Systemic inhibition of nitric oxide synthesis in non-diabetic individuals produces a significant deterioration in glucose tolerance by increasing insulin clearance and inhibiting insulin secretion

• Published in: Diabetologia 2013-05, Vol.56 (5), p.1183-1191
• Main Authors: Natali, A., Ribeiro, R., Baldi, S., Tulipani, A., Rossi, M., Venturi, E., Mari, A., Macedo, M. P., Ferrannini, E.
• Format: Article
• Language: English
• Subjects: Adult; Biological and medical sciences; Blood pressure; Diabetes; Diabetes. Impaired glucose tolerance; Dose-Response Relationship, Drug; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Endothelium, Vascular - physiopathology; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - adverse effects; Enzymes; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Glucose; Glucose Clamp Technique; Glucose Intolerance - chemically induced; Glucose Intolerance - etiology; Glucose Intolerance - metabolism; Glucose Intolerance - physiopathology; Glucose Tolerance Test; Heart rate; Homeostasis; Human Physiology; Humans; Hyperglycemia - etiology; Hyperglycemia - physiopathology; Hypertension - etiology; Infusions, Intravenous; Insulin - blood; Insulin - metabolism; Insulin Antagonists - administration & dosage; Insulin Antagonists - adverse effects; Insulin resistance; Insulin Secretion; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Internal Medicine; Liver; Male; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolism; Models, Biological; Musculoskeletal system; Nervous system; NG-Nitroarginine Methyl Ester - administration & dosage; NG-Nitroarginine Methyl Ester - adverse effects; Nitric oxide; Nitric Oxide - antagonists & inhibitors; Nitric Oxide - metabolism; Nitric Oxide Synthase - antagonists & inhibitors; Nitric Oxide Synthase - metabolism; Physiology; Single-Blind Method; Young Adult
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-013-2836-x

Aims/hypothesis Endogenous NO inhibits insulin release in isolated beta cells and insulin-degrading enzyme activity in hepatocytes, while NO release from endothelial cells has been suggested to enhance insulin action. We assessed the overall effect of systemic inhibition of endogenous NO synthesis on glucose homeostasis in humans. Methods Twenty-four non-diabetic volunteers underwent two hyperglycaemic (+7 mmol/l) clamps with either saline or L-NG-nitroarginine methyl ester ( l -NAME, at rates of 2.5, 5, 10 and 20 μg min −1  kg −1 ) infusion. Another five volunteers underwent an OGTT with either saline or l -NAME (20 μg min −1  kg −1 ) infusion. Blood pressure and heart rate were measured to monitor NO blockade; during the OGTT, endothelial function was assessed by peripheral arterial tonometry and insulin secretion by C-peptide deconvolution and insulin secretion modelling. Results Compared with saline, l -NAME at the highest dose raised mean blood pressure (+20 ± 2 mmHg), depressed heart rate (−12 ± 2 bpm) and increased insulin clearance (+50%). First-phase insulin secretion was impaired, but insulin sensitivity ( M /I index) was unchanged. During the OGTT, l -NAME raised 2 h plasma glucose by 1.8 mmol/l ( p