Alterations in nitric oxide/cyclic-GMP pathway in nondiabetic siblings of patients with type 2 diabetes

In this study, we have compared resistance to insulin-mediated glucose disp osal and plasma concentrations of nitric oxide (NO) and cyclic-GMP in healt hy volunteers with (n = 35) or without (n = 27) at least one sibling and on e parent with type 2 diabetes. The 62 volunteers were further divided into groups of those with normal glucose tolerance or impaired glucose tolerance . Insulin-mediated glucose disposal was quantified by determining the insul in sensitivity index (ISI) in response to a low-dose, constant infusion of insulin (25 mU/kg.h) and glucose (4 mg/kg min) for 150 min. The mean (+/-SE M) ISI [(mL kg(-1) min(-1)/pmol/L) x 10(3)] was significantly greater in th ose without a family history (30.3 +/- 2.3) as compared with nondiabetic vo lunteers with a family history of type 2 diabetes, whether they had normal glucose tolerance (17.0 +/- 7.2) or impaired glucose tolerance (9.5 +/- 1.4 ). In addition, basal NO levels, evaluated by the measurement of its stable end products [i.e. nitrite and nitrate levels (NO2-/NO3-)], were significa ntly higher, and cyclic-GMP levels, its effector messenger, were significan tly lower in those with a family history, irrespective of their degree of g lucose tolerance, when compared with healthy volunteers without a family hi story of type 2 diabetes. Furthermore, when the 62 volunteers were analyzed as one group, there was a negative correlation between ISI and NO2-/NO3- l evels (r = -0.35; P < 0.005) and a positive correlation between ISI and cyc lic-GMP levels (r = 0.30; P < 0.02). These results have shown that alterati ons of the NO/cyclic-GMP pathway seem to be an early event in nondiabetic i ndividuals with a family history of type 2 diabetes and these changes are c orrelated with the degree of insulin resistance.