Pathological activation of the renin-angiotensin system (RAS) is associated with the metabolic syndrome, and the new onset of type 2 diabetes can be delayed by RAS inhibition. In animal models of type 2 diabetes, inhibition of the RAS improves insulin secretion. However, the direct effects of angiotensin II on islet function and underlying mechanisms independent of changes in blood pressure remain unclear. Here we show that exposure of human and mouse islets to angiotensin II induces interleukin (IL)-1-dependent expression of IL-6 and MCP-1, enhances b-cell apoptosis, and impairs mitochondrial function and insulin secretion. In vivo, mice fed a high-fat diet and treated with angiotensin II and the vasodilator hydralazine to prevent hypertension showed defective glucose-stimulated insulin secretion and deteriorated glucose tolerance. Application of an anti-IL-1b antibody reduced the deleterious effects of angiotensin II on islet inflammation, restored insulin secretion, and improved glycemia. We conclude that angiotensin II leads to islet dysfunction via induction of inflammation and independent of vasoconstriction. Our findings reveal a novel role for the RAS and an additional rationale for the treatment of type 2 diabetic patients with an IL-1b antagonist.Obesity and type 2 diabetes are related to hypertension and to increased activation of the renin-angiotensin system (RAS) (1-3). Multiple trials have shown that RAS blockade reduces the incidence of new-onset type 2 diabetes in high-risk populations (4). On the basis of several meta-analyses, this reduction ranges between 22% and 30% (5,6). In addition, in different animals models of type 2 diabetes, treatment with either angiotensinreceptor blockers or ACE inhibitors improves glucose tolerance and b-cell function (2,7-10). All of this suggests a role for angiotensin II in the development of type 2 diabetes.The RAS is classically known as a systemic hormonal system regulating blood pressure, fluid balance, and electrolyte absorption (11). Finding a local RAS in various tissues and organs such as brain, kidney (12), heart (13), liver, and adipose tissue (14) has expanded its role to diverse physiological functions in addition to its effects on circulation. All key components of the RAS also have been localized to the endocrine pancreas, including the precursor angiotensinogen and the angiotensin II type 1 receptor (15,16). Furthermore, obesity and hyperglycemia increases the expression of the local RAS in pancreatic islets (17), adipose tissue (18), and skeletal muscle.

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Therapeutic use of Endothelial Progenitor Cells (EPCs) is known to repair and protect against cardiovascular damage. Since androgens are associated with cardiovascular protection in men, we investigated the mechanism(s) by which androgens (dihydrotestosterone; DHT) can modulate androgen receptor (AR) dependent EPC activity. Tube/capillary formation and androgen receptor expression by cultured EPCs was assessed using 2D-cultures/co-cultures, western blotting and RT-PCR. Treatment with DHT (100nM) induced capillary/tube formation by EPCs (≈179±3%; p<.05 vs control) and these effects were attenuated by AR antagonist flutamide and AR siRNA. DHT (10-100nM) up-regulated AR protein expression and this effect was abrogated by AR antagonist flutamide (1μM), AR silencing siRNA and cycloheximide (protein synthesis inhibitor). Compared to AR protein, DHT did not induce AR mRNA expression and DHT-induced AR expression was not blocked by the transcription inhibitor actinomycin-D (10ng/ml). Treatment with proteasome inhibitor MG132 (100nM) mimicked the effects of DHT on AR protein expression, moreover, when combined with DHT, the stimulatory effects on AR expression were additive. To ascertain the role of protein stabilization in mediating AR up-regulation in EPCs, the effects of MG132 and DHT on Raf-1, which is known to undergo proteasomal degradation, were assessed. Treatment with MG132, but not DHT, increased Raf-1 expression in EPCs. Moreover, the stimulatory effects of DHT on capillary formation were enhanced in presence of MG132. These findings suggest that DHT up-regulates AR expression and function in EPCs via protein stabilization, however, participation of other pathways cannot be ruled out. In EPCs, DHT induces capillary formation via AR and regulates AR expression in an autologous fashion. Since, androgens induce endothelial growth, and most patients receiving EPCs for cardiovascular repair are older, the low endogenous levels of androgens would decrease the potential of stem cell mediated tissue repair. More importantly, pretreatment of patients or priming of EPCs with androgens/DHT, as well as co-administration of DHT with EPCs may potentiate ARs and EPC mediate cardiovascular tissue repair in men.