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 normal endothelium produces a number of vasodilator substances such as nitric oxide (NO) and prostacyclin (PGI2) that regulate vasomotor tone, reduce platelet aggregation, and inhibit the recruitment and activity of inflammatory cells. The functions of vascular endothelial cells are disturbed in diabetic patients. The major cause for mortality and a great percent of morbidity in patients with diabetes mellitus is atherosclerosis. Insulin has recently been shown to stimulate NO release and the expression of NO synthase by the endothelium. Insulin is thus a vasodilator, has anti-platelet activity, and now has been shown to be anti-inflammatory and thus, potentially anti-atherogenic. Similar anti-inflammatory effects of thiazolidenediones (TZDs), troglitazone, and rosiglitazone suggest that they too may have potential anti-atherogenic effects. These effects of insulin and TZDs are of importance since the two major states of insulin resistance, obesity and type 2 diabetes, are associated with a marked increase in atherosclerosis, coronary heart disease, and stroke. These recent observations have extremely important implications for the understanding of the pathogenesis of atherosclerosis in insulin-resistant states and for a rational approach to their comprehensive treatment, including the prevention of atherosclerosis and its complications. This review challenges the previously proposed hypothesis that hyperinsulinemia represents a common pathophysiological pathway of diabetic complications and advances our hypothesis that insulin, through its effect on the endothelium, leucocytes, and platelets, has anti-inflammatory and thus potentially anti-atherogenic properties. Furthermore, through its anti-inflammatory effects, its use improves clinical outcomes in at least two clinical states characterized by profound inflammation-acute myocardial infarction and sepsis.
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PMID:Endothelium, inflammation, and diabetes. 1837 Jun 22

Current classifications of diabetes distinguish between type 1 diabetes (T1D) and type 2 diabetes (T2D), however recent evidence highlights overlap between T1D and T2D. Earlier studies have suggested altered nitric oxide (NO) metabolism in both T1D and T2D. In the present case-control study, we investigated whether the endothelial NO synthase gene intron 4 a/b polymorphism is associated with T1D and T2D in the island of Crete, a well-defined area with genetically homogeneous population. Mutated allele "a" was more common in individuals with both T1D and T2D than in controls (odds ratio [OR] = 1.71, 95% confidence interval [CI] = 1.06-2.77, p = 0.013; and OR = 1.50, 95% CI = 0.930-2.42, p = 0.047, respectively). Mutated genotype (a/a or a/b) was more common in individuals with T1D than in nondiabetic individuals (OR = 1.93, 95% CI = 1.12-3.32, p = 0.008); this increased frequency was also observed for T2D, although not at a significant level (OR = 1.38, 95% CI = 0.802-2.37). No difference was found in the frequency of mutated allele a or mutated genotype (a/a or a/b) between T1D and T2D populations. In conclusion, our results indicate that allele a of the intron 4 endothelial NO synthase gene is associated with susceptibility to both T1D and T2D and may represent a common genetic factor for diabetes.
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PMID:Intron 4 a/b polymorphism of the endothelial nitric oxide synthase gene is associated with both type 1 and type 2 diabetes in a genetically homogeneous population. 1848 63

The aim of this study was to determine whether the pathway of inducible NO synthase (iNOS) in blood vessels is changed by type 2 diabetes. Lipopolysaccharide (LPS)-induced nitric oxide (NO) production and expression of iNOS and effects of LPS on phenylephrine-induced contractile force were compared in aortae isolated from Goto-Kakizaki (G-K) diabetes rats and aortae isolated from control Wistar rats. Both LPS-stimulated nitrite generation and iNOS expression levels were significantly higher in aortae from G-K rats than in those from control rats. Phenylephrine-induced contractile force in the presence of LPS was significantly lower in aortae from G-K rats than in those from control rats, while contractile force in the absence of LPS was comparable in the diabetic and control groups. On the other hand, incubation of aortae in high glucose-containing medium did not affect the LPS-stimulated nitrite accumulation and iNOS expression and the phenylephrine-induced contractile force, regardless of the presence of LPS. These results suggest that LPS-induced NO production through the iNOS pathway is increased and subsequent attenuation of contractile force by excess NO is enhanced in arteries of rats with type 2 diabetes.
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PMID:Increased induction of inducible nitric oxide synthase expression in aortae of type 2 diabetes rats. 1856 22

Dietary obesity is associated with type 2 diabetes and cardiovascular diseases, although the underlying mechanism is unknown. This study was undertaken to elucidate the role of angiotensin II and apoptosis signal regulating kinase-1 (ASK1) in obesity/diabetes-associated cardiovascular complications and hepatic steatosis. Mice fed a high-fat diet were treated with olmesartan, an angiotensin II type 1 receptor blocker, to elucidate the role of angiotensin II in diabetic mice. Treatment of mice fed a high-fat diet with olmesartan markedly suppressed cardiac inflammation and fibrosis, as well as vascular endothelial dysfunction and remodeling, induced by obesity/diabetes. Moreover, olmesartan suppressed the disruption of the vascular endothelial NO synthase dimer in diabetic mice. Olmesartan also significantly prevented hepatic steatosis and fibrosis in diabetic mice. These beneficial effects of olmesartan on diabetic mice were associated with the attenuation of ASK1 activation in these mice. ASK1-deficient mice and wild-type mice were compared, regarding the effects of a high-fat diet. A comparison between ASK1-deficient and wild-type mice showed that ASK1 deficiency attenuated cardiac inflammation and fibrosis, as well as vascular endothelial dysfunction and remodeling induced by obesity/diabetes. The amelioration of vascular endothelial impairment by ASK1 deficiency was attributed to the prevention of endothelial NO synthase dimer disruption. ASK1 deficiency also significantly lessened hepatic steatosis in diabetic mice. In conclusion, our work provided the evidence that ASK1 is significantly activated in diet-induced diabetic mice and contributes to cardiovascular diseases and hepatic steatosis in diabetic mice. Moreover, the beneficial effects of angiotensin II inhibition on dietary diabetic mice seem to be mediated by the inhibition of ASK1 activation.
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PMID:Olmesartan prevents cardiovascular injury and hepatic steatosis in obesity and diabetes, accompanied by apoptosis signal regulating kinase-1 inhibition. 1867 90

Endothelin (ET)-1 is a likely candidate for a key role in diabetic vascular complications. However, no abnormalities in the vascular responsiveness to ET-1 have been identified in the chronic stage of type 2 diabetes. Our goal was to look for abnormalities in the roles played by ET receptors (ET(A) and ET(B)) in the mesenteric artery of the type 2 diabetic Goto-Kakizaki (GK) rat and to identify the molecular mechanisms involved. Using mesenteric arteries from later-stage (32-38 wk old) individuals, we compared the ET-1-induced contraction and the relaxation induced by the selective ET(B) receptor agonist IRL1620 between GK rats and control Wistar rats. Mesenteric artery ERK activity and the protein expressions for ET receptors and MEK were also measured. In GK rats (vs. age-matched Wistar rats), we found as follows. 1) The ET-1-induced contraction was greater and was attenuated by BQ-123 (ET(A) antagonist) but not by BQ-788 (ET(B) antagonist). In the controls, BQ-788 augmented this contraction. 2) Both the relaxation and nitric oxide (NO) production induced by IRL1620 were reduced. 3) ET-1-induced contraction was enhanced by N(G)-nitro-l-arginine (l-NNA; NO synthase inhibitor) but suppressed by sodium nitroprusside (NO donor). 4) The enhanced ET-1-induced contraction was reduced by MEK/ERK pathway inhibitors (PD-98059 or U0126). 5) ET-1-stimulated ERK activation was increased, as were the ET(A) and MEK1/2 protein expressions. 6) Mesenteric ET-1 content was increased. These results suggest that upregulation of ET(A), a defect in ET(B)-mediated NO signaling, and activation of the MEK/ERK pathway together represent a likely mechanism mediating the hyperreactivity to ET-1 examined in this study.
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PMID:Involvement of NO and MEK/ERK pathway in enhancement of endothelin-1-induced mesenteric artery contraction in later-stage type 2 diabetic Goto-Kakizaki rat. 1928 64

Insulin promotes the cardiovascular protective functions of the endothelium including NO production by endothelial NO synthase (eNOS), which it stimulates via Akt kinase which phosphorylates eNOS Ser1179. C-reactive protein (CRP) is an acute-phase reactant that is positively correlated with cardiovascular disease risk in patients with type 2 diabetes. We previously showed that CRP inhibits eNOS activation by insulin by blunting Ser1179 phosphorylation. We now elucidate the underlying molecular mechanisms. We first show in mice that CRP inhibits insulin-induced eNOS phosphorylation, indicating that these processes are operative in vivo. In endothelial cells we find that CRP attenuates insulin-induced Akt phosphorylation, and CRP antagonism of eNOS is negated by expression of constitutively active Akt; the inhibitory effect of CRP on Akt is also observed in vivo. A requirement for the IgG receptor FcgammaRIIB was demonstrated in vitro using blocking antibody, and reconstitution experiments with wild-type and mutant FcgammaRIIB in NIH3T3IR cells revealed that these processes require the ITIM (immunoreceptor tyrosine-based inhibition motif) of the receptor. Furthermore, we find that endothelium express SHIP-1 (Src homology 2 domain-containing inositol 5'-phosphatase 1), that CRP induces SHIP-1 stimulatory phosphorylation in endothelium in culture and in vivo, and that SHIP-1 knockdown by small interfering RNA prevents CRP antagonism of insulin-induced eNOS activation. Thus, CRP inhibits eNOS stimulation by insulin via FcgammaRIIB and its ITIM, SHIP-1 activation, and resulting blunted activation of Akt. These findings provide mechanistic linkage among CRP, impaired insulin signaling in endothelium, and greater cardiovascular disease risk in type 2 diabetes.
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PMID:C-reactive protein inhibits insulin activation of endothelial nitric oxide synthase via the immunoreceptor tyrosine-based inhibition motif of FcgammaRIIB and SHIP-1. 1942 45

Bank voles kept in captivity may develop diabetes. We recently characterized beta-cell function of pancreatic islets from normal and glucose intolerant/diabetic bank voles. These animals had features of both human type 1 and type 2 diabetes. Cytokines may impair beta-cell function in both types of diabetes. Presently, we studied how pancreatic islets isolated from normal, i.e. glucose tolerant bank voles are affected by proinflammatory cytokines in vitro. Islets were exposed to hIL-1beta (25U/ml) alone or in combination with hTNF-alpha (1000U/ml)+mIFN-gamma (1000U/ml) for 48h, whereupon islet functions were assessed. Cytokines markedly reduced insulin gene expression and the (pro)insulin biosynthesis rate, which was accompanied by a profound depletion of the islet insulin content. The cytokines did not affect the culture medium insulin accumulation and the glucose oxidation rate, but caused a modest increase in medium nitrite, an indicator of nitric oxide (NO) generation. Cytokine-induced decrease in islet insulin content was not prevented by the preferential inducible NO synthase inhibitor aminoguanidine. These findings suggest that the reduction in islet insulin content is not attributed to enhanced exocytosis or related to altered glucose metabolism, but is rather due to a decline in insulin production. The suppressive effects of islet functions elicited by cytokines seem to be mediated by an NO-independent mechanism. In relation to previous studies on cytokine effects on islets from various species, the bank vole islets show a pattern which more resembles human islets than rat or murine islets.
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PMID:Suppression of bank vole pancreatic islet function by proinflammatory cytokines. 1943 55

Obesity and type 2 diabetes mellitus are characterized by insulin resistance, reduced bioavailability of the antiatherosclerotic signaling molecule nitric oxide (NO), and accelerated atherosclerosis. IGF-I, the principal growth-stimulating peptide, which shares many of the effects of insulin, may, like insulin, also be involved in metabolic and vascular homeostasis. We examined the effects of IGF-I on NO bioavailability and the effect of obesity/type 2 diabetes mellitus on IGF-I actions at a whole-body level and in the vasculature. In aortic rings IGF-I blunted phenylephrine-mediated vasoconstriction and relaxed rings preconstricted with phenylephrine, an effect blocked by N(G)-monomethyl L-arginine. IGF-I increased NO synthase activity to an extent similar to that seen with insulin and in-vivo IGF-I led to serine phosphorylation of endothelial NO synthase (eNOS). Mice rendered obese using a high-fat diet were less sensitive to the glucose-lowering effects of insulin and IGF-I. IGF-I increased aortic phospho-eNOS levels in lean mice, an effect that was blunted in obese mice. eNOS activity in aortae of lean mice increased 1.6-fold in response to IGF-I compared with obese mice. IGF-I-mediated vasorelaxation was blunted in obese mice. These data demonstrate that IGF-I increases eNOS phosphorylation in-vivo, increases eNOS activity, and leads to NO-dependent relaxation of conduit vessels. Obesity is associated with resistance to IGF-I at a whole-body level and in the endothelium. Vascular IGF-I resistance may represent a novel therapeutic target to prevent or slow the accelerated vasculopathy seen in humans with obesity or type 2 diabetes mellitus.
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PMID:Vascular insulin-like growth factor-I resistance and diet-induced obesity. 1960 53

The health-promoting effects of various constituents of the olive tree (Olea europaea) are mainly associated with hypoglycaemic and insulin-sensitising activities and have been widely demonstrated in the metabolic syndrome and type 2 diabetes. However, their biological activity in autoimmune type 1 diabetes (T1D) is poorly characterised. Therefore, the influence of O. europaea-derived components present in dry olive leaf extract (DOLE) was examined in two established preclinical models of human T1D, which differ in some aspects of diabetogenesis: multiple low-dose streptozotocin-induced diabetes in susceptible C57BL/6 and CBA/H mouse strains; cyclophosphamide-accelerated diabetes in non-obese diabetic mice. In both T1D models, in vivo administration of DOLE significantly reduced clinical signs of diabetes (hyperglycaemia and body weight loss) and led to complete suppression of histopathological changes in pancreatic islets. In line with these, insulin expression and release were restored in DOLE-treated mice. Interestingly, inducible NO synthase expression and NO production were significantly elevated in peripheral tissues but were down-regulated within the local environment of the endocrine pancreas. This interference was reflected in NO-mediated suppression of T lymphocyte proliferation and lower production of the proinflammatory cytokines interferon-gamma, IL-17 and TNF-alpha in the spleen, with subsequent blockade of beta-cell destruction. The results suggest that DOLE interferes with development of autoimmune diabetes by down-regulating production of proinflammatory and cytotoxic mediators. Therefore, the potential use of a DOLE-enriched diet for prophylaxis/treatment of human T1D, and possibly other autoimmune diseases, is worthy of further investigation.
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PMID:Dried leaf extract of Olea europaea ameliorates islet-directed autoimmunity in mice. 2002 35

Hedysarum polybotrys polysaccharide (HPS) is the principal active fraction responsible for the antidiabetic properties of this species. The aim of this study was to determine the antidiabetic properties of 4 purified fractions of different molecular weight range HPSs (HPS1, HPS2, HPS3, HPS4). HPS3 was selected for examination of its hypoglycemic mechanism because of its significant hypoglycemic effect in alloxan-induced diabetic mice. The changes in blood glucose levels and oral glucose tolerance tests (OGTT) showed that hypoglycemia was more pronounced in HPS3-treated groups than in the diabetes mellitus model (DM) control group. The interleukin-6, tumor necrosis factor-alpha, leptin, and free fatty acid levels were significantly lower in the HPS3-treated groups and HPS3 + metformin (HPS3+MET) group than in the DM control group, while plasma insulin, hepatic glycogen, superoxide dismutase, and nitric oxide synthetase activity were significantly higher. Treatment with HPS3 or HPS3+MET also significantly lowered malonaldehyde levels compared with the DM control group, while it elevated the nitric oxide and total antioxidant capacity. HPS3 altered the plasma lipid levels by lowering cholesterol and triglyceride concentrations, while elevating the plasma high-density lipoprotein cholesterol level. Therefore, these results suggest that HPS3 may partly ameliorate hyperglycemia and hyperlipidemia associated with type 2 diabetes through increased insulin secretion, inhibition of lipid peroxidation, promotion of sensitivity to insulin, suppression of gluconeogenesis and reduction in the biosynthesis fatty acid, cholesterol and cell cytokines related to insulin resistance, and it could be a useful adjunct therapy to a proven first-line therapy for type 2 diabetes using metformin.
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PMID:Antidiabetic properties of purified polysaccharide from Hedysarum polybotrys. 2013 Jul 40


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