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Long-Term Oral L-Arginine Administration Improves Peripheral and Hepatic Insulin Sensitivity in Type 2 Diabetic Patients

¹ Metabolic Diseases Unit
² Medicine I Division
³ Mass-Spectrometry Unit Cattedra di Clinica Medica Generale e Terapia Medica, Università Vita-Salute, IRCCS H. San Raffaele
⁴ University of Milano-Bicocca, Faculty of Medicine, Milan, Italy
⁵ Department of Diabetes and Metabolism, School of Clinical Medical Sciences, University of Newcastle, Newcastle upon Tyne, U.K.

OBJECTIVE—The aim of this study was to evaluate whether long-term administration of L-arginine acting through a normalization of NO/cyclic-guanosine-3',5'-cyclic monophosphate (cGMP) pathway was able to ameliorate peripheral and hepatic insulin sensitivity in 12 lean type 2 diabetic patients.

RESEARCH DESIGN AND METHODS—A double-blind study was performed for 3 months. In the first month, patients were treated with their usual diet. Then they were randomly allocated into two groups. In group 1, patients were treated with diet plus placebo (orally three times per day) for 2 months. In group 2 patients were treated for 1 month with diet plus placebo (orally, three times per day) and then for 1 month with diet plus L-arginine (3 g three times per day). At the end of the first and the second month of therapy, patients underwent a euglycemic-hyperinsulinemic clamp combined with [6,6-²H₂]glucose infusion. A total of 10 normal subjects underwent the same test as control subjects.

RESULTS—In group 1, no changes in basal cGMP levels, systolic blood pressure, forearm blood flow, glucose disposal, and endogenous glucose production were observed throughout. In group 2, L-arginine normalized basal cGMP levels and significantly increased forearm blood flow by 36% and glucose disposal during the clamp by 34%, whereas it decreased systolic blood pressure and endogenous glucose production by 14 and 29%, respectively. However, compared with normal subjects, L-arginine treatment was not able to completely overcome the defect in glucose disposal.

CONCLUSIONS—L-Arginine treatment significantly improves but does not completely normalize peripheral and hepatic insulin sensitivity in type 2 diabetic patients.

Abbreviations: cGMP, cyclic-guanosine-3',5'-cyclic monophosphate • CV, coefficient of variation • NO, nitric oxide • NOS, NO synthase

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