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Alterations in Nitric Oxide/Cyclic-GMP Pathway in Nondiabetic Siblings of Patients with Type 2 Diabetes¹

IRCSS H. San Raffaele (P.M.P., L.D.M., G.V., C.V.P., S.C., M.C., E.P.S., A.E.P.), 20132 Milan, Italy; Cattedra di Clinica Medica Generale e Terapia Medica, Università Vita e Salute, (G.P.), 20132 Milan, Italy; University of Parma (I.Z.), 43100 Parma, Italy; University of Pavia (B.S.), 27100 Pavia, Italy; and Stanford University School of Medicine (G.R.), Stanford, California

Address correspondence and requests for reprints to: PierMarco Piatti, M.D., Metabolic Diseases Unit, Division of Medicine, IRCCS H. San Raffaele, Via Olgettina 60, 20132 Milano, Italy.

In this study, we have compared resistance to insulin-mediated glucose disposal and plasma concentrations of nitric oxide (NO) and cyclic-GMP in healthy volunteers with (n = 35) or without (n = 27) at least one sibling and one 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 insulin 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 (±SEM) ISI [(mL kg^-1 min^-1/pmol/L) x 10³] was significantly greater in those without a family history (30.3 ± 2.3) as compared with nondiabetic volunteers 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 (NO_2^-/NO_3^-)], were significantly higher, and cyclic-GMP levels, its effector messenger, were significantly lower in those with a family history, irrespective of their degree of glucose tolerance, when compared with healthy volunteers without a family history of type 2 diabetes. Furthermore, when the 62 volunteers were analyzed as one group, there was a negative correlation between ISI and NO_2^-/NO_3^- levels (r = -0.35; P < 0.005) and a positive correlation between ISI and cyclic-GMP levels (r = 0.30; P < 0.02). These results have shown that alterations of the NO/cyclic-GMP pathway seem to be an early event in nondiabetic individuals with a family history of type 2 diabetes and these changes are correlated with the degree of insulin resistance.

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