The Role of NAD+ Metabolism in Obesity-Induced Pancreatic Beta-Cell Dysfunction

Weill Medical Coll Of Cornell Univ, New York NY

Investigators

Abstract

Project Summary One in every ten adults in the US suffers from Type 2 Diabetes (T2D), driven in part by an epidemic of obesity. Currently, identifying a therapy to restore the population and insulin-secreting function of beta cells is the number one unmet need in T2D. Our long-term goal is to reverse pancreatic beta cell failure to treat T2D. NAD+, an energy-sensing metabolite and redox co-factor, is implicated to play a crucial role in determining the function and survival of beta cells. Depletion of NAD, caused by inhibition of NAD synthesis or overactivation of NAD consumers, leads to impaired insulin secretion and increased cytotoxicity in beta cells. Moreover, NAD booster compounds show promises in improving insulin secretion in diet-induced obese mice. Our lab has recently discovered that dihydronicotinamide riboside (NRH), a new and potent NAD booster synthesized by us, significantly enhances insulin secretion and increases total insulin content in the pancreas of obese mice. Unlike other NAD boosters, NRH is metabolized through a previously unrecognized NAD synthesis pathway and has higher bioavailability in the pancreas. Our data suggest NRH acts by directly modulating beta cell NAD levels, replenishing NAD content in pancreatic islets reduced by obesity. Based on this knowledge, our objective is to uncover the mechanism of NAD depletion in obesity-exposed dysfunctional beta cells and identify metabolic pathways through which NAD boosters including NRH can restore their functional mass. We will use mice models of different T2D stages and human islets from healthy or T2D donors to define the correlation between beta cell NAD content and their gradual functional loss. Primary mouse and human islets, beta cell lines, and mice with different stages of beta cell dysfunction will be used to test two major aims. Aim 1 will define the changes in NAD biosynthesis and degradation pathways in beta cells under obesity-induced deterioration towards T2D. Aim 2 will use an optimized NAD boosting strategy to rescue pancreatic beta cell mass and function in T2D models. Completion of this project will provide new pathophysiological mechanisms driving beta cell deterioration due to NAD depletion. These discoveries could revolutionize therapeutic approaches, offering NAD restoration in pancreatic beta cells as new treatment strategies to not only prevent but also reverse the progression of T2D.