The main finding in this study is that in essential hypertensives the L-arginine and endogenous inhibitor of nitric oxide synthase, ADMA, are inversely related to endothelial function.

Abstract-It has been suggested that serine (Ser) phosphorylation of insulin receptor substrate-1 (IRS-1) decreases the ability of IRS-1 to be phosphorylated on tyrosine, thereby attenuating insulin signaling. There is evidence that angiotensin II (AII) may impair insulin signaling to the IRS-1/phosphatydilinositol 3-kinase (PI 3-kinase) pathway by enhancing Ser phosphorylation. Insulin stimulates NO production by a pathway involving IRS-1/PI3-kinase/Akt/endothelial NO synthase (eNOS). We addressed the question of whether AII affects insulin signaling involved in NO production in human umbilical vein endothelial cells and tested the hypothesis that the inhibitory effect of AII on insulin signaling was caused by increased site-specific Ser phosphorylation in IRS-1. Exposure of human umbilical vein endothelial cells to AII resulted in inhibition of insulin-stimulated production of NO. This event was associated with impaired IRS-1 phosphorylation at Tyr 612 and Tyr 632 , two sites essential for engaging the p85 subunit of PI3-kinase, resulting in defective activation of PI 3-kinase, Akt, and eNOS. This inhibitory effect of AII was reversed by the type 1 receptor antagonist losartan. AII increased c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) 1/2 activity, which was associated with a concomitant increase in IRS-1 phosphorylation at Ser 312 and Ser 616 , respectively. Inhibition of JNK and ERK1/2 activity reversed the negative effects of AII on insulin-stimulated NO production. Our data suggest that AII, acting via the type 1 receptor, increases IRS-1 phosphorylation at Ser 312 and Ser 616 via JNK and ERK1/2, respectively, thus impairing the vasodilator effects of insulin mediated by the IRS-1/PI 3-kinase/Akt/eNOS pathway. Key Words: endothelium Ⅲ angiotensin II Ⅲ nitric oxide Ⅲ insulin E ndothelial dysfunction is an early event in the pathogenesis of atherosclerosis and a feature of insulin-resistant conditions, including type 2 diabetes, obesity, and hypertension. 1-4 Several preclinical and clinical studies have established the involvement of angiotensin II (AII) and its type 1 receptor (AT 1 ) in endothelial dysfunction. [5][6][7] Insulin promotes vasodilatation by activation of the signaling pathway involving the insulin receptor/insulin receptor substrate-1 (IRS-1)/ phosphatidylinositol 3-kinase (PI 3-kinase)/Akt that leads to activation of endothelial NO synthase (eNOS) in endothelium. 8 Cross-talk between the renin-angiotensin system (RAS) and insulin signaling has been demonstrated. 9 Inhibition of RAS by angiotensin-converting enzyme inhibitors or AT 1 antagonists has been shown to both increase insulin sensitivity and improve endothelial function. 10 -12 Evidence has been provided that AII interferes with insulin signaling in vascular cells mainly by affecting insulin-induced tyrosine phosphorylation of IRS-1 and impairing its interaction with the p85 regulatory subunit of PI 3-kinase. 9 However, it is still unclear whether AII adversely affects the downstream signaling path...

OBJECTIVE -We studied the relationships between plasma IGF-I concentrations and insulin sensitivity in subjects with various degrees of glucose tolerance.RESEARCH DESIGN AND METHODS -A total of 357 nondiabetic subjects, 54 subjects with impaired glucose tolerance and 98 newly diagnosed type 2 diabetic subjects, were consecutively recruited, and anthropometric and biochemical characteristics were collected.RESULTS -IGF-I concentrations were negatively correlated with age, BMI, waist-to-hip ratio, triglyceride levels, and systolic and diastolic blood pressure. IGF-I concentrations were positively correlated with HDL cholesterol and homeostasis model assessment of insulin sensitivity (HOMA-S). The correlations remained significant after adjusting for sex, age, and BMI. Correlations for HOMA-S with these metabolic and anthropometric variables were of a similar degree and direction to those for IGF-I concentrations. Stepwise linear regression analysis in a model, which included well-known modulators of insulin sensitivity such as sex, age, BMI, glucose tolerance status, family history of diabetes, waist-to-hip ratio, systolic and diastolic blood pressure, HDL cholesterol, and triglyceride levels, revealed that IGF-I concentrations were independently associated with insulin sensitivity accounting for 10.8% of its variation (P Ͻ 0.0001). IGF-I concentrations were significantly lower in subjects with World Health Organization (WHO)-defined metabolic syndrome compared with subjects without metabolic syndrome (P Ͻ 0.0001). Logistic regression analysis showed that each unit increase in log-transformed IGF-I concentrations was associated with a 90.5% reduction in the risk of WHO-defined metabolic syndrome.CONCLUSIONS -These data indicate that IGF-I has the characteristics to be a marker for the insulin resistance syndrome. This suggests that low IGF-I levels may be a useful marker for identifying subjects at risk for cardiovascular disease. Diabetes Care 28:132-137, 2005

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NGT-1h-high subjects exhibit a higher risk of developing diabetes than those with IFG or NGT-1h-low, likely due to decreased insulin sensitivity and beta-cell function.