Nitric oxide vs insulin secretion, action and clearance

Abstract

Abbreviations ADMAAsymmetric dimethylarginine IR Insulin resistance L-NAME N G -nitro-L-arginine methylester TXNIP Thioredoxin-interacting proteinTo 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. Moreover, mice with genetic disruption of endothelial NO synthase, used as a model of chronic NO deficiency, exhibit insulin resistance (IR) in the liver and peripheral tissues [2]. Nevertheless, it can be speculated that depressed insulin secretion and enhanced insulin degradation, when superimposed on concomitant IR, might further impair glucose tolerance and accelerate the development of type 2 diabetes mellitus under conditions associated with reduced NO bioavailability.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. 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].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]. Mittermayer et al [5] observed an independent association of declining glucose tolerance during almost 3 years with higher ADMA but not HOMA-IR 14-16 weeks after delivery, whereas in our hands ADMA and HOMA-IR independently predicted deteriorating glucose tolerance [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 ...

Differential associations of angiographic extent and severity of coronary artery disease with asymmetric dimethylarginine but not insulin resistance in non-diabetic men with stable angina: a cross-sectional study

“…Furthermore, Reaven [86] recently raised concerns with regard to using HOMA-IR as a measure of IR when altered insulin clearance considerably affects changes in fasting insulinaemia, which was shown on acute NO formation blockade [82]. This limitation constrains conclusions based on HOMA-IR in our previous study [43] and also the present one, all the more because interindividual differences in ADMA could influence NO bioavailability [87]. Nonetheless, for feasibility reasons, we were not able to perform the clamps in a series of CAD patients referred to diagnostic coronary angiography.…”

Effects of Nitrate Intake on Myocardial Ischemia-Reperfusion Injury in Diabetic Rats

“…24 However, it remains disputable whether conclusions from a short-term study could be extended to a long-term situation. 25 Therefore, we assessed the effects of chronic low-dose nitrate intake on IR injury in STZ-NA-induced diabetic rats. This is a suitable model for assessment of the effectiveness of new potential antidiabetic agents and has been reported to be close to human type 2 diabetes.…”

Type II Diabetes Patients under Sildenafil Citrate: Case Series Showing Benefits and a Side Effect

“…NO also plays an important role in the systemic regulation of blood glucose levels and insulin metabolism. All of the mentioned regulations can be controlled by phosphodiesterase inhibitors, which extend the action of cGMP [5,6].…”