Year of Publication
Doctor of Philosophy (PhD)
Pharmacology and Nutritional Sciences
Dr. Lisa Cassis
Diet-induced obesity promotes type 2 diabetes (T2D). Drugs that inhibit the renin-angiotensin system (RAS) have been demonstrated in clinical trials to decrease the onset of T2D. Previously, we demonstrated that mice made obese from chronic consumption of a high-fat (HF) diet have marked elevations in systemic concentrations of angiotensin II (AngII). Pancreatic islets have been reported to possess components of the renin-angiotensin system (RAS), including angiotensin type 1a receptors (AT1aR), the primary receptor for AngII, and angiotensin converting-enzyme 2 (ACE2), which negatively regulates the RAS by catabolizing AngII to angiotensin-(1-7) (Ang-(1-7)). These two opposing proteins have been implicated in the regulation of β-cell function. We hypothesized that the RAS contributes to the decline of β-cell function during the development of T2D with obesity. To test this hypothesis we first examined the effects of whole-body deficiency of ACE2 in mice on β-cell function in vivo and in vitro during the development of T2D. Whole-body deficiency of ACE2 resulted in impaired β-cell adaptation to insulin resistance with HF-feeding and a reduction of in vivo glucose-stimulated insulin secretion (GSIS) associated with reduced β- cell mass and proliferation. These results demonstrate that ACE2 plays a role in the adaptive response to hyperinsulinemia with obesity. In islets from HF-fed mice, AngII inhibited GSIS. In mice with pancreatic-specific deletion of AT1aR, AngII-induced inhibition of GSIS in vitro from islets of HF-fed mice was abolished. However, there was no effect of pancreatic AT1aR-deficiency on glucose homeostasis in vivo in HF-fed mice exhibiting pronounced hyperinsulinemia. Notably, pancreatic weight, insulin content and basal and glucose-stimulated insulin secretion from islets were decreased in mice with pancreatic AT1aR deficiency. These results suggest that AT1aR may contribute to pancreatic cell development, and also contribute to AngII-induced reductions in GSIS from islets of HF-fed mice. Overall, these studies suggest a role for the RAS in the regulation of β-cell function in T2D.
Shoemaker, Robin C., "REGULATION OF PANCREATIC β-CELL FUNCTION BY THE RENIN-ANGIOTENSIN SYSTEM IN TYPE 2 DIABETES" (2015). Theses and Dissertations--Pharmacology and Nutritional Sciences. 9.