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 reduced form of glutathione (GSH) is the most important cell antioxidant and is also an essential cofactor for nitric oxide (NO) synthase that synthesizes NO from l-arginine. Reduced levels of GSH, due both to a hyperglycaemia-induced increase of free radical production and to a decrease of NADPH levels [like in diabetes mellitus (DM)], can hamper the endothelial cell functions. This condition may play an important role in the aetiology of some clinical signs, like erectile dysfunction (ED). The aim of this study was to test the hypothesis that GSH concentration is reduced in patients with ED and type 2 diabetes mellitus. We studied 111 male patients with ED: 64 with diabetes (ED/DM) and 47 without diabetes (ED/wDM); 20 patients with diabetes but without ED (DM) and 26 male normal subjects as a control group (C). The GSH red blood cell concentration was significantly lower in ED than in C (X +/- SD; 1782.12 +/- 518.02 vs. 2269.20 +/- 231.56 mumol/L, p < 0.001). In particular, GSH was significantly reduced in ED/DM vs. ED/wDM (1670.74 +/- 437.68 vs. 1930.63 +/- 581.01 micromol/L, p < 0.01). In DM, GSH was significantly lower than in C and significantly higher than in ED/DM (2084.20 +/- 118.14 vs. 2269.20 +/- 231.56 and vs. 1670.74 +/- 437.68 micromol/L, p < 0.002 and p < 0.001 respectively). GSH showed a negative correlation with fasting glucose concentrations (r = -0.34, p < 0.01) and with the duration of DM (r = -0.25, p < 0.05). A GSH depletion can lead to a reduction of NO synthesis, thus impairing vasodilation in the corpora cavernosa.
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PMID:Glutathione levels in patients with erectile dysfunction, with or without diabetes mellitus. 1591 May 41

During the past several decades, the incidence of obesity has significantly increased worldwide. Enormous efforts have been devoted to understanding the molecular mechanisms underlying obesity and its related metabolic disorders such as type 2 diabetes, cardiovascular disease, atherosclerosis, and hypertension. It is now well-established that altered adipocyte metabolism in obese patients is closely associated with the induction of various metabolic stresses including hyperglycemia, hyperlipidemia, hyperinsulinemia, and chronic inflammation. However, the cellular factor(s) which sense metabolic changes and/or initiate the pathological progression of obesity-induced metabolic disorders remain to be elucidated. In this review, we will discuss the possible roles of cellular NADP(+)/NADPH, which function as redox potential regulators, in the induction of obesity-associated oxidative stress, chronic inflammation, and insulin resistance and suggest G6PD, a NADPH-generating enzyme, as a novel target for treating metabolic disorders.
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PMID:New evaluations of redox regulating system in adipose tissue of obesity. 1745 57

Intracellular glucocorticoid (GC) receptor (GR) function determines tissue sensitivity to GCs and strongly affects the development of type 2 diabetes and obesity. 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) mediates intracellular steroid exposure to mouse liver GR by prereceptor reactivation of GCs and is crucially dependent on hexose-6-phosphate dehydrogenase (H6PDH)-generating NADPH system. Pharmacological inhibition of 11beta-HSD1 improves insulin intolerance and obesity. Here, we evaluated the potential beneficial effects of 11beta-HSD1 inhibitor carbenoxolone (CBX) in diet-induced obese (DIO) and insulin-resistant mice by examining the possible influence of CBX on the expression of GR, 11beta-HSD1, and H6PDH in vivo and in vitro in hepatocytes. Treatment of DIO mice with CBX markedly reduced hepatic GR mRNA levels and reduced weight gain, hyperglycemia, and insulin resistance. The reduction of hepatic GR gene expression was accompanied by CBX-induced inhibition of both 11beta-HSD1 and H6PDH activity and mRNA in the liver. Moreover, CBX treatment also suppressed the expression of both phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase enzyme (G6Pase) mRNA and improved hepatic [1, 2-(3)H] deoxy-d-glucose uptake in DIO mice. In addition, the treatment of primary cultures of hepatocytes with increasing concentrations of CBX led to a dose-dependent downregulation of GR mRNA levels, which correlated with the suppression of both 11beta-HSD1 and H6PDH activity and their gene expression. Addition of CBX to primary hepatocytes also resulted in suppression of both PEPCK and G6Pase mRNA levels. These findings suggest that CBX exerts some of its beneficial effects, at least in part, by inhibiting hepatic GR and H6PDH expression.
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PMID:Reduction of hepatic glucocorticoid receptor and hexose-6-phosphate dehydrogenase expression ameliorates diet-induced obesity and insulin resistance in mice. 1852 70

Type 2 diabetes (noninsulin-dependent diabetes mellitus) develops from a pre-diabetic condition that is characterized by insulin resistance and glucose intolerance, and is exacerbated by obesity. In this study, we compared the ability of over-the-counter analgesic drugs (OTCAD) [acetaminophen (APAP); ibuprofen (IBU); naproxen (NAP); aspirin (ASA)], to protect against the development of a pre-diabetic state in mice fed a high fat diet. After 10 weeks on the high fat diet, mice had normal fasting blood glucose (FBG) levels, but exhibited impaired glucose tolerance. Treatment with 20 mg OTCADs/kg body weight improved glucose tolerance, with the order of efficacy, APAP=ASA>IBU, while NAP proved ineffective. Mice fed the high fat diet also exhibited increases in weight gain associated with an increase in body fat. OTCADs prevented in part this increase in body fat, in the order of efficacy, APAP=IBU>NAP=ASA. In isolated liver mitochondria, OTCADs inhibited succinate-dependent H2O2 production, while in white adipose tissue, APAP inhibited NADPH-oxidase mediated H2O2 production and lipid peroxidation. Thus, OTCADs diminish pro-oxidant processes that might otherwise exacerbate inflammation and a pre-diabetic state. We conclude that OTCADs, especially APAP and IBU, may be valuable tools to delay or prevent the development of type 2 diabetes from a pre-diabetic condition.
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PMID:Over-the-counter analgesics normalize blood glucose and body composition in mice fed a high fat diet. 1855 74

Glucose-stimulated insulin secretion (GSIS) is central to normal control of metabolic fuel homeostasis, and its impairment is a key element of beta-cell failure in type 2 diabetes. Glucose exerts its effects on insulin secretion via its metabolism in beta-cells to generate stimulus/secretion coupling factors, including a rise in the ATP/ADP ratio, which serves to suppress ATP-sensitive K(+) (K(ATP)) channels and activate voltage-gated Ca(2+) channels, leading to stimulation of insulin granule exocytosis. Whereas this K(ATP) channel-dependent mechanism of GSIS has been broadly accepted for more than 30 years, it has become increasingly apparent that it does not fully describe the effects of glucose on insulin secretion. More recent studies have demonstrated an important role for cyclic pathways of pyruvate metabolism in control of insulin secretion. Three cycles occur in islet beta-cells: the pyruvate/malate, pyruvate/citrate, and pyruvate/isocitrate cycles. This review discusses recent work on the role of each of these pathways in control of insulin secretion and builds a case for the particular relevance of byproducts of the pyruvate/isocitrate cycle, NADPH and alpha-ketoglutarate, in control of GSIS.
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PMID:Metabolic cycling in control of glucose-stimulated insulin secretion. 1872 21

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

Glucose metabolism through the glycolysis and hexosamine pathway has been shown to be altered in type 2 diabetes. However, the fate of glucose through the pentose phosphate pathway (PPP) is currently unclear. In this study, we determined whether the activity of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the PPP, is modulated in the liver of Zucker obese fa/fa rats (9-11 weeks of age). We found that G6PD expression and activity, NADPH levels, and 6-phosphogluconate generation were significantly increased in the liver of fa/fa rats. Inhibition of PI3 kinase and Src kinases decreased (p < 0.05) G6PD activity in the fa/fa but not in the lean rat liver, suggesting that G6PD activity is regulated by PI3/Src kinase signaling pathways. G6PD-derived NADPH increased (p < 0.05) superoxide anion levels by 70-90% in fa/fa vs lean rat liver, which was inhibited by the NADPH oxidase inhibitor gp91(ds-tat) (50 microM) and G6PD inhibitors 6-aminonicotinamide (1 mM) and dehydroepiandrosterone (100 microM), therefore indicating that elevated G6PD activity may be responsible for mediating superoxide generation. Interestingly, we also found a positive correlation between liver hypertrophy/increased G6PD activity (r2 = 0.77; p = 0.0009) and liver hypertrophy/superoxide production (r2 = 0.51; p = 0.0091) in fa/fa rats. Increased G6PD and NADPH oxidase expression and activity, in young hyperglycemic and hyperinsulinemic rats before the development of diabetes, seems to be a contributing factor in the induction of oxidative stress. Because inhibition of G6PD activity decreases oxidative stress, we conclude that G6PD behaves as a pro-oxidant in the fa/fa rat liver in type 2 diabetes.
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PMID:Synergistic activation of glucose-6-phosphate dehydrogenase and NAD(P)H oxidase by Src kinase elevates superoxide in type 2 diabetic, Zucker fa/fa, rat liver. 1923 Aug 46

Increased oxidative stress is a known cause of cardiac dysfunction in animals and patients with diabetes, but the sources of reactive oxygen species [e.g., superoxide anion (O(2)(-))] and the mechanisms underlying O(2)(-) production in diabetic hearts are not clearly understood. Our aim was to determine whether NADPH oxidase (Nox) is a source of O(2)(-) and whether glucose-6-phosphate dehydrogenase (G6PD)-derived NADPH plays a role in augmenting O(2)(-) generation in diabetes. We assessed cardiac function, Nox and G6PD activities, NADPH levels, and the activities of antioxidant enzymes in heart homogenates from young (9-11 wk old) Zucker lean and obese (fa/fa) rats. We found that myocardial G6PD activity was significantly higher in fa/fa than in lean rats, whereas superoxide dismutase and glutathione peroxidase activities were decreased (P < 0.05). O(2)(-) levels were elevated (70-90%; P < 0.05) in the diabetic heart, and this elevation was blocked by the Nox inhibitor gp-91(ds-tat) (50 microM) or by the mitochondrial respiratory chain inhibitors antimycin (10 microM) and rotenone (50 microM). Inhibition of G6PD by 6-aminonicotinamide (5 mM) and dihydroepiandrosterone (100 microM) also reduced (P < 0.05) O(2)(-) production. Notably, the activities of Nox and G6PD in the fa/fa rat heart were inhibited by chelerythrine, a protein kinase C inhibitor. Although we detected no changes in stroke volume, cardiac output, or ejection fraction, left ventricular diameter was slightly increased during diastole and systole, and left ventricular posterior wall thickness was decreased during systole (P < 0.05) in Zucker fa/fa rats. Our findings suggest that in a model of severe hyperlipidema and hyperglycemia Nox-derived O(2)(-) generation in the myocardium is fueled by elevated levels of G6PD-derived NADPH. Similar mechanisms were found to activate O(2)(-) production and induce endothelial dysfunction in aorta. Thus G6PD may be a useful therapeutic target for treating the cardiovascular disease associated with type 2 diabetes, if second-generation drugs specifically reducing the activity of G6PD to near normal levels are developed.
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PMID:Superoxide production by NAD(P)H oxidase and mitochondria is increased in genetically obese and hyperglycemic rat heart and aorta before the development of cardiac dysfunction. The role of glucose-6-phosphate dehydrogenase-derived NADPH. 1942 15

Patients with type 2 diabetes lose beta cells, but the underlying mechanisms are incompletely understood. Glucose-6-phosphate dehydrogenase (G6PD) is the principal source of the major intracellular reductant, NADPH, which is required by many enzymes, including enzymes of the antioxidant pathway. Previous work from our laboratory has shown that high glucose impairs G6PD activity in endothelial and kidney cells, which leads to decreased cell survival. Pancreatic beta cells are highly sensitive to increased ROS. This study aimed to determine whether G6PD and NADPH play central roles in beta-cell survival. Human and mouse islets, MIN6 cell line, and G6PD deficient mice were studied. High glucose inhibited G6PD expression and activity. Inhibition of G6PD with siRNA led to increased ROS and apoptosis, decreased proliferation, and impaired insulin secretion. High glucose decreased insulin secretion, which was improved by overexpressing G6PD. G6PD-deficient mice had smaller islets and impaired glucose tolerance compared with control mice, which suggests that G6PD deficiency per se leads to beta-cell dysfunction and death. G6PD plays an important role in beta-cell function and survival. High-glucose-mediated decrease in G6PD activity may provide a mechanistic explanation for the gradual loss of beta cells in patients with diabetes.
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PMID:High glucose inhibits glucose-6-phosphate dehydrogenase, leading to increased oxidative stress and beta-cell apoptosis. 2003 14

Plant drug mixtures are widely used in the adjuvant therapy of type 2 diabetes mellitus for the prevention of complications. The drug mixtures generally contribute to the efficiency of the therapy and may also reduce undesirable side effects. Two herbal extracts (lyophilized aqueous extracts of plant drug mixtures 1: Myrtilli folium, Phaseoli fructus sine seminibus and 2: Myrtilli folium, Phaseoli fructus sine seminibus, Salviae folium) were investigated in in vitro rat models. The content of bioactive constituents (polyphenol, flavonoid and vitamin C) in plant drug mixtures and lyophilized samples was evaluated. The antioxidant activity of lyophilized extracts was determined by measuring the ferric reducing ability of the plant, Fe2+ induced lipid peroxidation (LPO) in rat brain homogenates and NADPH (beta-nicotinamide adenine dinucleotide phosphate reduced form) induced LPO in cerebral microsomes. The antioxidant activity of lyophilized extracts was compared to that of quercetin and rutin. Both teas of lyophilized extracts had significant reducing ability (2694 and 2771 micromol/l) and inhibited LPO (IC50 28.0 and 20.6 microl in NADPH induced LPO, 17.3 and 8.7 microl in Fe2+ induced LPO). The high concentration of polyphenol/flavonoid (12.38-13.00 and 1.45-5.22 g/100 g, respectively) and vitamin C (0.099-0.165 g/100 g) in the herbal extracts is related to their significant antioxidant properties. The tea mixtures have significant nutritional value, since the consumption of 2 or 3 cups of tea a day covers 50% of the daily requirement of vitamin C and it is also relevant polyphenol source. The high polyphenol/flavonoid content may restore the redox imbalance and contribute to the prevention of diabetic complications.
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PMID:Inhibition of lipid peroxidation of herbal extracts (obtained from plant drug mixtures of Myrtilli folium, Phaseoli fructus sine seminibus and Salviae folium) used in type 2 diabetes mellitus. 2019 98


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