UC Merced

Obesity is a risk factor for the development of pancreatic dysfunction, insulin resistance. Obesity-associated factors such as adipocyte dysfunction, inflammation, leptin resistance, and inappropriately activation of the renin-angiotensin system (RAS) contribute to the development of these disorders. RAS inhibition improves glucose homeostasis by improving pancreatic dysfunction, insulin resistance. The objectives of this project were to evaluate the mechanisms by which angiotensin receptor type 1(AT1) improves pancreatic dysfunction and insulin resistance. In the second chapter, we demonstrated that AT1 blockade before the development of hypertension normalized glucose-stimulated insulin secretion by increasing the circulating levels of glucagon-like peptide-1 (GLP-1) and by increasing the protein expression of pancreatic GLP-1 receptor. In the third chapter, we demonstrated that chronic AT1 blockade started after the development of hypertension decreased the abundance of large adipocytes, improved the ability to suppress non-esterified free fatty acids levels after an acute glucose challenge, decreased fasting plasma glucose, and protected against the worsening of glucose intolerance. The fourth chapter, we showed that that chronic AT1 blockade decreased hyperglycemia by enhancing adipose-specific insulin signaling and by decreasing the expression of genes involved in hepatic gluconeogenesis. Additionally, this study demonstrated that chronic AT1 inhibition increased the expression of CD36 protein in retroperitoneal fat and blunted the protein expression of fatty acid synthase in response to an acute glucose challenge, suggesting that AT1 blockade reduces the obesity-associated hepatic triglyceride accumulation by decreasing hepatic lipogenesis and decreasing the sequestration of free fatty acids from circulation. Our findings expand our knowledge of how inappropriately activated RAS contributes to the development of pancreatic dysfunction and insulin resistance. By understanding the mechanisms by which AT1 blockade improves these disorders, we will be able to identify new molecular targets to be used to develop better therapeutic approaches aimed at decreasing the prevalence of type 2 diabetes.