Effects of low‐dose l‐arginine on insulin‐mediated vasodilatation and insulin sensitivity

The present study was carried out to evaluate the effect of a low‐dose intravenous supplementation of l‐arginine on insulin‐mediated vasodilatation and insulin sensitivity. The study was performed in healthy subjects (n = 7) and patients with obesity (n = 9) and non‐insulin‐dependent diabetes mellitus (NIDDM) (n = 9). Insulin‐mediated vasodilatation was measured by venous occlusion plethysmography during the insulin suppression test, evaluating insulin sensitivity. Experiments were performed twice in each subject in the presence or absence of a concomitant infusion of l‐arginine (0.52 mg kg−1 min−1). l‐Arginine restored the impaired insulin‐mediated vasodilatation observed in obesity (22.4 ± 4.1%, P < 0.01 vs. without l‐arginine) and NIDDM (20.3 ± 3.2%, P < 0.01 vs. without l‐arginine). In healthy subjects, no effect on insulin mediated‐vasodilatation was observed (24.8 ± 3.1% vs. 21.4 ± 3.1%). Insulin sensitivity was improved significantly (P < 0.001) in all three groups by infusion of l‐arginine. No effect of l‐arginine was observed on insulin, insulin‐like growth factor I (IGF‐I), free fatty acids (FFAs) or C‐peptide levels during the insulin suppression test. Our data indicate that defective insulin‐mediated vasodilatation in obesity and NIDDM can be normalized by intravenous l‐arginine. Furthermore, l‐arginine improves insulin sensitivity in obese patients and NIDDM patients as well as in healthy subjects, indicating a possible mechanism that is different from the restoration of insulin‐mediated vasodilatation.

[1]  R. Bergman,et al.  Insulin transport across capillaries is rate limiting for insulin action in dogs. , 1989, The Journal of clinical investigation.

[2]  Farris K. Timimi,et al.  Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes mellitus. , 1996, The Journal of clinical investigation.

[3]  M. Laakso,et al.  Impaired Insulin-Mediated Skeletal Muscle Blood Flow in Patients With NIDDM , 1992, Diabetes.

[4]  G. Reaven,et al.  Assessment of Insulin Resistance with the Insulin Suppression Test and the Euglycemic Clamp , 1981, Diabetes.

[5]  R. Bergholm,et al.  Dissociation between insulin sensitivity of glucose uptake and endothelial function in normal subjects , 1996, Diabetologia.

[6]  A. Baron,et al.  Insulin-mediated skeletal muscle vasodilation contributes to both insulin sensitivity and responsiveness in lean humans. , 1995, The Journal of clinical investigation.

[7]  A. Struthers,et al.  Arginine, lysine and ornithine as vasodilators in the forearm of man , 1996, European journal of clinical investigation.

[8]  A. Baron,et al.  Hemodynamic actions of insulin. , 1994, The American journal of physiology.

[9]  A. Quyyumi,et al.  Endothelial Dysfunction in Patients With Chest Pain and Normal Coronary Arteries , 1992, Circulation.

[10]  G. Rubanyi.  Reversal of hypercholesterolemia-induced endothelial dysfunction by L-arginine. , 1991, Circulation.

[11]  G. Paolisso,et al.  Plasma GSH/GSSG affects glucose homeostasis in healthy subjects and non-insulin-dependent diabetics. , 1992, The American journal of physiology.

[12]  D. Harrison.  Endothelial dysfunction in the coronary microcirculation: a new clinical entity or an experimental finding? , 1993, The Journal of clinical investigation.

[13]  L. Ignarro,et al.  Depletion of arterial L-arginine causes reversible tolerance to endothelium-dependent relaxation. , 1989, Biochemical and biophysical research communications.

[14]  K. Lundholm,et al.  Insulin time‐dependent effects on the leg exchange of glucose and amino acids in man , 1991, European journal of clinical investigation.

[15]  E. Froesch,et al.  Synthesis and secretion of insulin-like growth factor and its binding protein by the perfused rat liver: dependence on growth hormone status. , 1983, Endocrinology.

[16]  S. Eddahibi,et al.  L-arginine restores endothelium-dependent relaxation in pulmonary circulation of chronically hypoxic rats. , 1992, The American journal of physiology.

[17]  M. Jensen,et al.  Contribution of Blood Flow to Leg Glucose Uptake During a Mixed Meal , 1995, Diabetes.

[18]  A. Mengel,et al.  Comparison of the effects of growth hormone and insulin-like growth factor I on substrate oxidation and on insulin sensitivity in growth hormone-deficient humans. , 1994, The Journal of clinical investigation.

[19]  D. Tsikas,et al.  L-arginine induces nitric oxide-dependent vasodilation in patients with critical limb ischemia. A randomized, controlled study. , 1996, Circulation.

[20]  E. Arvat,et al.  Low dose orally administered arginine is able to enhance both basal and growth hormone-releasing hormone-induced growth hormone secretion in normal short children , 1993, Journal of endocrinological investigation.

[21]  M. Laakso,et al.  Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. A novel mechanism for insulin resistance. , 1990, The Journal of clinical investigation.

[22]  P. Vollenweider,et al.  Nitric oxide release accounts for insulin's vascular effects in humans. , 1994, The Journal of clinical investigation.

[23]  L. Ignarro,et al.  L-arginine-dependent vascular smooth muscle relaxation and cGMP formation. , 1990, The American journal of physiology.

[24]  G. Paolisso,et al.  Plasma vitamin C affects glucose homeostasis in healthy subjects and in non-insulin-dependent diabetics. , 1994, The American journal of physiology.

[25]  J. K. Lloyd,et al.  Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis , 1992, The Lancet.

[26]  D. Eugene Hokanson,et al.  An Electrically Calibrated Plethysmograph for Direct Measurement of Limb Blood Flow , 1975, IEEE Transactions on Biomedical Engineering.

[27]  W. Sheu,et al.  Additive effects of obesity, hypertension, and type 2 diabetes on insulin resistance. , 1994, Hypertension.

[28]  W. Malaisse,et al.  Stimulus-secretion coupling of arginine-induced insulin release. Uptake of metabolized and nonmetabolized cationic amino acids by pancreatic islets. , 1989, Endocrinology.

[29]  P. Vallance,et al.  Dilator actions of arginine in human peripheral vasculature. , 1991, Clinical science.

[30]  A. Hermetter,et al.  Vascular effects of L-arginine: anything beyond a substrate for the NO-synthase? , 1997, Biochemical and biophysical research communications.

[31]  H. Drexler,et al.  Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolaemic patients by L-arginine , 1991, The Lancet.

[32]  J. Christiansen,et al.  Insulin-like growth factor I stimulates lipid oxidation, reduces protein oxidation, and enhances insulin sensitivity in humans. , 1993, The Journal of clinical investigation.

[33]  E A Anderson,et al.  Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans. , 1991, The Journal of clinical investigation.

[34]  M. Creager,et al.  Impaired Endothelium‐Dependent Vasodilation in Patients With Insulin‐Dependent Diabetes Mellitus , 1993, Circulation.