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)

Low adiponectin expression is common in obesity and is tightly linked to insulin resistance and fat mass expansion. Whereas normal adipocytes offer effective metabolic buffering through well-controlled release and uptake of free fatty acids on demand, adipocyte expansion induced by caloric excess and modulated by genetic, regional, and systemic factors elicits major unfavorable changes in fat cell phenotypes. Large, dysfunctional adipocytes show increased lipolysis and enhanced expression and secretion of proinflammatory and pro-oxidative cytokines. Low adiponectin secretion is a hallmark of impaired adipocyte function; its secretion is inhibited by cytokines such as tumor necrosis factor alpha, interleukin 6 and plasminogen activator inhibitor 1 and by high oxidative stress induced by increased fatty acids that activate nicotinamide adenine dinucleotide phosphate-oxidase. The ensuing hypoadiponectinemia may aggravate insulin resistance and facilitate the evolution of type 2 diabetes. Only massive weight loss allows true and sustained recovery of normal fat cell function as reflected by adiponectin secretion.
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PMID:Hypoadiponectinemia as a marker of adipocyte dysfunction--part II: the functional significance of low adiponectin secretion. 1805 13

11Beta-hydroxysteroid dehydrogenase type 1 regulates glucocorticoid action and inhibition of this enzyme is a viable therapeutic strategy for the treatment of type 2 diabetes and the metabolic syndrome. Here, we report a potent and selective 11beta-hydroxysteroid dehydrogenase type 1 inhibitor with a binding mode elucidated from the co-crystal structure with the human 11beta-hydroxysteroid dehydrogenase type 1. The inhibitor is bound to the steroid-binding pocket making contacts with the catalytic center and the solvent channel. The inhibitor binding is facilitated by two direct hydrogen bond interactions involving Tyrosine183 of the catalytic motif Tyr-X-X-X-Lys and Alanine172. In addition, the inhibitor makes many hydrophobic interactions with both the enzyme and the co-factor nicotinamide adenine dinucleotide phosphate (reduced). In lean C57BL/6 mice, the compound inhibited both the in vivo and ex vivo 11beta-hydroxysteroid dehydrogenase type 1 activities in a dose-dependent manner. The inhibitory effects correlate with the plasma compound concentrations, suggesting that there is a clear pharmacokinetic and pharmacodynamic relationship. Moreover, at the same doses used in the pharmacokinetic/pharmacodynamic studies, the inhibitor did not cause the activation of the hypothalamic-pituitary-adrenal axis in an acute mouse model, suggesting that this compound exhibits biological effects with minimal risk of activating the hypothalamic-pituitary-adrenal axis.
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PMID:Structural characterization and pharmacodynamic effects of an orally active 11beta-hydroxysteroid dehydrogenase type 1 inhibitor. 1806 89

The objective of this paper is to evaluate adaptations in hepatic mitochondrial protein mass, function and efficiency in a rat model of high-fat diet-induced obesity and insulin resistance that displays several correlates to human obesity. Adult male rats were fed a high-fat diet for 7 weeks. Mitochondrial state 3 and state 4 respiratory capacities were measured in liver homogenate and isolated mitochondria by using nicotinamide adenine dinucleotide, flavin adenine dinucleotide and lipid substrates. Mitochondrial efficiency was evaluated by measuring proton leak kinetics. Mitochondrial mass was assessed by ultrastructural observations and citrate synthase (CS) activity measurements. Mitochondrial oxidative damage and antioxidant defence were also considered by measuring lipid peroxidation, aconitase and superoxide dismutase (SOD) specific activity. Whole body metabolic characteristics were obtained by measuring 24-h oxygen consumption (VO2), carbon dioxide production (VCO2), respiratory quotient (RQ) and nonprotein respiratory quotient (NPRQ), using indirect calorimetry with urinary nitrogen analysis. Whole body glucose homeostasis was assessed by measuring plasma insulin and glucose levels after a glucose load. Adult rats fed a high-fat diet for 7 weeks, exhibit not only obesity, insulin resistance and hepatic steatosis, but also reduced respiratory capacity and increased oxidative stress in liver mitochondria. Our present results indicate that alterations in the mitochondrial compartment induced by a high-fat diet are associated with the development of insulin resistance and ectopic fat storage in the liver. Our results thus fit in with the emerging idea that mitochondrial dysfunction can led to the development of metabolic diseases, such as obesity, type 2 diabetes mellitus and nonalcoholic steatohepatitis.
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PMID:Alterations in hepatic mitochondrial compartment in a model of obesity and insulin resistance. 1827 91

Oxidative stress is a principal pathway for the dysfunction and ultimate destruction of cells in the neuronal and vascular systems for several disease entities, not promoting the ravages of oxidative stress to any less of a degree than diabetes mellitus. Diabetes mellitus is increasing in incidence as a result of changes in human behavior that relate to diet and daily exercise and is predicted to affect almost 400 million individuals worldwide in another two decades. Furthermore, both type 1 and type 2 diabetes mellitus can lead to significant disability in the nervous and cardiovascular systems, such as cognitive loss and cardiac insufficiency. As a result, innovative strategies that directly target oxidative stress to preserve neuronal and vascular longevity could offer viable therapeutic options to diabetic patients in addition to more conventional treatments that are designed to control serum glucose levels. Here we discuss the novel application of nicotinamide, Wnt signaling, and erythropoietin that modulate cellular oxidative stress and offer significant promise for the prevention of diabetic complications in the nervous and vascular systems. Essential to this process is the precise focus upon diverse as well as common cellular pathways governed by nicotinamide, Wnt signaling, and erythropoietin to outline not only the potential benefits, but also the challenges and possible detriments of these therapies. In this way, new avenues of investigation can hopefully bypass toxic complications, or at the very least, avoid contraindications that may limit care and offer both safe and robust clinical treatment for patients.
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PMID:Triple play: promoting neurovascular longevity with nicotinamide, WNT, and erythropoietin in diabetes mellitus. 1834 81

The development of type 2 diabetes is accompanied by decreased immune function and the mechanisms are unclear. We hypothesize that oxidative damage and mitochondrial dysfunction may play an important role in the immune dysfunction in diabetes. In the present study, we investigated this hypothesis in diabetic Goto-Kakizaki rats by treatment with a combination of four mitochondrial-targeting nutrients, namely, R-alpha-lipoic acid, acetyl-L-carnitine, nicotinamide and biotin. We first studied the effects of the combination of these four nutrients on immune function by examining cell proliferation in immune organs (spleen and thymus) and immunomodulating factors in the plasma. We then examined, in the plasma and thymus, oxidative damage biomarkers, including lipid peroxidation, protein oxidation, reactive oxygen species, calcium and antioxidant defence systems, mitochondrial potential and apoptosis-inducing factors (caspase 3, p53 and p21). We found that immune dysfunction in these animals is associated with increased oxidative damage and mitochondrial dysfunction and that the nutrient treatment effectively elevated immune function, decreased oxidative damage, enhanced mitochondrial function and inhibited the elevation of apoptosis factors. These effects are comparable to, or greater than, those of the anti-diabetic drug pioglitazone. These data suggest that a rational combination of mitochondrial-targeting nutrients may be effective in improving immune function in type 2 diabetes through enhancement of mitochondrial function, decreased oxidative damage, and delayed cell death in the immune organs and blood.
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PMID:Mitochondrial nutrients improve immune dysfunction in the type 2 diabetic Goto-Kakizaki rats. 1841 May 24

Dipeptidyl peptidase (DPP)-IV inhibitors are expected to become a useful new class of antidiabetic agent. The aim of the present study is to characterize the in vitro and in vivo profile of ASP8497, (2S,4S)-4-fluoro-1-({[4-methyl-1-(methylsulfonyl)piperidin-4-yl]amino}acetyl)pyrrolidine-2-carbonitrile monofumarate, which is a novel DPP-IV inhibitor. ASP8497 inhibited DPP-IV in plasma from mice, rats, dogs and humans with IC(50) values of 3.86, 2.36, 5.53 and 5.30 nM, respectively. In contrast, ASP8497 did not potently inhibit DPP8 or DPP9 activity (IC(50)>200 nM). Kinetic analysis indicated that ASP8497 inhibits DPP-IV activity in a competitive manner. In streptozotocin-nicotinamide-induced diabetic mice, ASP8497 (3 mg/kg) significantly reduced glucose excursion during the oral glucose tolerance test conducted 0.5 and 8.5 h after administration, with increases in plasma insulin and active glucagon-like peptide-1 (GLP-1) levels. In contrast, ASP8497 (3 and 30 mg/kg) did not cause hypoglycemia in fasted normal mice. Furthermore, administration of exogenous GLP-1 induced significant inhibition of gastric emptying and small intestinal transit rates, but ASP8497 (30 mg/kg) had no significant effects in normal mice. These present preclinical studies indicate that ASP8497 is a novel selective DPP-IV inhibitor with long-acting antidiabetic effect that might be a potential agent for type 2 diabetes.
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PMID:ASP8497 is a novel selective and competitive dipeptidyl peptidase-IV inhibitor with antihyperglycemic activity. 1846 82

Succinic acid monoethyl ester (EMS) was recently proposed as an insulinotropic agent for the treatment of type 2 diabetes. The aim of the study was to investigate the effect of EMS and metformin administration on tail collagen content and its characteristics in streptozotocin-nicotinamide-induced type 2 diabetic rats. EMS was administered intraperitoneally for 30 days to normal and diabetic rats. In the diabetic rats, a significant increase in the levels of glucose, glycated hemoglobin, hydroxyproline, collagen content, extent glycation, fluorescence, neutral salt, acid and pepsin soluble collagen content was absorbed with a significant decrease in the level of insulin, hemoglobin in streptozotocin-nicotinamide diabetic rats. Moreover, a daily administration of nonglucidic nutrient EMS and metformin significantly decreased the levels of glucose, glycated hemoglobin, hydroxyproline, collagen content, extent glycation, fluorescence, neutral salt, acid and pepsin soluble collagen content, whereas it increased insulin, hemoglobin levels in diabetic rats. The positive influence of nonglucidic nutrient on both collagen content and its properties suggests a potential mechanism for the ability of EMS to delay diabetic complications.
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PMID:Effect of succinic acid monoethyl ester on hemoglobin glycation and tail tendon collagen properties in type 2 diabetic rats. 1848 47

Visfatin is a newly discovered adipocyte hormone with a direct relationship between plasma visfatin level and type 2 diabetes mellitus. Visfatin binds to the insulin receptor at a site distinct from that of insulin and causes hypoglycaemia by reducing glucose release from liver cells and stimulating glucose utilization in adipocytes and myocytes. Visfatin is upregulated by hypoxia, inflammation and hyperglycaemia and downregulated by insulin, somatostatin and statins. This hormone is found in the cytoplasm as well as the nucleus of cells and has been identified in many tissues and organs including the brain, kidney, lung, spleen and testis but preferentially expressed in visceral adipose tissue and upregulated in some animal models of obesity. Visceral adipose tissue is regarded to be more pernicious than subcutaneous adipose tissue. Visfatin is an endocrine, autocrine as well as paracrine peptide with many functions including enhancement of cell proliferation, biosynthesis of nicotinamide mono- and dinucleotide and hypoglycaemic effect. Visfatin, also known as a pre-B cell colony-enhancing factor, consists of 491 amino acids (aa) in human, chimpanzee, cattle, pig, rat and mouse, 490 aa in rhesus monkey, 285 aa in sheep, 587 in opossum and 588 aa in canines. Visfatin gene is well preserved during evolution. For example, the canine visfatin protein sequence is 96% and 94% identical to human and rodent visfatin, respectively. Since evidence of a direct link between visfatin genotype and human type 2 diabetes mellitus is still weak, more molecular, physiological and clinical studies are needed to determine the role of visfatin in the etiology and pathogenesis of type 2 diabetes mellitus.
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PMID:Visfatin: structure, function and relation to diabetes mellitus and other dysfunctions. 1869 Oct 43

Dipeptidyl peptidase-IV (DPP-IV) is the primary inactivator of glucoregulatory incretin hormones, and DPP-IV inhibitors are expected to become a useful new class of anti-diabetic agent. The aim of the present study is to characterize the chronic in vivo profile of the DPP-IV inhibitor ASP8497. In streptozotocin-nicotinamide-induced diabetic mice, ASP8497 was administered orally for 3 weeks at 1, 3, or 10 mg/kg once daily, which improved the hemoglobin A(1c), non-fasting plasma insulin, fasting blood glucose levels, glucose intolerance, and lipid profiles (plasma triglyceride, non-esterified fatty acid and total cholesterol) with neutral effect on body weight. The pancreatic insulin content and hepatic phosphoenolpyruvate carboxykinase (PEPCK) activity recovered dose-dependently in ASP8497-treated groups. These results revealed that ASP8497 was successful in improving glycemic control and metabolic parameters in streptozotocin-nicotinamide-induced diabetic mice. It is therefore suggested that ASP8497 may be a potential agent for the treatment of type 2 diabetes.
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PMID:Chronic inhibition of dipeptidyl peptidase-IV with ASP8497 improved the HbA(1c) level, glucose intolerance, and lipid parameter level in streptozotocin-nicotinamide-induced diabetic mice. 1876 13

In this study, streptozotocin-induced severely diabetic rats and streptozotocin-nicotinamide-induced mildly diabetic rats were established to compare their characteristics and to investigate the hypoglycaemic effects of antidiabetic drugs. Results show that in streptozotocin-induced severely diabetic rats, the pancreatic insulin content decreased to approximately 10% of that in normal rats. These severely diabetic rats also exhibited marked hyperglycaemia and impaired glucose tolerance due to insulin secretory deficiency. In contrast, the pancreatic insulin content was approximately 50% of normal levels in streptozotocin-nicotinamide-induced mildly diabetic rats. These mildly diabetic rats exhibited moderate hyperglycaemia and impaired glucose tolerance due to loss of early-phase insulin secretion. Voglibose (alpha-glucosidase inhibitor), metformin (biguanide), glibenclamide (sulfonylurea), sitagliptin (dipeptidyl peptidase-4 inhibitor) and insulin significantly improved glucose tolerance in streptozotocin-nicotinamide-induced mildly diabetic rats. In contrast, in streptozotocin-induced severely diabetic rats, voglibose, metformin and insulin significantly improved glucose tolerance, but no significant effect was observed for glibenclamide and sitagliptin due to a decreased insulinotropic effect. These results suggest that streptozotocin-nicotinamide-induced mildly diabetic rats, which exhibit a mild decline in glucose tolerance due to loss of early-phase insulin secretion, are sensitive to the hypoglycaemic effects of insulinotropic agents and have many pathological features resembling type 2 diabetes, which may be useful in the pharmacological investigation of numerous antidiabetic drugs.
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PMID:Hypoglycaemic effects of antidiabetic drugs in streptozotocin-nicotinamide-induced mildly diabetic and streptozotocin-induced severely diabetic rats. 1879 71


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