Molecular mechanism of metabolic stress in the pancreatic beta cells

About This Grant

Type 2 diabetes (T2D) is one of the most prevalent chronic disorders with a substantial healthcare burden. The hallmark of T2D is beta cell dysfunction. High glucose and high lipid levels (herein referred to as overnutrition) are the two most salient environmental risk factors associated with T2D. However, the specific impacts of these factors on beta cells, as well as the mechanisms underlying such impacts, remain unclear. Adding to the complexity is the observation that beta cells exhibit both adaptive and maladaptive responses to overnutrition, contingent on the dosage and duration of exposure. The goal of this proposed research is to determine the molecular mechanisms underlying beta cell overnutrition response. Our central hypothesis is that the transition from glucolipoadaptation to glucolipotoxicity in beta cells is mediated by epigenetic programs. To gain a deeper understand of overnutrition-induced beta cell state changes, we have established an in vitro human beta cell metabolic stress model. We have also generated single- cell transcriptomic maps from primary human pancreatic islets exposed to metabolic stress as well as pharmacological induced endoplasmic reticulum stress. Combined with targeted drug screening, we identified histone H3K9 methyltransferases G9a/GLP to be important mediators of beta cell stress. Building on these findings, we have developed two aims to translate the laboratory discovery into mechanistic biological knowledge of T2D. In Aim 1, we will perform a series of -omic assays with dense time course to delineate the molecular landscape and beta cell dynamic state changes in response to overnutrition challenge. We will connect the T2D variants identified by genome-wide association studies with nutrition-responsive chromatin and transcriptomic changes and experimentally establish causality between variants to functions in beta cells. In Aim 2, we will dissect the molecular pathways linking overnutrition with G9a/GLP, and beta cell cellular molecular changes. Together, our study has significant and broad impacts by providing (1) novel biological mechanisms and therapeutic targets of T2D; (2) a molecular network encompassing epigenetic regulators, nutrition-responsive cis-regulatory elements, and their genetic targets in human beta cells that enables interpreting of T2D pathogenesis in signaling-dependent genetic programs.