Pancreatic beta cells compensate to changing insulin demands by the regulation of insulin secretion and production. Diabetes develops when inadequate compensation occurs. Nutrients are key mediators of this compensation. While nutrients such as glucose, fatty acids, and amino acids have well described role in pancreatic beta cell compensation, the role of others nutrients such as short chain fatty acids (SCFAs) are not clear. Interestingly, SCFAs are derived via fermentation from the gut flora, and recently an association between the gut flora and obesity has been revealed. Because of this, we examined if SCFAs can regulate pancreatic beta cell function. Exploring this possibility, we have observed that SCFAs at physiologic concentrations seen in circulation can regulate insulin secretion in both mouse and human islets. How this regulation occurs is not known. Of relevance here is that specific receptors from the G-protein coupled receptor (GPCR) family that are activated by SCFAs, free fatty acid receptor 2 and -3 (FFAR2 and FFAR3), have recently been identified and we have observed that both FFAR2 and FFAR3 are expressed in mouse and human pancreatic beta cells. Along with these data, we have also observed that insulin resistant states alter the expression of these receptors in mouse islets. Overall, these data suggest a role of SCFAs and their receptors in pancreatic beta cell function. Given these compelling findings, the goal of this proposal is to define the role of SCFAs signaling through their receptors, FFAR2 and FFAR3, in the regulation of pancreatic beta cell function, in particular insulin secretion and production. Using a variety of mouse models obtained and/or created by the PI, these studies will explore the above goal through in vitro (Aim 1) and in vivo (Aim 2) models. Additionally, translational studies with human islets will also explore these pathways (Aim 3). Data from these studies will advance our understanding of this novel pathway in pancreatic beta cells, and reveal a possible link between the gut flora and obesity. And finally, considering that these receptors are GPCRs, a family of receptors that are major drug targets, these studies may reveal exciting new therapeutic targets for diabetes.
Obesity-associated diabetes is a major public health epidemic that is also highly prevalent in our population of Veterans. Understanding the factors that lead to pancreatic beta cell failure, the hallmark of diabetes, is paramount. A novel class of nutrients, short chain fatty acids and their receptors, FFAR2 and FFAR3, which are expressed in the pancreatic beta cells, may be involved in the adaptive response of beta cells to insulin resistance. The goal of this research is to understand the role of short chain fatty acids and their cognate receptors in pancreatic beta function and insulin resistant states.