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)

Plasma endothelin-1, the nitric oxide (NO) mediator intraplatelet cyclic guanosine monophosphate (cGMP), the prostacyclin mediator cyclic adenosine monophosphate (cAMP) and the macrophage derived inflammatory mediator plasma neopterin were measured in men with Type 2 diabetes mellitus (n=91), impaired glucose tolerance (IGT; n=51), previously abnormal glucose tolerance (PAGT; n=20), and 34 healthy control men. Plasma endothelin-1was higher in men with Type 2 diabetes mellitus than in controls [4.1 (1.0-14.3) vs. 2.1 (0.2-8. 7) ng/l; P<0.001). Intraplatelet cGMP was higher in men with PAGT [0. 84 (0.57-2.76) pmol/10(9) platelets; P<0.05], IGT [0.85 (0.48-3.53); P<0.001] and Type 2 diabetes mellitus [0.90 (0.47-3.86); P<0.001] than in controls [0.70 (0.42-1.70]. No differences existed between groups concerning intraplatelet cAMP or plasma neopterin. Plasma endothelin-1 correlated with fasting plasma glucose (r=0.33; P<0.001) and HbA1(c) (r=0.29; P<0.001). In conclusion, elevated plasma endothelin-1 in Type 2 diabetes mellitus and its relationship to glucose and HbA1(c) suggest a putative role for endothelin-1 in diabetic endothelial cell damage. Increased cGMP indicating enhanced production/activity of NO suggests that factors other than reduced NO activity contribute to enhanced platelet aggregation in diabetes.
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PMID:Increased plasma endothelin-1 and intraplatelet cyclic guanosine monophosphate in men with disturbed glucose metabolism. 1096 Jul 23

The expression of large and small vessel disease in type 2 diabetes differs from that observed in type 1, with a higher prevalence of atherosclerosis and hypertension, maculopathy rather than proliferative retinopathy, and nephropathy of a more complex nature. Such differences are mirrored by differences in vascular pathophysiology with an early impairment of microvascular vasodilatory reserve being a prominent feature. The defect appears to be endothelium dependent and in conjunction with evidence of endothelium activation suggests that the endothelium plays a crucial role in the pathogenesis of vascular disease in type 2 diabetes and may even be an intrinsic feature or common antecedent of the insulin resistance syndrome. Several cellular mechanisms may be proposed linking insulin resistance and endothelial dysfunction including (i) abnormalities of common signal transduction mechanisms, (ii) alterations in cell membrane fluidity altering the expression and/or presentation of a wide range of receptors, or (iii) changes in oxidative stress. It is intuitively unlikely that the alteration of a single signal transduction mechanism could be a common cause, particularly as aspects of endothelial dysfunction implicate different mechanisms. Accordingly, changes in oxidative stress, either stemming from glucose-mediated increased free-radical generation and/or reduction of antioxidant capacity, are strong contender mechanisms. Not only may increased oxidative stress result in the quenching of nitric oxide, neutralizing its many protective functions, but it may also damage DNA, protein structure, and membrane properties. Elucidating the links between oxidative stress, endothelial function, and insulin resistance has important implications for the prevention of diabetic angiopathy and perhaps for the prevention of diabetes itself.
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PMID:Possible pathophysiological mechanisms for diabetic angiopathy in type 2 diabetes. 1100 28

The endothelial nitric oxide synthase (eNOS) gene is responsible for constitutive nitric oxide synthesis and arterial vasodilatation. Recently two polymorphisms, the 27-bp repeat sequence in intron 4 and the Glu298Asp substitution in exon 7 of the eNOS gene have been reported to be related to coronary heart disease (CHD). We screened these polymorphisms of the eNOS gene in 308 unrelated nondiabetic subjects with CHD, in 251 unrelated patients with type 2 diabetes with CHD, and in 110 randomly selected healthy subjects without CHD. The 4a and Asp298 allele frequencies of the eNOS gene were 0.19 and 0.36 in nondiabetic patients with CHD, 0.21 and 0.27 in type 2 diabetic patients with CHD, and 0.16 and 0.31 in nondiabetic subjects without CHD (n.s. between the groups). The Asp298 allele in exon 7 of the eNOS gene was not associated with elevated blood pressure in any of the study groups. Among type 2 diabetic patients with CHD the 4a allele in intron 4 of the eNOS gene was associated with elevated levels of systolic (P=0.035) and mean arterial blood pressure (P=0.040). In nondiabetic subjects these associations were not statistically significant. When all study groups were pooled in statistical analysis the 4a allele of the eNOS gene was associated with elevated diastolic (P=0.032) and mean (P=0.030) arterial blood pressure even after adjustment for confounding factors. We conclude that the 4a allele of the eNOS gene is not associated with CHD or type 2 diabetes, but that it is related to elevated blood pressure levels particularly among type 2 diabetic patients with CHD.
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PMID:Intron 4 polymorphism of the endothelial nitric oxide synthase gene is associated with elevated blood pressure in type 2 diabetic patients with coronary heart disease. 1104 80

Diabetic macroangiopathy is a major cause of morbidity and mortality of patients with non-insulindependent diabetes mellitus. Bad metabolic control of diabetes increases the risk of developing atherosclerotic complications. Hyperglycemia aids to increase the process of non-enzymatic protein glycosylation. Advanced glycation end products (AGEs) created in Maillard reaction play multidirectional role in creation of atherosclerosis in NIDDM. AGEs form in LDL, HDL and VLDL particles and increase their oxidative modification. They aid deposition of cholesterol and its esters in macrophages as well as creation of foam cells. Reaction of LDL-AGE particles with proteoglycans of blood vessel intima results in its thickening. LDL-AGE and ox-LDL take part in formation of late atherosclerotic changes influencing the expression of genes for cytokines and growth factors. AGEs promote prothrombotic changes. They block formation of nitric oxide which results in impaired vessel relaxation. They also take part in progressive vessel narrowing up to complete vessel occlusion by atheroslerotic plaque.
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PMID:[The importance of advanced glycosylation end products in the creation and progression of atherosclerosis in non-insulin-dependent diabetes mellitus]. 1105 18

Vascular complications are the leading cause of increased mortality in patients with diabetes mellitus. Endothelial dysfunction, characterised by impaired endothelium-dependent vasoreactivity, is the first sign of blood vessel damage that precedes morphological changes of the vessel wall. With other factors altered bioavailability of nitric oxide, the most potent endothelium-derived vasodilator, contributes to the changes in vascular tone and integrity. In addition to the impairment of vascular reactivity and permeability, other anti-atherosclerotic functions of nitric oxide are also diminished, which may result in activated monocyte, leukocyte and platelet adhesion to the endothelium, increased platelet aggregation, lipoprotein influx to the subendothelial space and smooth muscle proliferation. Hyperglycaemia-induced increased oxidative stress and impairment of antioxidant defence are suggested to play a role in the pathomechanism of vascular damage, partly by influencing nitric oxide. Both in experimental and clinical Type 1 and Type 2 diabetes mellitus the apparently conflicting data of increased, unaltered or diminished nitric oxide action suggests a complex, time and localisation-dependent alteration of vascular function. The understanding of the mechanisms that lead to diabetic endothelial dysfunction and its early detection are necessary to establish appropriate intervention to prevent irreversible atherosclerotic vessel damage in patients with diabetes mellitus.
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PMID:Endothelial nitric oxide in diabetes mellitus: too much or not enough? 1110 72

Our laboratory has demonstrated that insulin rapidly stimulates myosin-bound phosphatase (MBP) activity in vascular smooth muscle cells (VSMCs). In this study, we examined whether diabetes is accompanied by alterations in MBP activation and elucidated the components of the signaling pathway that mediate the effects of diabetes. VSMCs isolated from Goto-Kakizaki (GK) diabetic rats (a model for type 2 diabetes) exhibited marked impairment in MBP activation by insulin that was accompanied by failure of insulin to decrease the phosphorylation of a regulatory myosin-bound subunit (MBS) of MBP and inhibit Rho kinase activity resulting in increased myosin light-chain (MLC)20 phosphorylation and VSMC contraction. In VSMCs isolated from control rats, insulin inactivates Rho kinase and decreases MBS phosphorylation, leading to MBP activation. In addition to this pathway, insulin also appears to activate MBP by stimulating the phosphatidylinositol (PI) 3-kinase/nitric oxide (NO)/cGMP signaling pathway because treatment with the synthetic inhibitors of PI 3-kinase, NO synthase (NOS), and cGMP all blocked insulin's effect on MBP activation, whereas cGMP agonists and sodium nitroprusside (SNP) mimicked insulin's effect on MBP activation. VSMCs from diabetic GK rats exhibit reductions in insulin-mediated induction of inducible NOS protein expression and cGMP generation but normal MBP activation in response to SNP and cGMP agonist. This observation led us to examine the effect of diabetes on the activation status of the upstream insulin-signaling components. Although GK diabetes did not affect insulin-stimulated tyrosine phosphorylation of the insulin receptor or its content, insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation was severely impaired. This was accompanied by marked reductions in IRS-1-associated PI 3-kinase activity. We conclude that insulin stimulates MBP via its regulatory subunit, MBS, by inactivating Rho kinase and stimulating NO/cGMP signaling via PI 3-kinase as part of a complex signaling network that controls MLC20 phosphorylation and VSMC contraction. Defective signaling via Rho kinase and the IRS-1/PI 3-kinase/NOS/cGMP pathway may mediate the inhibitory effects of hyperglycemia and diabetes on MBP activation in this experimental model.
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PMID:Diabetes in the Goto-Kakizaki rat is accompanied by impaired insulin-mediated myosin-bound phosphatase activation and vascular smooth muscle cell relaxation. 1111 23

It is proposed that an important function of leptin is to confine the storage of triglycerides (TG) to the adipocytes, while limiting TG storage in nonadipocytes. Excess TG deposition in nonadipocytes leads to impairment of functions, increased ceramide formation, which triggers nitric oxide-mediated lipotoxicity and lipoapoptosis. The fact that TG content in nonadipocytes normally remains within a very narrow range irrespective of excess caloric intake, while TG content of adipocytes rises, is consistent with a system of fatty acid (FA) homeostasis in nonadipose tissues. When leptin is deficient or leptin receptors are dysfunctional, TG content in nonadipose tissues such as pancreatic islets, heart and skeletal muscle, can increase 10-50-fold, suggesting that leptin controls the putative homeostatic system for intracellular TG. The fact that function and viability of nonadipocytes is compromised when their TG content rises above normal implies that normal homeostasis of their intracellular FA is critical for prevention of complications of obesity. FA overload of skeletal muscle, myocardium and pancreatic islets cause, respectively, insulin resistance, lipotoxic heart disease and adipogenic type 2 diabetes. All can be completely prevented by treatment with antisteatotic agents such as troglitazone. In diet-induced obesity, leptin signaling is normal initially and lipotoxic changes are at first prevented; later, however, post-receptor leptin resistance appears, leading to dysfunction and lipoapoptosis in nonadipose tissues, the familiar complications of obesity.
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PMID:Lipotoxic diseases of nonadipose tissues in obesity. 1112 36

The main etiology for mortality and a great percent of morbidity in patients with diabetes mellitus is atherosclerosis. A hypothesis for the initial lesion of atherosclerosis is endothelial dysfunction, defined pragmatically as changes in the concentration of the chemical messengers produced by the endothelial cell and/or by blunting of the nitric oxide-dependent vasodilatory response to acetylcholine or hyperemia. Endothelial dysfunction has been documented in patients with diabetes and in individuals with insulin resistance or at high risk for developing type 2 diabetes. Factors associated with endothelial dysfunction in diabetes include activation of protein kinase C, overexpression of growth factors and/or cytokines, and oxidative stress. Several therapeutic interventions have been tested in clinical trials aimed at improving endothelial function in patients with diabetes. Insulin sensitizers may have a beneficial effect in the short term, but the virtual absence of trials with cardiovascular end-points preclude any definitive conclusion. Two trials offer optimism that treatment with ACE inhibitors may have a positive impact on the progression of atherosclerosis. Although widely used, the effect of hypolipidemic agents on endothelial function in diabetes is not clear. The role of antioxidant therapy is controversial. No data have been published regarding the effects of hormonal replacement therapy on endothelial dysfunction in postmenopausal women with type 2 diabetes.
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PMID:Diabetes and endothelial dysfunction: a clinical perspective. 1115 15

Vascular endothelium is involved in the regulation of vascular tone, vessel permeability, and angiogenesis. Vessel tone is determined by the balance of various paracrine vasodilatory and vasoconstrictor factors, most notably nitric oxide (NO) and endothelin-1. Not surprisingly, endothelial dysfunction is believed to be crucial in the development of the chronic vascular complications of diabetes. Endothelial dysfunction, which may be examined by studying endothelial-dependent vasodilatation in humans, is also disturbed by many of the individual features of the insulin resistance syndrome including hypertension, dyslipidaemia, and hyperglycaemia. Therefore, it may be possible that endothelial dysfunction could be closely associated with, or even a common antecedent of, the insulin resistance syndrome (IRS). There is emerging evidence that impaired endothelial-dependent vasodilatation is present in populations at future risk of diabetes and even in children of low birth weight, who may exhibit features of the insulin resistance syndrome in later life. Endothelial dysfunction is an obvious therapeutic target if the vascular pathology associated with insulin resistance and type 2 diabetes is to be ameliorated.
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PMID:The association between insulin resistance and endotheliopathy. 1122 Feb 84

Several studies suggest that nitric oxide (NO) production is impaired in diabetes mellitus. Reduced levels of NO could contribute to cardiovascular mortality. Furthermore, NO synthesis is impaired in glutathione (GSH)-depleted human umbilical vein endothelial cells and GSH is reduced in patients with type 2 diabetes mellitus (T2DM). We tested the hypothesis that treatment with GSH may improve platelet constitutive NO sinthase (cNOS) activity in patients with T2DM. Fifteen patients with T2DM underwent a treatment with GSH 600 mg/day i.m. for 10 days. With respect to the basal values on the 10th day of treatment, the red blood cell GSH concentration and platelets cNOS increased (1.4+/-0.1 vs 1.9+/-0.1 micromol/10(10) RBC, p<0.001 and 0.7+/-0.1 vs 2.9+/-0.2 fmol x min(-1) x 10(-9) PLTs, p<0.001, respectively) and the plasma PAI-1 levels diminished (81.4+/-3.7 vs 68.7+/-4.0 ng/ml, p<0.002). A negative correlation between the cNOS and the PAI-1 was found on the basal values. After a wash-out of 30 days the values of red blood cell GSH concentration, platelet cNOS activity and PAI-1 Ag returned to the basal levels. These data suggest that the administration of GSH, in patients with T2DM, is able to improve platelet cNOS activity together with a reduction of PAI-1.
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PMID:Administration of glutathione in patients with type 2 diabetes mellitus increases the platelet constitutive nitric oxide synthase activity and reduces PAI-1. 1122 30


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