We identified an angiotensin-generating system in pancreatic islets and found that exogenously administered angiotensin II, after binding to its receptors (angiotensin II type 1 receptor [AT1R]), inhibits insulin release in a manner associated with decreased islet blood flow and (pro)insulin biosynthesis. The present study tested the hypothesis that there is a change in AT1R expression in the pancreatic islets of the obesity-induced type 2 diabetes model, the db/db mouse, which enables endogenous levels of angiotensin II to impair islet function. Islets from 10-week-old db/db and control mice were isolated and investigated. In addition, the AT1R antagonist losartan was administered orally to 4-week-old db/db mice for an 8-week period. We found that AT1R mRNA was upregulated markedly in db/db islets and double immunolabeling confirmed that the AT1R was localized to ␤-cells. Losartan selectively improved glucose-induced insulin release and (pro)insulin biosynthesis in db/db islets. Oral losartan treatment delayed the onset of diabetes, and reduced hyperglycemia and glucose intolerance in db/db mice, but did not affect the insulin sensitivity of peripheral tissues. The present findings indicate that AT1R antagonism improves ␤-cell function and glucose tolerance in young type 2 diabetic mice. Whether islet AT1R activation plays a role in the pathogenesis of human type 2 diabetes remains to be determined. Diabetes 55:367-374, 2006 T he prevalence of obesity is rising in North America, where 61% of adults are now overweight or obese, a trend mirrored worldwide (1). The accompanying epidemic of type 2 diabetes and its cardiovascular complications are evident in the Western world (2,3) and also in Asia (4). Therapies aimed at increasing insulin sensitivity offer only partial solutions, since ␤-cell dysfunction and ␤-cell loss may also contribute to disease progression. In this regard, the mechanisms that underlie islet failure have yet to be elucidated. A recently identified local renin-angiotensin system (RAS) may play an important role in pancreatic physiology and pathophysiology (5,6). While the acinar RAS regulates exocrine function (7) and pancreatitis (8), a local islet RAS also exists. The RAS constituents angiotensinogen, ACE, and angiotensin II types 1 and 2 receptors (AT1R and AT2R) have been demonstrated to be present in pancreatic islets, with the AT1R localized specifically to the ␤-cells (9). This local pancreatic islet RAS has the potential to regulate insulin release, in that AT1R activation may inhibit insulin release in response to glucose loading. This action is mediated, at least in part, through alterations in islet (pro)insulin synthesis and islet blood flow engendered by angiotensin II biosynthesis (9,10).The clinically observed benefits of RAS blockade in persons at risk for developing type 2 diabetes, namely a reduced incidence of developing diabetes (11,12), have been hard to explain. A better understanding of the protective effects of RAS inhibition on type 2 diabetes is of profound importance...

It requires little persuasion to convince nephrologists that diabetes type 2 and diabetic nephropathy have become major challenges to nephrology. Although the twin culprits of genetic predisposition (1) and modern lifestyle (2) are undoubtedly the major cause of the rising tide of type 2 diabetes, its incidence can be modified by the selection of the type of antihypertensive agents. The idea that blockade of the renin-angiotensin system (RAS) attenuates the risk of type 2 diabetes in hypertensive agents was initially raised by post hoc analysis of small studies (3). Some large studies solidly documented that both angiotensin-converting enzyme (ACE) inhibitors (4,5) and angiotensin receptor blockers (6 -8) lowered the risk of de novo type 2 diabetes compared with ␤-blockers or diuretics, respectively. The lingering doubt remained, however, that the difference in incidence of diabetes might reflect an increase of risk conferred by ␤-blockers and diuretics rather than a benefit conferred by RAS blockade. These concerns can today be laid to rest after the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) Trial (9) unequivocally showed that the rate of de novo diabetes was significantly lower in hypertensive patients treated with valsartan compared with amlodipin, i.e., an agent that is definitely metabolically neutral. The implications for efforts to reduce the frequency of diabetes are obvious. The issue remains, however, to identify the mechanisms accounting for the antidiabetogenic effect of RAS blockade.Against this background, the demonstration of a fully operative renin-angiotensin-system (RAS) in isolated pancreatic islets is of considerable interest. Theoretically, the RAS could augment the risk of diabetes by either increasing peripheral insulin resistance or interfering with insulin secretion (or a combination of both). Indeed, there are reports that angiotensin II (AngII) reduces insulin sensitivity by reducing blood flow in insulin-sensitive tissues and by nonhemodynamic mechanisms, and that, conversely, angiotensin receptor blockers enhance insulin sensitivity (9). Interestingly, however, we had seen paradoxically increased insulin sensitivity during AngII infusion in healthy volunteers (10). On the other hand, in the past a number of studies had documented that AngII reduced insulin secretion by pancreatic islets (11), but the initial observations failed to exclude artifacts resulting from AngII induced vasoconstriction (12). Good arguments were later provided that in the pancreatic islets AngII acted not (only) as a blood-borne agent, but also as a paracrine or autocrine agent generated by a local RAS. Furthermore, early studies showed by immunohistochemistry that some, but not all, components of the RAS were present in the human pancreas. Specifically, renin mRNA could be detected only in the blood vessels surrounding the islets (13).To fully understand this system, however, it was necessary (1) to characterize all of its components (angiotensinogen, ACE, angiotensin type 1 and type 2 [AT1 ...