O-GlcNAc transferase (OGT) is highly expressed in pancreatic ?-cells where it exclusively catalyzes the post- translational and dynamic glycosylation of select cytosolic proteins (referred to as O-GlcNAcylation). OGT is a multi-nutrient sensor and the ?-cell OGT knockout mouse develops severe type 2 diabetes, suggesting OGT plays a role in glucose homeostasis and metabolic disease. The long-term goal of this research is to understand how protein O-GlcNAcylation contributes to ?-cell health and function under various nutrient environments. While some studies have investigated ?-cell O-GlcNAcylation during hyperglycemia and in diabetic decompensation, little is known about OGT's role during hyperlipidemia or the prediabetic phase of obesity when ?-cell hyperinsulinemia compensates for peripheral insulin resistance to maintain euglycemia and prevent the onset of full diabetes. Our preliminary data shows that islet (?-cell) O-GlcNAcylation increases in response to obesity and that OGT-loss mice do not develop prediabetic hyperinsulinemia in response to high fat diet (HFD), in part due to impaired potentiation of islet insulin secretion. Our central hypothesis is that in response to diet-induced obesity, OGT is required for the initiation and maintenance of ?-cell hypersecretion by tightly controlling the O-GlcNAcylation status of specific protein regulators that modulate stimulus-secretion coupling. The objective of this proposal is to identify OGT-driven mechanisms and protein regulators that underlie prediabetic secretory adaptation.
Specific Aim 1 will evaluate lipid signaling and mitochondrial ATP production, well-known obesity-driven mechanisms of ?-cell secretory potentiation, in inducible ?-cell OGT KO (i?OGT KO) mice under HFD.
Specific Aim 2 will characterize human and mouse islet O-GlcNAcylation in response to obesity and use a differential gene expression analysis (RNA-seq) to identify protein regulators (i.e. of lipid and mitochondrial metabolism) whose O-GlcNAcylated expression is increased by diet-induced obesity. This investigation is innovative because very little is known about in vivo ?-cell O-GlcNAcylation in the context of hyperlipidemia and OGT-regulation of islet lipid metabolism is unexplored. If successful, this proposal will generate a set of OGT-responsive mechanisms and a prioritized list of critical proteins to guide future cause-and-effect studies that can directly test the role of OGT-targets in initiating or maintaining specific structural and functional adaptations that contribute to ?-cell success or failure in diet-induced obesity. The significance of this research is in revealing a novel role of the nutrient-sensor OGT in regulating adaptive hyperinsulinemia, especially contributions by lipid and mitochondrial metabolism, and revealing new therapeutic targets that may prevent prediabetic progression to type 2 diabetes in obese individuals.

Public Health Relevance

Obesity-precipitated type 2 diabetes is a key public health concern both for its own life-threatening symptoms and its role as a risk factor in other major diseases, driven largely by the negative consequences of chronic hyperglycemia. Hyperglycemia is averted during prediabetes, despite insulin-resistance, by ?-cell insulin hypersecretion through underexplored adaptive mechanisms that may provide insights into novel anti-diabetic therapies. In this proposal, we will study the requirement of OGT-regulated protein O-GlcNAcylation for ?-cell hyperinsulinemia, through lipid and mitochondrial metabolism, and generate a list of critical OGT targets with a high potential to regulate obesity-driven mechanisms of ?-cell hypersecretion with the long-term goal of generating new therapeutic targets to prevent type 2 diabetes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Predoctoral Individual National Research Service Award (F31)
Project #
Application #
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Castle, Arthur
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Minnesota Twin Cities
Schools of Medicine
United States
Zip Code