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 goals of this study were to determine the effects of type II diabetes mellitus on nitric oxide synthase-dependent responses of cerebral arterioles and on endothelial nitric oxide synthase (eNOS) protein in cerebral arterioles. We examined dilatation of cerebral (pial) arterioles in 13-15 week old male lean and diabetic obese Zucker rats in response to nitric oxide synthase-dependent agonists (acetylcholine and adenosine diphosphate (ADP)) and a nitric oxide synthase-independent agonist (nitroglycerin). We found that acetylcholine (10 microM) increased cerebral arteriolar diameter by 10 +/- 3% (mean +/- SE) in lean Zucker rats, but by only 2 +/- 2% in diabetic obese Zucker rats (p<0.05). In addition, ADP (100 microM) increased cerebral arteriolar diameter by 20 +/- 2% in lean Zucker rats, but by only 8 +/- 2% in diabetic obese Zucker rats (p<0.05). In contrast, nitroglycerin produced similar vasodilatation in lean and diabetic obese Zucker rats. Thus, impaired dilatation of cerebral arterioles in diabetic obese Zucker rats is not related to non-specific impairment of vasodilatation. Following these functional studies, we harvested cerebral microvessels for Western blot analysis of eNOS protein. We found that eNOS protein was significantly higher in diabetic obese Zucker rats than in lean Zucker rats (p<0.05). Thus, type II diabetes mellitus impairs nitric oxide synthase-dependent responses of cerebral arterioles. In addition, eNOS protein from cerebral blood vessels is increased in diabetic obese Zucker rats.
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PMID:Impaired nitric oxide synthase-dependent dilatation of cerebral arterioles in type II diabetic rats. 1457 82

We have previously obtained a new type 2 diabetic syndrome in adult rats given streptozotocin and nicotinamide, characterized by reduced beta-cell mass, partially preserved insulin response to glucose and tolbutamide and excessive responsiveness to arginine. We have also established that the neuronal isoform of constitutive NO synthase (nNOS) is expressed in beta-cells and modulates insulin secretion. In this study, we explored the kinetics of glucose- and arginine-stimulated insulin release in perifused isolated islets as well as the effect of N-omega-nitro-L-arginine methyl ester (L-NAME), a NOS inhibitor, to get insight into the possible mechanisms responsible for the arginine hypersensitivity observed in vitro in this and other models of type 2 diabetes. A reduced first phase and a blunted second phase of insulin secretion were observed upon glucose stimulation of diabetic islets, confirming previous data in the isolated perfused rat pancreas. Exposure of diabetic islets to 10 mM arginine, in the presence of 2.8 mM glucose, elicited a remarkable monophasic increment in insulin release, which peaked at 639 +/- 31 pg/islet/min as compared to 49 +/- 18 pg/islet/min in control islets (P << 0.01). The addition of L-NAME to control islets markedly enhanced the insulin response to arginine, as expected from the documented inhibitory effect exerted by nNOS activity in normal beta-cells, whereas it did not further modify the insulin secretion in diabetic islets, thus implying the occurrence of a defective nNOS activity in these islets. A reduced expression of nNOS mRNA was found in the majority but not in all diabetic islet preparations and therefore cannot totally account for the absence of L-NAME effect, that might also be ascribed to post-transcriptional mechanisms impairing nNOS catalytic activity. In conclusion, our results provide for the first time evidence that functional abnormalities of type 2 experimental diabetes, such as the insulin hyper-responsiveness to arginine, could be due to an impairment of nNOS expression and/or activity in beta-cells.
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PMID:Alteration of beta-cell constitutive NO synthase activity is involved in the abnormal insulin response to arginine in a new rat model of type 2 diabetes. 1514 29

The glucose disposal effect of insulin after a meal is accounted for in approximately equal measure by the direct action of insulin and the action of HISS (hepatic insulin sensitizing substance) released from the liver and acting on skeletal muscle to stimulate glucose storage as glycogen. The ability of insulin to cause HISS release is determined by hepatic parasympathetic nerves. Eliminating the parasympathetic signal by surgical denervation of the liver or by blockade of hepatic muscarinic receptors, hepatic nitric oxide synthase, or hepatic cyclooxygenase results in insulin resistance that can be accounted for by the absence of HISS action and is referred to as HISS-dependent insulin resistance (HDIR). Animal models in which the insulin resistance has been shown to be HDIR includes the spontaneously hypertensive rat, sucrose fed rats, animals with liver disease, adult offspring of fetal alcohol exposure, acute stress, and ageing. We suggest that HDIR accounts for the major metabolic disturbances in type 2 diabetes, including the postprandial hyperglycemia that results in the majority of pathologies related to diabetes. The observation of meal-induced insulin sensitization (MIS) and the role of HISS allows for consideration of a new paradigm relating meal processing, diabetes, obesity, and insulin resistance. New diagnostic approaches and therapeutic targets are described.
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PMID:A new paradigm for diabetes and obesity: the hepatic insulin sensitizing substance (HISS) hypothesis. 1515 45

Endothelial dysfunction reflects an imbalance of vasodilators and vasoconstrictors. Endogenous endothelin activity seems to be increased in human obesity and type 2 diabetes, and cellular studies suggest that this factor may itself reduce bioavailable nitric oxide (NO). We studied 20 lean, 20 obese, and 14 type 2 diabetic individuals under three protocols, measuring leg vascular responses to intra-arterial infusions of NG-monomethyl-l-arginine (l-NMMA; an inhibitor of NO synthase) alone or in combination with BQ123 (an antagonist of type A endothelin receptors) or phentolamine (used as a control vasodilator). NO synthase inhibition alone (study 1) produced an approximately 40% increase in leg vascular resistance (LVR) in all three participant groups, which was not statistically different across groups (increase in LVR: lean, 135 +/- 28; obese, 140 +/- 32; type 2 diabetic, 184 +/- 51 units; NS). By design, BQ123 at the infused rate of 3 micromol/min produced equivalent approximately 35% reductions in LVR across groups. The subsequent addition of l-NMMA produced a greater increase in LVR among obese participants than lean or type 2 diabetic participants (study 2: lean, 182 +/- 48; obese, 311 +/- 66; type 2 diabetic, 186 +/- 40; P = 0.07). Compared with study 1, the effect of l-NMMA was magnified by BQ123 in obese participants but not in lean or type 2 diabetic participants (P = 0.005, study 1 vs. 2; P = 0.03 for group effect). Phentolamine (75 mg/min) produced vasodilation in obese participants comparable to that seen with BQ123 but failed to augment the L-NMMA response. Endothelin antagonism unmasks or augments NO synthesis capacity in obese but not type 2 diabetic participants. This suggests that impaired NO bioavailability as a result of endogenous endothelin may contribute to endothelial dysfunction in obesity, in addition to direct vasoconstrictor effects of endothelin. In contrast, endothelin antagonism alone is insufficient to restore impaired NO bioavailability in diabetes.
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PMID:Interactions between endothelin and nitric oxide in the regulation of vascular tone in obesity and diabetes. 1527 86

Oxidative stress is thought to be one of the causative factors contributing to insulin resistance and type 2 diabetes. Previously, we showed that reactive oxygen species (ROS) production is significantly increased in adipocytes from high-fat diet-induced obese and insulin-resistant mice (HF). ROS production was also associated with the increased activity of PKC-delta. In the present studies, we hypothesized that PKC-delta contributes to ROS generation and determined their intracellular source. NADPH oxidase inhibitor diphenyleneiodonium chloride (DPI) reduced ROS levels by 50% in HF adipocytes, and inhibitors of NO synthase (L-NAME, 1 mM), xanthine oxidase (allopurinol, 100 microM), AGE formation (aminoguanidine, 10 microM), or the mitochondrial uncoupler (FCCP, 10 microM) had no effect. Rottlerin, a selective PKC-delta inhibitor, suppressed ROS levels by approximately 50%. However, neither GO-6976 nor LY-333531, effective inhibitors toward conventional PKC or PKC-beta, respectively, significantly altered ROS levels in HF adipocytes. Subsequently, adenoviral-mediated expression of wild-type PKC-delta or its dominant negative mutant (DN-PKC-delta) in HF adipocytes resulted in either a twofold increase in ROS levels or their suppression by 20%, respectively. In addition, both ROS levels and PKC-delta activity were sharply reduced by glucose depletion. Taken together, these results suggest that PKC-delta is responsible for elevated intracellular ROS production in HF adipocytes, and this is mediated by high glucose and NADPH oxidase.
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PMID:PKC-delta-dependent activation of oxidative stress in adipocytes of obese and insulin-resistant mice: role for NADPH oxidase. 1550 33

Endothelial dysfunction and increased arterial stiffness occur early in the pathogenesis of diabetic vasculopathy. They are both powerful independent predictors of cardiovascular risk. Advances in non-invasive methodologies have led to widespread clinical investigation of these abnormalities in diabetes mellitus, generating a wealth of new knowledge concerning the mechanisms of vascular dysfunction, risk factor associations and potential treatment targets. Endothelial dysfunction primarily reflects decreased availability of nitric oxide (NO), a critical endothelium-derived vasoactive factor with vasodilatory and anti-atherosclerotic properties. Techniques for assessing endothelial dysfunction include ultrasonographic measurement of flow-mediated vasodilatation of the brachial artery and plethysmography measurement of forearm blood flow responses to vasoactive agents. Arterial stiffness may be assessed using pulse wave analysis to generate measures of pulse wave velocity, arterial compliance and wave reflection. The pathogenesis of endothelial dysfunction in type 2 diabetes is multifactorial, with principal contributors being oxidative stress, dyslipidaemia and hyperglycaemia. Elevated blood glucose levels drive production of reactive oxidant species (ROS) via multiple pathways, resulting in uncoupling of mitochondrial oxidative phosphorylation and endothelial NO synthase (eNOS) activity, reducing NO availability and generating further ROS. Hyperglycaemia also contributes to accelerated arterial stiffening by increasing formation of advanced glycation end-products (AGEs), which alter vessel wall structure and function. Diabetic dyslipidaemia is characterised by accumulation of triglyceride-rich lipoproteins, small dense low-density lipoprotein (LDL) particles, reduced high-density lipoprotein (HDL)-cholesterol and increased postprandial free fatty acid flux. These lipid abnormalities contribute to increasing oxidative stress and may directly inhibit eNOS activity. Although lipid-regulating agents such as HMG-CoA reductase inhibitors (statins), fibric acid derivatives (fibrates) and fish oils are used to treat diabetic dyslipidaemia, their impact on vascular function is less clear. Studies in type 2 diabetes have yielded inconsistent results, but this may reflect sampling variation and the potential over-riding influence of oxidative stress, dysglycaemia and insulin resistance on endothelial dysfunction. Results of positive intervention trials suggest that improvement in vascular function is mediated by both lipid and non-lipid mechanisms, including anti-inflammatory, anti-oxidative and direct effects on the arterial wall. Other treatments, such as renin-angiotensin-aldosterone system antagonists, insulin sensitisers and lifestyle-based interventions, have shown beneficial effects on vascular function in type 2 diabetes. Novel approaches, targeting eNOS and AGEs, are under development, as are new lipid-regulating therapies that more effectively lower LDL-cholesterol and raise HDL-cholesterol. Combination therapy may potentially increase therapeutic efficacy and permit use of lower doses, thereby reducing the risk of adverse drug effects and interactions. Concomitant treatments that specifically target oxidative stress may also improve endothelial dysfunction in diabetes. Vascular function studies can be used to explore the therapeutic potential and mechanisms of action of new and established interventions, and provide useful surrogate measures for cardiovascular endpoints in clinical trials.
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PMID:Mechanisms, significance and treatment of vascular dysfunction in type 2 diabetes mellitus: focus on lipid-regulating therapy. 1561 50

Type 2 diabetes mellitus (DM) and the metabolic syndrome, both characterized by insulin resistance, are associated with an accelerated form of atherosclerotic vascular disease and poor outcomes following vascular interventions. These vascular effects are thought to stem from a heightened inflammatory environment and reduced bioavailability of nitric oxide (NO). To better understand this process, we characterized the vascular injury response in the obese Zucker rat by examining the expression of adhesion molecules, the recruitment of inflammatory cells, and the development of intimal hyperplasia. We also evaluated the ability of exogenous NO to inhibit the sequela of vascular injury in the metabolic syndrome. Obese and lean Zucker rats underwent carotid artery balloon injury. ICAM-1 and P-selectin expression were increased following injury in the obese animals compared with the lean rats. The obese rats also responded with increased macrophage infiltration of the vascular wall as well as increased neointima formation compared with their lean counterparts (intima/media = 0.91 vs. 0.52, P = 0.001). After adenovirus-mediated inducible NO synthase (iNOS) gene transfer, ICAM-1, P-selectin, inflammatory cell influx, and oxidized low-density lipoprotein (LDL) receptor expression were all markedly reduced versus injury alone. iNOS gene transfer also significantly inhibited proliferative activity (54% and 73%; P < 0.05) and neointima formation (53% and 67%; P < 0.05) in lean and obese animals, respectively. The vascular injury response in the face of obesity and the metabolic syndrome is associated with increased adhesion molecule expression, inflammatory cell infiltration, oxidized LDL receptor expression, and proliferation. iNOS gene transfer is able to effectively inhibit this heightened injury response and reduce neointima formation in this proinflammatory environment.
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PMID:Nitric oxide modulates vascular inflammation and intimal hyperplasia in insulin resistance and the metabolic syndrome. 1573 83

Rosiglitazone (ROSI), thiazolidione peroxisome proliferator-activated receptor-gamma (PPAR-gamma) activator, reduces insulin resistance in patients with type 2 diabetes (T2DM). It also improves vascular reactivity in T2DM patients and some animal models by unclear mechanisms. In order to investigate the effect of ROSI on aortic systolic and diastolic function of insulin resistant-hypertensive rats (IRHR) and the underlying mechanism, male Sprague-Dawley (SD) rats were fed with high fructose (HF) for 8 weeks to induce IRHR model. To verify IRHR model, systolic blood pressure (SBP), fasting blood sugar (FBS), fasting serum insulin (FSI) were measured respectively in each group, and insulin sensitive index (ISI) was also calculated. Subsequently, the vascular function test was performed. The thoracic aortic ring of SD rats was mounted on a bath system. The effect of rosiglitazone on the contraction elicited by L-phenylephrine (PE) and potassium chloride (KCl) and the relaxation induced by acetylcholine (ACh) and sodium nitroprusside (SNP) were measured. To explore the mechanism, nitric oxide synthase (NOS) inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) was used and serum nitric oxide (NO) was measured. The results obtained were as follows: (1) Rosiglitazone reduced the level of SBP, serum insulin and improved insulin resistance in IRHRs. (2) The contractive responses of thoracic aortic rings to PE and KCl were enhanced and the relaxation response to ACh was depressed significantly in the HF group, and the effect was reversed by ROSI. (3) After pretreatment with L-NAME, the relaxation response to ACh was further impaired in the HF group, this effect was partly reversed by ROSI. (4) Sodium nitroprusside (SNP)-induced vasodilator responses did not differ significantly among the groups. (5) Aortic systolic and diastolic function of the control group was not affected markedly by ROSI. (6) Compared with the control group, serum nitric oxide was significantly reduced in the HF group, but after rosiglitazone treatment it was remarkably increased. These findings suggest that ROSI can improve aortic diastolic function of insulin resistant-hypertensive rats, the mechanism of this effect might be associated with an increase in nitric oxide mediated partly by NOS pathway, a decrease in the level of blood pressure, serum insulin and the improvement of insulin resistance.
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PMID:[Effects of rosiglitazone on aortic function in rats with insulin resistant-hypertension]. 1583 95

Endothelium-derived nitric oxide (NO) facilitates skeletal muscle glucose uptake. Energy expenditure induces the endothelial NO synthase (eNOS) gene, providing a mechanism for insulin-independent glucose disposal. The object was to test 1) the association of genetic variation in eNOS, as assessed by haplotype-tagging single nucleotide polymorphisms (htSNPs) with type 2 diabetes, and 2) the interaction between eNOS haplotypes and total energy expenditure on glucose intolerance. Using multivariate models, we tested associations between eNOS htSNPs and diabetes (n = 461 and 474 case and control subjects, respectively) and glucose intolerance (two cohorts of n = 706 and 738 U.K. and Spanish Caucasians, respectively), and we tested eNOS x total energy expenditure interactions on glucose intolerance. An overall association between eNOS haplotype and diabetes was observed (P = 0.004). Relative to the most common haplotype (111), two haplotypes (121 and 212) tended to increase diabetes risk (OR 1.22, 95% CI 0.96-1.55), and one (122) was associated with decreased risk (0.58, 0.39-0.86). In the cohort studies, no association was observed between haplotypes and 2-h glucose (P > 0.10). However, we observed a significant total energy expenditure-haplotype interaction (P = 0.007). Genetic variation at the eNOS locus is associated with diabetes, which may be attributable to an enhanced effect of total energy expenditure on glucose disposal in individuals with specific eNOS haplotypes. Gene-environment interactions such as this may help explain why replication of genetic association frequently fails.
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PMID:Variation in the eNOS gene modifies the association between total energy expenditure and glucose intolerance. 1612 71

Melatonin, which is synthesized in the pineal gland and other tissues, has a variety of physiological, immunological, and biochemical functions. It is a direct scavenger of free radicals and has indirect antioxidant effects due to its stimulation of the expression and activity of antioxidative enzymes such as glutathione peroxidase, superoxide dismutase and catalase, and NO synthase, in mammalian cells. Melatonin also reduces serum lipid levels in mammalian species, and helps to prevent oxidative stress in diabetic subjects. Long-term melatonin administration to diabetic rats reduced their hyperlipidemia and hyperinsulinemia, and restored their altered ratios of polyunsaturated fatty acid in serum and tissues. It was recently reported that melatonin enhanced insulin-receptor kinase and IRS-1 phosphorylation, suggesting the potential existence of signaling pathway cross-talk between melatonin and insulin. Because TNF-alpha has been shown to impair insulin action by suppressing insulin receptor-tyrosine kinase activity and its IRS-1 tyrosine phosphorylation in peripheral tissues such as skeletal muscle cells, it was speculated that melatonin might counteract TNF-alpha-associated insulin resistance in type 2 diabetes. This review will focus on the physiological and metabolic effects of melatonin and highlight its potential use for the treatment of cholesterol/lipid and carbohydrate disorders.
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PMID:Metabolic effects of melatonin on oxidative stress and diabetes mellitus. 1621 26


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