Angiotensin II Type 1 Receptor Blockade Improves β-Cell Function and Glucose Tolerance in a Mouse Model of Type 2 Diabetes

Abstract

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...

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“…Concurrently, we have demonstrated local RAS expression in pancreatic islets, which varies with glycaemic control [1] and is excessively expressed in a mouse model of type 2 diabetes [2]; angiotensin II type 1 receptor (AT 1 receptor) blockade improves islet function and glucose tolerance in hyperglycaemia [2]. Hyperglycaemia may be worsened through AT 1 receptor-induced uncoupling protein 2-driven oxidative stress, reducing islet beta cell mass and insulin secretion [3].…”

Metabolic actions of angiotensin receptor antagonists: PPAR-γ agonist actions or a class effect?

“…By contrast, other reports on isolated rat and human pancreatic islets show that angiotensin II impairs the first phase of glucose-stimulated insulin secretion [18][19][20]. Angiotensin II also impairs insulin biosynthesis and promotes β cell apoptosis [21]. Thus, despite its acute action to stimulate release of insulin, the long-term effects of angiotensin II on the pancreas promote the development of diabetes.…”

Betacellulin Overexpression in Mesenchymal Stem Cells Induces Insulin Secretion In Vitro and Ameliorates Streptozotocin-Induced Hyperglycemia in Rats

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