The prevalence of diabetes has reached epidemic proportions in the United States, gravely afflicting patients and burdening societies with productivity loss and health care costs. Diabetes is characterized by a reduction in beta cell mass in the pancreas, or a failure of beta cells to secrete enough insulin to fully compensate for insulin resistance. Augmenting or preserving functional beta cell mass is an attractive objective for preventing or treating diabetes; however, we have insufficient intervention targets. The long-term goal of our research is to better understand how intestinal lipid processing controls systemic metabolism and explore intervention targets to combat metabolic diseases. We have reported that acyl CoA:monoacylglycerol acyltransferase 2 (MGAT2) mediates intestinal fat absorption and regulates systemic energy balance. Although mice lacking a functional MGAT2 gene (Mogat2?/?) or lacking MGAT2 specifically in the intestine absorb normal amounts of dietary fat, they exhibit delayed fat absorption, increased energy expenditure, and resistance to obesity and related disorders. Intriguingly, we found that loss of MGAT2 protects mice against chemically- and genetically-induced diabetes by preserving functional beta cell mass. Associated with the protection, Mogat2?/? mice have increased plasma bile acids, known to have potent metabolic effects as ligands for membrane and nuclear receptors that regulate metabolism. Further, increasing plasma bile acids ? by feeding mice ursodeoxycholic acid, treating mice with broad-spectrum antibiotics, or raising mice germ-free? is sufficient to protect functional beta cell mass against the beta-cell toxin, streptozotocin. Intriguingly, we also found reduced bile salt hydrolase (BSH) activity in cecum, where most gut microbiota reside, and increased GLP1 in pancreatic alpha-cells. To understand the physiological and molecular mechanisms underlying MGAT2 deficiency-mediated protection, we propose here to rigorously test our overarching hypothesis that that loss of intestinal MGAT2 (1) decreases microbial BSH activity, which (2) enhances reabsorption through the apical sodium-dependent bile salt transporter (ASBT), leading to (3) increased GLP1 secretion from pancreatic a-cells that induces GLP1 receptor (GLP1r)-signaling in b-cells, and thereby protects pancreatic islet function.
In Aim 1, we will determine if a reduction in BSH activity is necessary and/or sufficient to increase plasma bile acids and protect mice again beta cell insults.
In Aim 2, we will determine if loss of MGAT2 enhances re-absorption of bile acids and if the process requires ASBT.
In Aim 3, we will determine if GLP1 produced in alpha cells and if GLP1 receptors on beta cells are required for the effects of MGAT2 deficiency. Our proposed work represents essential steps to elucidate novel pathways that link intestinal lipid processing and bile acid metabolism with pancreatic islet function. Our findings will describe a novel example of interorgan communication that controls systemic metabolism setting the stage for targeting MGAT2 inhibition to combat diabetes by decreasing bacterial bile salt hydrolase, increasing conjugated primary bile acids, and modulating intra-islet signaling.
The proposed research will advance our understanding of underlying mechanisms linking intestinal lipid processing and bile acid metabolism with pancreatic islet function. This work will both increase our knowledge about how metabolism of a key macronutrient influences systemic metabolic health as well as provide insights into potential preventive or therapeutic interventions for obesity and diabetes.
