People with diabetes have reduced beta cell mass;developing therapies that increase beta cell mass, to increase insulin secretory capacity, is a primary goal in diabetes research. Beta cell proliferation rates are low in human autopsy studies, suggesting that factors either intrinsic or extrinsic to the beta cell restrain beta cell proliferation. Supporting this hypothesis is the observation that genome-wide association studies consistently link type 2 diabetes risks with the genetic locus encoding the cell cycle inhibitor p16, a strong beta cell anti- proliferative signal. Factors that restrain beta cell proliferation via p16 action remain unknown. One of the hallmarks of obesity and the metabolic syndrome is elevated circulating free fatty acids (FFAs). Using intravenous infusion of lipids into mice, we have discovered that FFAs block the compensatory beta cell proliferation induced by hyperglycemia. FFAs act directly on the beta cell, as FFA treatment of either primary islet cells or INS-1 cells also eliminates glucose-stimulated proliferation. Intriguingly, FFAs induce p16 expression in islets in vivo. Furthermore, p16 is also induced by FFAs in INS-1 cells, and knockdown of p16 eliminates the anti-proliferative effects of FFAs. We propose to dissect the mechanism and human relevance of these findings through the following specific aims:
Aim 1 : Establish whether p16 is required for FFA-inhibition of beta cell proliferation in mice, Aim 2: Explore the impact of aging-related p16 induction on glucose and FFA effects on beta cell proliferation, and Aim 3: Determine whether FFAs restrict human beta cell proliferation. To address these questions we will use a combination of novel and powerful techniques we have recently developed, including continuous intravenous infusion of glucose and/or lipids into genetically modified mice, into aging mice, and into mice engrafted with human islets. These studies have the potential to shed light on how the p16 locus contributes to diabetes risk, to explore a novel form of lipotoxicity (anti-proliferative), and to define a new arena of therapeutic targets: enhancing beta cell mass by blocking factors that restrict human beta cell proliferation.
Diabetes mellitus occurs when pancreatic beta cell mass is insufficient to produce enough insulin to maintain healthy glucose metabolism. We have discovered that free fatty acids (FFAs) block beta cell proliferation by inducing a cell cycle inhibitor, p16. Here we propose to explore the relationship between FFAs, p16, and aging and how they interfere with mouse and human beta cell proliferation;this work has the potential to identify new drug targets to increase insulin secretory capacity in people with diabetes.
|Stamateris, Rachel E; Sharma, Rohit B; Kong, Yahui et al. (2016) Glucose Induces Mouse ?-Cell Proliferation via IRS2, MTOR, and Cyclin D2 but Not the Insulin Receptor. Diabetes 65:981-95|
|Roth Flach, Rachel J; Danai, Laura V; DiStefano, Marina T et al. (2016) Protein Kinase Mitogen-activated Protein Kinase Kinase Kinase Kinase 4 (MAP4K4) Promotes Obesity-induced Hyperinsulinemia. J Biol Chem 291:16221-30|
|Kong, Yahui; Sharma, Rohit B; Nwosu, Benjamin U et al. (2016) Islet biology, the CDKN2A/B locus and type 2 diabetes risk. Diabetologia 59:1579-93|
|Lakshmipathi, Jayalakshmi; Alvarez-Perez, Juan Carlos; Rosselot, Carolina et al. (2016) PKC? Is Essential for Pancreatic ?-Cell Replication During Insulin Resistance by Regulating mTOR and Cyclin-D2. Diabetes 65:1283-96|
|Singamsetty, Srikanth; Shah, Faraaz Ali; Guo, Lanping et al. (2016) Early initiation of low-level parenteral dextrose induces an accelerated diabetic phenotype in septic C57BL/6J mice. Appl Physiol Nutr Metab 41:12-9|
|Sharma, Rohit B; O'Donnell, Amy C; Stamateris, Rachel E et al. (2015) Insulin demand regulates ? cell number via the unfolded protein response. J Clin Invest 125:3831-46|
|Mordes, John P; Alonso, Laura C (2015) Evaluation, Medical Therapy, and Course of Adult Persistent Hyperinsulinemic Hypoglycemia After Roux-en-Y Gastric Bypass Surgery: A Case Series. Endocr Pract 21:237-46|
|Song, Woo-Jin; Mondal, Prosenjit; Wolfe, Andrew et al. (2014) Glucagon regulates hepatic kisspeptin to impair insulin secretion. Cell Metab 19:667-81|
|Kilic, Gamze; Alvarez-Mercado, Ana I; Zarrouki, Bader et al. (2014) The islet estrogen receptor-? is induced by hyperglycemia and protects against oxidative stress-induced insulin-deficient diabetes. PLoS One 9:e87941|
|Sharma, Rohit B; Alonso, Laura C (2014) Lipotoxicity in the pancreatic beta cell: not just survival and function, but proliferation as well? Curr Diab Rep 14:492|
Showing the most recent 10 out of 12 publications