduction, are thought to be mediated by direct action on bone formation. Moreover, potential reduction in the development of diabetes as observed in the West of Scotland Coronary Prevention Study (WOSCOPS) may relate to the improvement in insulin sensitivity. These actions are mediated, in part, by the effects on small G-proteins, modulation of signaling cascades, transcription, and gene expression. In particular, the inhibition of small GTP-binding proteins, Rho, Ras, and Rac, whose proper membrane localization and function are dependent on isoprenylation, may play an important role in mediating the direct cellular effects of statins on the vascular wall. The clinical relevance of these effects is beginning to be recognized, and ongoing studies will be able to answer these many questions in the near future. Actions of statins on vascular, glomerular, bone, and insulin-sensitive tissue as well as effects of statins on cognitive function and oncoprotection will be discussed in this review.
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PMID:Clinical significance of pleiotropic effects of statins: lipid reduction and beyond. 1236 81

Identification of regulatory mutations of glutamate dehydrogenase (GDH) in a form of congenital hyperinsulinism (GDH-HI) is providing a model for basal insulin secretion (IS) and amino acid (AA)-stimulated insulin secretion (AASIS) in which glutaminolysis plays a key role. Leucine and ADP are activators and GTP is an inhibitor of GDH. GDH-HI mutations impair GDH sensitivity to GTP inhibition, leading to fasting hypoglycemia, leucine hypersensitivity, and protein-induced hypoglycemia, indicating the importance of GDH in basal secretion and AASIS. The proposed model for glutaminolysis in IS is based on GDH providing NADH and alpha-ketoglutarate (alpha-KG) to the Krebs cycle, hence increasing the beta-cell ATP-to-ADP ratio to effect insulin release. The process operates with 1) sufficient lowering of beta-cell phosphate potential (i.e., fasting) and when 2) AAs provide leucine for allosteric activation and glutamate from transaminations. To test this hypothesis, IS studies were performed in rat and GDH-HI mouse models. In the rat study, rat islets were isolated, cultured, and then perifused in Krebs-Ringer bicarbonate buffer with 2 mmol/l glutamine using 10 mmol/l 2-aminobicyclo[2,2,1]-heptane-2-carboxylic acid (BCH) or a BCH ramp after 50 or 120 min of glucose deprivation. In the GDH-HI mouse study, the H454Y GDH-HI mutation driven by the rat insulin promoter was created for H454Y beta-cell-specific expression. Cultured, isolated islets were perifused in leucine 0-10 mmol/l with 2 mmol/l glutamine 0-25 mmol/l, AA 0-10 mmol/l, or glucose 0-25 mmol/l. Rat islets displayed enhanced BCH-stimulated IS after 120 min of glucose deprivation, but not when energized by fuel. H454Y and control islets had similar glucose-stimulated IS, but H454Y mice had lower random blood glucose. Leucine-stimulated IS and AASIS occurred at lower thresholds and were greater in H454Y versus control islets. Glutamine stimulated IS in H454Y but not control islets. The clinical manifestations of GDH-HI and related animal studies suggest that GDH regulates basal IS and AASIS. Energy deprivation enhanced GDH-mediated IS, and H454Y mice were hypoglycemic, substantiating roles for GDH and its regulation by the phosphate potential in basal IS. Excessive IS from H454Y islets upon exposure to GDH substrates or stimuli indicate that regulation of GDH by the beta-cell phosphate potential plays a critical role in AASIS. These findings provide a foundation for defining pathways of basal secretion and AASIS, augmenting our understanding of beta-cell function.
Diabetes 2002 Dec
PMID:Glutaminolysis and insulin secretion: from bedside to bench and back. 1247 85

The present studies were undertaken to examine if the impaired vascular function observed in diabetes is attributed to the altered levels of G-protein. Diabetes was induced in Sprague Dawley rats by a single intraperitoneal injection of streptozotocin (STZ) (60 mg/kg body wt) and after a period of 5 days, the aorta were used for adenylyl cyclase activity determination and protein quantification. A temporal relationship between the expression of Gialpha proteins and development of diabetes was also examined on day 1, 2, 3, 4 and 5 of injection of STZ. Blood glucose levels were significantly increased from day 1 in STZ-rats as compared to their counterpart control rats and reached to about 20 mM on 3rd day and 30 mM on 5th day. The expression of Gialpha-2 and Gialpha-3 proteins as determined by immunoblotting techniques was decreased by about 70 and 50% respectively in aorta from STZ rats compared to the control rats after 5 days of treatment, whereas 40% decrease in Gialpha-2 and Gialpha-3 was observed after 3rd day of STZ injection. On the other hand, the expression of Gsalpha was unaltered in STZ rats. In addition, the stimulatory effect of cholera toxin (CT) on GTP-mediated stimulation of adenylyl cyclase was not different in STZ as compared to the control group. However, the stimulatory effects of isoproterenol, glucagon, NaF and FSK on adenylyl cyclase activity were significantly enhanced in STZ rats as compared to control rats, whereas basal adenylyl cyclase activity was significantly lower in STZ-rats as compared to control rats. In addition, GTPgammaS inhibited FSK-stimulated adenylyl cyclase activity in concentration-dependent manner (receptor-independent functions of Gialpha) in control rats which was completely attenuated in STZ-rats. In addition, receptor-mediated inhibitions of adenylyl cyclase by angiotensin II, oxotremorine, atrial natriuretic peptide (ANP99-126) and C-ANP4-23 were also attenuated (receptor-dependent functions of Gialpha) in STZ-rats. These results indicate that aorta from diabetic rats exhibit decreased levels of cAMP and decreased expression of Gialpha. The decreased expression of Gialpha may be responsible for the altered responsiveness of adenylyl cyclase to hormonal stimulation and inhibition in STZ-rats. It may thus be suggested that the impaired adenylyl cyclase-Gialpha protein signaling may be one of the possible mechanisms responsible for the impaired vascular functions in diabetes.
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PMID:Streptozotocin-induced diabetes impairs G-protein linked signal transduction in vascular smooth muscle. 1248 72

Apophysomyces elegans was considered a rare but medically important zygomycete. We analyzed the clinical records of eight patients from a single center in whom zygomycosis due to A. elegans was diagnosed over a span of 25 months. We also attempted a DNA-based method for rapid identification of the fungi and looked for interstrain polymorphism using microsattelite primers. Three patients had cutaneous and subcutaneous infections, three had isolated renal involvement, one had rhino-orbital tissue infection, and the final patient had a disseminated infection involving the spleen and kidney. Underlying illnesses were found in two patients, one with diabetes mellitus and the other with chronic alcoholism. A history of traumatic implantation was available for three patients. All except two of the patients responded to surgical and/or medical therapy; the diagnosis for the two exceptions was made at the terminal stage of infection. Restriction enzyme (MboI, MspI, HinfI) digestion of the PCR-amplified internal transcribed spacer region helped with the rapid and specific identification of A. elegans. The strains could be divided into two groups according to their patterns, with clustering into one pattern obtained by using microsatellite [(GTG)(5) and (GAC)(5)] PCR fingerprinting. The study highlights the epidemiology, clinical spectrum, and diagnosis of emerging A. elegans infections.
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PMID:Apophysomyces elegans: an emerging zygomycete in India. 1257 83

To determine the difference between alcoholic hepatitis (AH) and non-alcoholic steatohepatitis (NASH) in Japan, six patients with Ah and four patients with NASH, recently treated at our institute, were clinically and pathologically evaluated. Clinical features of the diseases differed: in NASH patients, mean age was higher, mean body mass index much higher, and the prevalence of diabetes mellitus was higher than in AH patients. The patients with NASH presented with unremarkable symptoms and signs. Abnormalities in liver function tests including prothrombin time and choline esterase were mild in NASH patients, except for the indocyanine green test. They had ALT-dominant hypertransaminasemia. AST, ALT and gamma GTP did not normalize as promptly as in AH patients after admission. However, there was no significant difference in the histological grade of fibrosis, inflammation or hepatocytic metamorphosis between NASH and AH patients. Stellate-form fibrosis was characteristic of AH, whereas pericellular and perivenular types were common in NASH patients. Focal cell necrosis was rather intense, and fatty deposits prominent, in NASH patients. However, it was difficult to histopathologically discriminate between NASH and AH patients. If AH is histologically suspected in non-alcoholic patients, the possibility of NASH should always be considered. Furthermore, even in patients with suspected simple fatty liver, a liver biopsy should be performed, especially in cases with prolonged abnormal liver function findings.
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PMID:Clinical and pathological differences between alcoholic hepatitis and non-alcoholic steatohepatitis. 1268 23

Recently, we have demonstrated regulatory roles for G-proteins (e.g., H-Ras) in IL-1beta induced NO release from HIT-T15 cells. Herein, we report a similar regulatory mechanism for IL-1beta induced NO release from RIN5F and INS-1 cells. Our data indicate that functional inactivation of Ras, either by Clostridial toxins or by specific inhibitors of Ras function, results in a significant inhibition in IL-1beta induced NO release, suggesting that activation of specific G-proteins is essential for IL-1beta induced NO release. In the present study, we report possible loci where IL-1beta treatment might result in functional activation of these G-proteins. For example, IL-1beta treatment resulted in significant reduction in (high-and low-affinity) GTPase activities in lysates derived from normal rat islets; such a scenario might lead to retention of candidate G-proteins in GTP-bound, active conformation. Further, IL-1beta treatment increased the G-protein carboxyl methyl transferase activity as well as carboxyl methylation of endogenous beta-cell proteins; such a modification has been shown to increase the membrane association and interaction of these G-proteins with their respective effector proteins. Also, we report immunologic localization of H-Ras regulatory proteins including its nucleotide exchange factor (GRF-1) and its effector protein (eg., Raf-1) in isolated beta-cells. Together, our data indicate localization, and regulation by IL-1beta, of specific enzymes that are critical to activation of G-proteins. Based on these preliminary findings, we propose a model for the involvement of G-proteins in IL-1beta induced NO release and subsequent demise of the pancreatic beta-cell.
Diabetes Metab 2002 Dec
PMID:IL-1beta-induced nitric oxide release from insulin-secreting beta-cells: further evidence for the involvement of GTP-binding proteins. 1268 37

We recently described novel regulatory roles for protein histidine phosphorylation of key islet proteins (e.g., nucleoside diphosphate kinase and succinyl thiokinase) in insulin secretion from the islet beta-cell (Kowluru A. Diabetologia 44: 89-94, 2001; Kowluru A, Tannous M, and Chen HQ. Arch Biochem Biophys 398: 160-169, 2002). In this context, we also characterized a novel, ATP- and GTP-sensitive protein histidine kinase in isolated beta-cells that catalyzed the histidine phosphorylation of islet (endogenous) proteins as well as exogenously added histone 4, and we implicated this kinase in the activation of islet endogenous G proteins (Kowluru A. Biochem Pharmacol 63: 2091-2100, 2002). In the present study, we describe abnormalities in ATP- or GTP-mediated histidine phosphorylation of nucleoside diphosphate kinase in islets derived from the Goto-Kakizaki (GK) rat, a model for non-insulin-dependent diabetes. Furthermore, we provide evidence for a marked reduction in the activities of ATP- or GTP-sensitive histidine kinases in GK rat islets. On the basis of these observations, we propose that alterations in protein histidine phosphorylation could contribute toward insulin-secretory abnormalities demonstrable in the diabetic islet.
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PMID:Defective protein histidine phosphorylation in islets from the Goto-Kakizaki diabetic rat. 1279 14


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