Endocrine Abstracts

Background/objectives: We have previously shown the existence of a pancreatic islet renin-angiotensin system and its key component AT₁ receptor (AT1R) was upregulated in an obese Type 2 diabetes mellitus (T2DM) mouse model. Blockade of the AT1R was found to improve beta-cell function and glucose-stimulated insulin secretion in this T2DM model. However, the mechanism(s) remain equivocal. In this context, oxidative stress was suggested to be a critical regulator for the beta-cell dysfunction and apoptosis. On the other hand, uncoupling protein-2 (UCP-2) was demonstrated to be activated by oxidative stress and down regulating insulin secretion. The present study is, therefore, aimed at investigating the role of AT1R mediated oxidative stress and UCP-2 induced beta-cell dysfunction using an obesity-induced T2DM model.

Methods: mg/kg/day losartan was given to 4-week-old obese db/db mice for 8 weeks so as to block the AT1R activation chronically. Water-fed db/db and m+/db mice were employed as the positive and negative controls, respectively. After 8-week treatment, the islets were isolated from the mice for analyses. Levels of oxidative stress were determined by the mRNA and protein expression of NADPH oxidase subunits (p22 phox and gp91 phox) and nitrotyrosine. Apoptosis of beta cells was examined by the staining of the fragmentated DNA using the TUNEL method. The mRNA and protein expression of UCP-2 were assessed by real-time PCR and Western blot, respectively. The secretory function of the beta cells was monitored by measuring islet insulin release.

Results: Results showed that blockade of AT1R inhibited oxidative stress production via the down regulation of NADPH oxidase, which in turn suppressed UCP-2 expression. In addition, the levels of apoptosis were significantly lowered. On the other hand, beta-cell function was consequently improved as evidenced by an increase of insulin secretion.

Conclusions: The data suggest that AT1R blockade improves beta-cell function and inhibits apoptosis in an obesity-induced mouse model of T2DM, probably via a reduction of oxidative stress and down regulation of UCP-2 expression.