Abstract
BackgroundThe 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.MethodsC57BL/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.ResultsAll 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.ConclusionOur 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.
Highlights
Obesity is strongly associated with both type 2 diabetes mellitus (T2DM) and hypertension, a combination that has become a major public health problem because of its epidemic proportions worldwide [1]
After eight weeks of diet, the animals fed HF chow were randomly allocated into four groups, and each group received one of the following treatments over six weeks: a) HF group (n=15), untreated; b) HF-A group (n=15), HF diet treated with aliskiren (50 mg/kg/day), Rasilez, Novartis; c) HF-E group (n=15), HF diet treated with enalapril maleate (30 mg/kg/day), Renitec, Merck; d) HF-L group (n=15), HF diet treated with losartan (10 mg/kg/day), Cozaar, Merck
ACE2 is expressed in the liver, adipose tissue, pancreas and skeletal muscle, which constitute the primary organs implicated in insulin resistance [25,26] and exhibits its tissue-protective effects by decreasing Ang II and by producing Ang (1-7)
Summary
Obesity is strongly associated with both type 2 diabetes mellitus (T2DM) and hypertension, a combination that has become a major public health problem because of its epidemic proportions worldwide [1]. 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. Enalapril treatment improved the protein expression of the pancreatic islet Pdx, GLUT2, ACE2 and Mas receptors. Enalapril appears to be responsible for the normalization of islet morphology and function, of alpha and beta cell mass and of Pdx 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
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