Renin-angiotensin system blockers protect pancreatic islets against diet-induced obesity and insulin resistance in mice

PLoS One. 2013 Jul 22;8(7):e67192. doi: 10.1371/journal.pone.0067192. Print 2013.

Abstract

Background: The associations between obesity, hypertension and diabetes are well established, and the renin-angiotensin system (RAS) may provide a link among them. The effect of RAS inhibition on type 2 diabetes is still unclear; however, RAS seems to play an important role in the regulation of the pancreas and glucose intolerance of mice fed high-fat (HF) diet.

Methods: C57BL/6 mice fed a HF diet (8 weeks) were treated with aliskiren (50 mg/kg/day), enalapril (30 mg/kg/day) or losartan (10 mg/kg/day) for 6 weeks, and the protective effects were extensively compared among groups by morphometry, stereological tools, immunostaining, Western blotting and hormonal analysis.

Results: All RAS inhibitors significantly attenuated the increased blood pressure in mice fed a HF diet. Treatment with enalapril, but not aliskiren or losartan, significantly attenuated body mass (BM) gain, glucose intolerance and insulin resistance, improved the alpha and beta cell mass and prevented the reduction of plasma adiponectin. Furthermore, enalapril treatment improved the protein expression of the pancreatic islet Pdx1, GLUT2, ACE2 and Mas receptors. Losartan treatment showed the greatest AT2R expression.

Conclusion: Our findings indicate that ACE inhibition with enalapril attenuated several of the deleterious effects of the HF diet. In summary, enalapril appears to be responsible for the normalization of islet morphology and function, of alpha and beta cell mass and of Pdx1 and GLUT2 expression. These protective effects of enalapril were attributed, primarily, to the reduction in body mass gain and food intake and the enhancement of the ACE2/Ang (1-7) /Mas receptor axis and adiponectin levels.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II Type 1 Receptor Blockers / pharmacology
  • Animals
  • Body Size / drug effects
  • Diet, High-Fat / adverse effects*
  • Eating / drug effects
  • Glucose Tolerance Test
  • Insulin Resistance*
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / physiopathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Obesity / etiology*
  • Obesity / metabolism*
  • Obesity / physiopathology
  • Protease Inhibitors / pharmacology
  • Receptor, Angiotensin, Type 1 / metabolism
  • Receptor, Angiotensin, Type 2 / metabolism
  • Renin / antagonists & inhibitors
  • Renin-Angiotensin System / drug effects*

Substances

  • Angiotensin II Type 1 Receptor Blockers
  • Protease Inhibitors
  • Receptor, Angiotensin, Type 1
  • Receptor, Angiotensin, Type 2
  • Renin

Grant support

The present work received financial support by the agencies CNPq (Brazilian Council of Science and Technology, www.cnpq.br) [grant number E26/110.549/2010, C.A.M.L.] and FAPERJ (Rio de Janeiro State Foundation for Scientific Research, www.faperj.br) [grant number 302154/2011-6, C.A.M.L.]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.