Activation of Angiotensin Type 2 Receptors Partially Ameliorates Streptozotocin-Induced Diabetes in Male Rats by Islet Protection

We have previously demonstrated that rat islets express a high density of angiotensin type 2 receptors and that activation of this receptor evokes insulinotropic effect. In this study, we evaluated the protective effects of Compound 21 (C21), a nonpeptide angiotensin type 2 receptor agonist, on islets in streptozotocin (STZ)-induced diabetes. Rats were assigned to five groups: normal, STZ, and STZ plus C21 (0.24, 0.48, and 0.96 mg/kg.d). C21 was continually infused by a sc implanted osmotic minipump for 14 days, and STZ was bolus injected on day 7. Body weight, water intake, urine excretion, and blood glucose were monitored daily. On the last day, the rats received an oral glucose tolerance test, and the pancreata were saved to examine islet morphology and biochemical parameters of oxidative stress and apoptosis. We found that, compared with control STZ rats, C21-treated STZ rats displayed less water intake and urine excretion, lower blood glucose, higher serum insulin concentration, and improved glucose tolerance. These rats had more islets, larger islet mass, and up-regulated insulin protein and proinsulin 2 mRNA expressions in the pancreas. Their islets displayed lower superoxide, decreased gp91 expression, and increased superoxide dismutase 1 expression as well as less apoptosis and down-regulated caspase-3 expression. In the epididymal adipose tissue of these rats, we found a decreased adipocyte size and up-regulated adipocyte protein 2 expression. The protective effects of C21 on beta-cells against the toxic effects of STZ were also confirmed in cultured INS-1E cells. These data suggest that C21 ameliorates STZ-induced diabetes by protecting pancreatic islets via antioxidative and antiapoptotic effects.