Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The question was investigated whether mitochondria in the mammalian skeletal muscle fiber syncytium incorporate gene products encoded by one or many nuclei. Mouse chimeras were produced from strains which differ in their electrophoretic variants of the nuclear-coded mitochondrial protein, malic enzyme (MOD-2, E.C. 1.1.1.40, L-malate NADP+ oxidoreductase decarboxylating). The MOD-2 phenotypes of skeletal muscles of these chimeras were characterized in a starch gel electrophoretic system. The results indicate that individual mitochondria can contain products encoded by multiple nuclei and therefore that, for skeletal muscle mitochondria, the cell is not subdivided into nuclear territories. Possible mechanisms of gene product distribution in skeletal muscle fibers are discussed.
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PMID:Mitochondrial malic enzyme in mosaic skeletal muscle of mouse chimeras. 54 12

11beta-hydroxysteroid dehydrogenases (11beta-HSDs) catalyze the interconversion of active glucocorticoids (cortisol, corticosterone) and inert 11-keto forms (cortisone, 11-dehydrocorticosterone). 11beta-HSD type 2 has a well recognized function as a potent dehydrogenase that rapidly inactivates glucocorticoids, thus allowing aldosterone selective access to otherwise nonselective mineralocorticoid receptors in the distal nephron. In contrast, the function of 11beta-HSD type 1 has, until recently, been little understood. 11beta-HSD1 is an ostensibly reversible oxidoreductase in vitro, which is expressed in liver, adipose tissue, brain, lung, and other glucocorticoid target tissues. However, increasing data suggest that 11beta-HSD1 acts as a predominant 11beta-reductase in many intact cells, whole organs, and in vivo. This reaction direction locally regenerates active glucocorticoids within expressing cells, exploiting the substantial circulating levels of inert 11-keto steroids. While the biochemical determinants of the reaction direction are not fully understood, insights to its biological importance have been afforded by use of inhibitors in vivo, including in humans, and the generation of knockout mice. Such studies suggest 11beta-HSD1 effectively amplifies glucocorticoid action at least in the liver, adipose tissue, and the brain. Inhibition of 11beta-HSD1 represents a potential target for therapy of disorders that might be ameliorated by local reduction of glucocorticoid action, including type 2 diabetes, obesity, and age-related cognitive dysfunction.
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PMID:Minireview: 11beta-hydroxysteroid dehydrogenase type 1- a tissue-specific amplifier of glucocorticoid action. 1125 Sep 14

Skeletal muscle is strongly dependent on oxidative phosphorylation for energy production. Because the insulin resistance of skeletal muscle in type 2 diabetes and obesity entails dysregulation of the oxidation of both carbohydrate and lipid fuels, the current study was undertaken to examine the potential contribution of perturbation of mitochondrial function. Vastus lateralis muscle was obtained by percutaneous biopsy during fasting conditions from lean (n = 10) and obese (n = 10) nondiabetic volunteers and from volunteers with type 2 diabetes (n = 10). The activity of rotenone-sensitive NADH:O(2) oxidoreductase, reflecting the overall activity of the respiratory chain, was measured in a mitochondrial fraction by a novel method based on providing access for NADH to intact mitochondria via alamethicin, a channel-forming antibiotic. Creatine kinase and citrate synthase activities were measured as markers of myocyte and mitochondria content, respectively. Activity of rotenone-sensitive NADH:O(2) oxidoreductase was normalized to creatine kinase activity, as was citrate synthase activity. NADH:O(2) oxidoreductase activity was lowest in type 2 diabetic subjects and highest in the lean volunteers (lean 0.95 +/- 0.17, obese 0.76 +/- 0.30, type 2 diabetes 0.56 +/- 0.14 units/mU creatine kinase; P < 0.005). Also, citrate synthase activity was reduced in type 2 diabetic patients (lean 3.10 +/- 0.74, obese 3.24 +/- 0.82, type 2 diabetes 2.48 +/- 0.47 units/mU creatine kinase; P < 0.005). As measured by electron microscopy, skeletal muscle mitochondria were smaller in type 2 diabetic and obese subjects than in muscle from lean volunteers (P < 0.01). We conclude that there is an impaired bioenergetic capacity of skeletal muscle mitochondria in type 2 diabetes, with some impairment also present in obesity.
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PMID:Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. 1235 31

Intrauterine growth retardation (IUGR) has been linked to the development of type 2 diabetes in adulthood. We have developed an IUGR model in the rat whereby the animals develop diabetes between 3 and 6 mo of age that is associated with insulin resistance. Alterations in hepatic glucose metabolism are known to contribute to the hyperglycemia of diabetes; however, the mechanisms underlying this phenomenon have not been fully explained. To address this issue, intact liver mitochondria were isolated from IUGR and control offspring at different ages to examine the nature and time course of possible defects in oxidative metabolism. Phosphoenolpyruvate carboxykinase (PEPCK) expression was also measured in livers of IUGR and control offspring. Rates of ADP-stimulated (state 3) oxygen consumption were increased for succinate in the fetus and for alpha-ketoglutarate and glutamate at day 1, reflecting possible compensatory metabolic adaptations to acute hypoxia and acidosis in IUGR rats. By day 14, oxidation of glutamate and alpha-ketoglutarate had returned to normal, and by day 28, oxidation rates of pyruvate, glutamate, succinate, and alpha-ketoglutarate were significantly lower than those of controls. Rotenone-sensitive NADH-O2 oxidoreductase activity was similar in control and IUGR mitochondria at all ages, showing that the defect responsible for decreased pyruvate, glutamate, and alpha-ketoglutarate oxidation in IUGR liver precedes the electron transport chain and involves pyruvate and alpha-ketoglutarate dehydrogenases. Increased levels of manganese superoxide dismutase suggest that an antioxidant response has been mounted, and hydroxynonenal (HNE) modification of pyruvate dehydrogenase E2-(catalytic) and E3-binding protein subunits suggests that HNE-induced inactivation of this key enzyme may play a role in the mechanism of injury. The level of PEPCK mRNA was increased 250% in day 28 IUGR liver, indicating altered gene expression of the gluconeogenic enzyme that precedes overt hyperglycemia. These results indicate that uteroplacental insufficiency impairs mitochondrial oxidative phosphorylation in the liver and that this derangement predisposes the IUGR rat to increased hepatic glucose production by suppressing pyruvate oxidation and increasing gluconeogenesis.
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PMID:Impaired oxidative phosphorylation in hepatic mitochondria in growth-retarded rats. 1460 83

11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) is a NADPH dependent oxidoreductase of the endoplasmic reticulum lumen which converts cortisone to cortisol and plays a role in the pathogenesis of metabolic syndrome and type 2 diabetes. The aim of our study was to investigate the correlation between the expression/activity of 11betaHSDI and obesity. Liver and adipose tissue microsomes of an obese (Zucker) and a non-obese (Goto-Kakizaki) type 2 diabetes model rat strains were used. 11betaHSDI expression was detected at mRNA, protein and activity level. The activity of 11betaHSD1 was increased in the adipose tissue and decreased in the liver of the obese Zucker rat, while its mRNA levels were significantly different only in the adipose tissue. In diabetic Goto-Kakizaki rat both the expression and the activity of 11betaHSD1 were elevated in liver, but not in adipose tissue. These results suggest that the prereceptorial glucocorticoid activation is different in the liver and adipose tissue of the two diabetes models. This phenomenon might be responsible for the obese and lean phenotypes in type 2 diabetes.
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PMID:Different expression and distribution of 11beta-hydroxysteroid dehydrogenase type 1 in obese and lean animal models of type 2 diabetes. 1900 16

Chronic hyperglycemia contributes to pancreatic beta-cell dysfunction during the development of type 2 diabetes. Treatment of pancreatic beta-cells with prolonged high glucose concentrations has been shown to reduce insulin promoter activity and insulin gene expression. Here, we examined the effect of high glucose on endoplasmic reticulum (ER) stress pathway activation and insulin production in INS-1 832/13 pancreatic beta-cells. Treatment of cells with 25 mm glucose for 24-48 h decreased insulin mRNA and protein levels and reduced the proinsulin translation rate, which was accompanied by enhanced unfolded protein response pathway activation (XBP-1 mRNA splicing and increased phospho-eIF2alpha, CHOP, and active ATF6 levels). Overexpressing the ER chaperone GRP78 partially rescued high glucose-induced suppression of proinsulin levels and improved glucose-stimulated insulin secretion with no effect on insulin 2 mRNA levels. Under these conditions, there was little effect of GRP78 overexpression on ER stress markers. Knockdown of GRP78 expression under basal glucose conditions reduced cellular insulin levels and glucose-stimulated insulin secretion. Thus, GRP78 is essential for insulin biosynthesis, and enhancing chaperone capacity can improve beta-cell function in the presence of prolonged hyperglycemia. In contrast, overexpression of the ER chaperone and oxidoreductase protein-disulfide isomerase (PDI) reduced glucose-stimulated insulin secretion and induced ER stress resulting from the accumulation of proinsulin in the ER. These results suggest a role for both GRP78 and PDI in insulin biosynthesis, although an excess of PDI disrupts normal proinsulin processing.
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PMID:GRP78, but Not Protein-disulfide Isomerase, Partially Reverses Hyperglycemia-induced Inhibition of Insulin Synthesis and Secretion in Pancreatic {beta}-Cells. 1910 94

Disulfide-bond-A oxidoreductase-like protein (DsbA-L) has been suggested to take part in the disulfide bond formation progress of proteins, including insulin and adiponectin. Recent study has demonstrated that expression of DsbA-L was decreased in obese mice and human subject, indicating that DsbA-L might be a potential target for treatment of metabolic diseases. We investigated the association of SNP-1308G/T (rs1917760) of DsbA-L gene with metabolic diseases. 589 normal glucose tolerance (NGT) subjects and 556 type 2 diabetes (T2DM) subjects were recruited. Each group was divided into normal weight (NW) (BMI<24 kg/m(2)) subgroup and overweight/obesity (OW/OB) (BMI>/=24 kg/ m(2)) subgroup. Genotype distributions and allele frequencies of SNP (-1308G/T) in DsbA-L gene were not associated with T2DM and obesity. However, it was observed that T allele carriers had better insulin secretion function compared with non-T allele carriers in NGT-NW group, not only the first phase insulin secretion (P=0.007) but also the second phase insulin secretion (P=0.031). Multiple linear regression analysis revealed that SNP-1308G/T polymorphism (rs1917760) was independently correlated with both first and second phase insulin secretion in NGT-NW group (R(2)=0.055, P=0.007; R(2)=0.029, P=0.041). Otherwise, T carriers had more visceral fat than non-T carriers (P=0.020) in NGT-OW/OB group. In conclusion, the SNP-1308G/T (rs1917760) genotypes of DsbA-L gene might participate in insulin secretion and body fat distribution. It is possible that polymorphisms of DsbA-L gene associated with metabolic diseases.
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PMID:Polymorphism of DsbA-L gene associates with insulin secretion and body fat distribution in Chinese population. 1922 11

Glucocorticoids (GC) play a fundamental role in controlling physiologic homeostasis and, when present in excess, can have a detrimental impact on glucose control, blood pressure and lipid levels. The oxidoreductase 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) mainly catalyzes the intracellular regeneration of active GCs (cortisol, corticosterone) from inert inactive 11-keto forms (cortisone) in liver, adipose tissue and brain, amplifying local GC action. Multiple lines of evidence have indicated that 11beta-HSD1-mediated intracellular cortisol production may have a pathogenic role in type 2 diabetes and its co-morbidities. The 11beta-HSD1 becomes a novel target for anti-type 2 diabetes drug developments, and inhibition of 11beta-HSD1 offers a potential therapy to attenuate the type 2 diabetes. In the past several years, a lot of 11beta-HSD1 inhibitors have been designed, synthesized, screened and discovered. Lowering intracellular glucocorticoid concentrations through administration of small molecule 11beta-HSD1 selective inhibitors, significantly attenuates the signs and symptoms of disease in preclinical animal models and clinical trials of diabetes and metabolic syndrome. Among published inhibitors, DIO-902 from DiObex Inc. and INCB13739 from Incyte Inc. are now being investigated under Phase 2B clinical trials. However, the selectivity of current selective 11beta-HSD1 inhibitors has been just focused on the difference between 11beta-HSD1 and 11beta-HSD2. They inhibit the bi-directional activities of 11beta-HSD1, both 11beta-HSD1 reductase (major) and oxidase (minor). In our lab, we have recently found novel chemicals that not only inhibit 11beta-HSD1 reductase activity but also increase its oxidase activity without inhibition against 11beta-HSD2. We propose that this dual modulation on 11beta-HSD1 may provide a better therapeutic strategy for type 2 diabetes.
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PMID:11beta-hydroxysteroid dehydrogenase type 1 inhibitors as promising therapeutic drugs for diabetes: status and development. 2001 40

Hydrogen sulfide (H2S) therapy protects nondiabetic animals in various models of myocardial injury, including acute myocardial infarction and heart failure. Here, we sought to examine whether H2S therapy provides cardioprotection in the setting of type 2 diabetes. H2S therapy in the form of sodium sulfide (Na2S) beginning 24 h or 7 days before myocardial ischemia significantly decreased myocardial injury in db/db diabetic mice (12 wk of age). In an effort to evaluate the signaling mechanism responsible for the observed cardioprotection, we focused on the role of nuclear factor E2-related factor (Nrf2) signaling. Our results indicate that diabetes does not alter the ability of H2S to increase the nuclear localization of Nrf2, but does impair aspects of Nrf2 signaling. Specifically, the expression of NADPH quinine oxidoreductase 1 was increased after the acute treatment, whereas the expression of heme-oxygenase-1 (HO-1) was only increased after 7 days of treatment. This discrepancy was found to be the result of an increased nuclear expression of Bach1, a known repressor of HO-1 transcription, which blocked the binding of Nrf2 to the HO-1 promoter. Further analysis revealed that 7 days of Na2S treatment overcame this impairment by removing Bach1 from the nucleus in an Erk1/2-dependent manner. Our findings demonstrate for the first time that exogenous administration of Na2S attenuates myocardial ischemia-reperfusion injury in db/db mice, suggesting the potential therapeutic effects of H2S in treating a heart attack in the setting of type 2 diabetes.
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PMID:Hydrogen sulfide preconditions the db/db diabetic mouse heart against ischemia-reperfusion injury by activating Nrf2 signaling in an Erk-dependent manner. 2347 60

The physiological role of the spliced form of X-box-binding protein 1 (XBP1s), a key transcription factor of the endoplasmic reticulum (ER) stress response, in adipose tissue remains largely unknown. In this study, we show that overexpression of XBP1s promotes adiponectin multimerization in adipocytes, thereby regulating systemic glucose homeostasis. Ectopic expression of XBP1s in adipocytes improves glucose tolerance and insulin sensitivity in both lean and obese (ob/ob) mice. The beneficial effect of adipocyte XBP1s on glucose homeostasis is associated with elevated serum levels of high-molecular-weight adiponectin and, indeed, is adiponectin-dependent. Mechanistically, XBP1s promotes adiponectin multimerization rather than activating its transcription, likely through a direct regulation of the expression of several ER chaperones involved in adiponectin maturation, including glucose-regulated protein 78 kDa, protein disulfide isomerase family A, member 6, ER protein 44, and disulfide bond oxidoreductase A-like protein. Thus, we conclude that XBP1s is an important regulator of adiponectin multimerization, which may lead to a new therapeutic approach for the treatment of type 2 diabetes and hypoadiponectinemia.
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PMID:Adipocyte spliced form of X-box-binding protein 1 promotes adiponectin multimerization and systemic glucose homeostasis. 2424 34


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