OBJECTIVE -Reactive oxygen and nitric oxide (NO) have recently been considered to be involved in the cardiovascular complications of patients with type 2 diabetes, as NO is thought to lose its beneficial physiological effects in the presence of oxygen radicals. For this reason, we tested the effects of L-arginine (ARG) and N-acetylcysteine (NAC) administration in increasing NO bioavailability by reducing free radical formation. RESEARCH DESIGN AND METHODS-A double-blind study was performed on 24 male patients with type 2 diabetes and hypertension divided into two groups of 12 patients that randomly received either an oral supplementation of placebo or NAC ϩ ARG for 6 months.RESULTS -The NAC ϩ ARG treatment caused a reduction of both systolic (P Ͻ 0.05) and diastolic (P Ͻ 0.05) mean arterial blood pressure, total cholesterol (P Ͻ 0.01), LDL cholesterol (P Ͻ 0.005), oxidized LDL (P Ͻ 0.05), high-sensitive C-reactive protein (P Ͻ 0.05), intracellular adhesion molecule (P Ͻ 0.05), vascular cell adhesion molecule (P Ͻ 0.01), nitrotyrosine (P Ͻ 0.01), fibrinogen (P Ͻ 0.01), and plasminogen activator inhibitor-1 (P Ͻ 0.05), and an improvement of the intima-media thickness during endothelial postischemic vasodilation (P Ͻ 0.02). HDL cholesterol increased (P Ͻ 0.05). No changes in other parameters studied were observed.CONCLUSIONS -NAC ϩ ARG administration seems to be a potential well-tolerated antiatherogenic therapy because it improves endothelial function in hypertensive patients with type 2 diabetes by improving NO bioavailability via reduction of oxidative stress and increase of NO production. Our study's results give prominence to its potential use in primary and secondary cardiovascular prevention in these patients. Diabetes Care 31:940-944, 2008

Several conditions have been described to cause osteoporosis, including diabetes mellitus. While the relationship between type 1 diabetes and osteopenia is well documented in the literature, data on the presence of this complication in type 2 diabetes have not been well established. We studied a population composed of 66 post-menopausal women with type 2 diabetes and a control population. We examined bone mineral density with the dual-energy X-ray absorptiometry (DXA) technique at the lumbar and femoral levels and, in a subgroup of patients, we also measured the levels of markers of bone remodelling. We found significantly higher levels of bone mineral density at the femoral (but not lumbar) level in the diabetic subjects compared with the control population in all the examined subregions, except Ward's triangle. Moreover, we found higher levels of some markers of bone resorption (urinary calcium and hydroxyproline, telopeptide) in the patients with diabetes, while urinary crosslinks were higher in the controls. On the basis of these results, we suggest that osteoporosis cannot be considered a complication of type 2 diabetes and that, from a metabolic point of view, bone resorption is greater in diabetic patients than in normal subjects, as suggested by the high levels of most of the markers of osteoclastic activity.

Ghrelin secretion in humans is inhibited by OGTT-induced hyperglycaemia and ITT but not by glucagon and arginine, two substances able to increase insulin and glucose levels. These findings question the assumption that glucose and insulin directly regulate ghrelin secretion. On the other hand, ghrelin secretion is not associated with the GH response to ITT or arginine, indicating that the somatotroph response to these stimuli is unlikely to be mediated by ghrelin.

Ghrelin, a 28-amino acid peptide mainly produced by the stomach, is a natural ligand of the type 1a growth hormone secretagogue receptor (GHS-R1a) that also binds synthetic peptidyl and nonpeptidyl GHSs. GHS-R1a and various GHS-R1a-related receptor subtypes are widely distributed in central and peripheral tissues, particularly in the cardiovascular system. In agreement with this distribution of GHS-R, ghrelin and synthetic GHSs exert a wide spectrum of actions, including cardiac and vascular activities. Ghrelin, as well as peptidyl and nonpeptidyl GHSs, is able to increase cardiac performances both in animals and in humans and to exert protective effects on ischemia/reperfusion injury of isolated rat heart. Moreover, both ghrelin and synthetic GHSs have been shown as able to act as survival factors, protecting cardiomyocytes and endothelial cells from doxorubicin-induced apoptosis. Despite the fact that the neuroendocrine actions of ghrelin are dependent on its acylation in serine 3, these cardiovascular effects are exerted by unacylated as well as by acylated ghrelin. This evidence indicates that these actions are not likely to be mediated by a type 1a GHS-R, which, by definition, binds acylated ghrelin only. However, synthetic peptidyl GHSs, but not nonpeptidyl, and even ghrelin itself are able to reduce atherosclerotic lesion development in apolipoprotein-E-deficient mice. This action seems to be mediated by a specific receptor for synthetic peptidyl GHSs only, identified as CD36, a multifunctional B-type scavenger receptor involved in atherogenesis and mainly expressed in cardiomyocytes and microvascular endothelial cells. Thus, there are similarities, but also differences, between ghrelin and synthetic GHSs, in terms of cardiac actions that are likely to be related to the existence of multiple GHS-R subtypes that mediate the cardiovascular actions of the above substances. These actions indicate their potential pharmacotherapeutic implications in cardiovascular diseases.

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