Decreased Pancreatic Insulin Secretion is associated with increased AT1 Activation during Glucose Supplementation in a Model of Metabolic Syndrome

Abstract

Blockade of the renin‐angiotensin‐system improves glucose intolerance, insulin resistance and beta cell function. The contributions of angiotensin receptor activation and glucose supplementation to impaired insulin secretion in the pathogenesis of metabolic syndrome are, however, not well defined. After 6 weeks of glucose supplementation and ARB treatment, an oral glucose tolerance test (oGTT) was performed to assess insulin resistance in 5 groups of rats: 1) untreated, lean LETO, 2) untreated, obese OLETF, 3) OLETF + ARB (olmesartan; 10 mg/kg/d; OLETF ARB), 4) OLETF + 5% glucose water (OLETF HG), and 5) OLETF + HG + ARB (OLETF HG/ARB). ARB treatment reduced the oGTT response 19% and increased pancreatic insulin secretion 64% and 113% in OLETF ARB and OLETF HG/ARB, respectively. ARB treatment in OLETF ARB and OLETF HG/ARB did not have an effect on insulin signaling proteins in skeletal muscle; however, it reduced pancreatic AT1 protein expression 20% and 27%, increased pancreatic GLP‐1r protein expression 41% and 88%, respectively, and increased fasting plasma GLP‐1 approximately 2.5‐fold in OLETF ARB. The results suggest that improvement of glucose intolerance is independent of an improvement in muscle insulin signaling, but rather by improved glucose‐stimulated insulin secretion associated with decreased pancreatic AT1 activation, and increased GLP‐1 signaling. (NIH NCMHD 9T37MD001480)