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

Abstract

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-NGnitroarginine methyl ester (L-NAME, at rates of 2.5, 5, 10 and 20 μgmin −1 kg −1 ) infusion. Another five volunteers underwent an OGTT with either saline or L-NAME (20 μgmin −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<0.01), doubled insulin clearance and impaired beta cell glucose sensitivity while depressing endothelial function. Conclusions/interpretation In humans, systemic NO blockade titrated to increase blood pressure and induce endothelial dysfunction does not affect insulin action but significantly impairs glucose tolerance by increasing plasma insulin clearance and depressing insulin secretion, namely first-phase and beta cell glucose sensitivity.

Nitric oxide vs insulin secretion, action and clearance

“…The results by Natali et al [1] also explain the previously reported association between the endogenous NO synthesis inhibitor asymmetric dimethylarginine (ADMA) and the risk of future deterioration of glucose tolerance [5,6]. Following the report of this association by Mittermayer et al [5] in 77 women with previous gestational diabetes, we have identified the same relationship in 80 non-diabetic men with stable angina who were followed for a 4.5 year period [6].…”

“…Moreover, in both reports ADMA and HOMA-IR were unrelated [5,6]. Thus, on the basis of the findings by Natali et al [1], the predictive ability of ADMA in these studies [5,6] might hypothetically be attributable not to concomitant IR but possibly to accompanying relative insulin deficiency, inasmuch as the long-term effects of ADMA are similar to those of shortterm NO inhibition. Nevertheless, this concept is challenged by the recent concerns raised by Reaven [7] with regard to using HOMA-IR as an index of IR when altered insulin clearance is the major determinant of the change in fasting insulinaemia.…”

“…Since the dose of L-NAME shown to decrease insulinaemia also induced endothelial dysfunction [1], these findings support the notion of impaired endothelial function, largely mediated by decreased NO bioavailability, as an independent predictor of new-onset type 2 diabetes [3,4]. Furthermore, the report by Natali et al [1] appears to link these observations to relatively reduced insulin concentrations (i.e.…”

“…Furthermore, the report by Natali et al [1] appears to link these observations to relatively reduced insulin concentrations (i.e. lower than would be expected for the degree of IR), in contrast to other investigators who have suggested that endothelial dysfunction in skeletal muscle-via blunted muscular perfusion, reduced capillary recruitment and decreased insulin delivery into the interstitium-could lead to IR thus predisposing individuals to type 2 diabetes [3,4].…”

“…To the Editor: In their Diabetologia article, Natali and colleagues [1] reported a decrease in glucose tolerance in response to acute inhibition of NO generation by N G -nitro-L-arginine methylester (L-NAME), which resulted from a 40% drop in beta cell glucose sensitivity and doubled insulin clearance, whereas peripheral insulin sensitivity did not change. Admittedly, whether conclusions from an acute experiment can apply to a long-term impairment of NO bioavailability remains disputable.…”