ATF6 and the Beta Cell

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ABSTRACT Diabetes mellitus results when pancreatic beta cells fail to produce enough insulin to maintain glucose homeostasis, either due to beta cell destruction (T1D) or insulin resistance (T2D). Beta cell failure can result from loss of beta cell number, reduced insulin secretory function, or both. Two important goals in diabetes research are to understand the causes of islet failure and to find therapies that restore functional beta cells. To date, my group has focused on identifying ways to increase beta cell mass by inducing proliferation of endogenous beta cells. We recently made the surprising, but in retrospect logical, observation that engaging mild ER stress stimulates beta cell proliferation (Sharma et al, JCI 2015). This concept suggests a beta-cell-autonomous explanation for compensatory beta cell proliferation in response to increased insulin demand. We have traced the proliferative signal to Atf6, which is one of three canonical UPR signaling pathways. Stepping back, Atf6 is a transcription factor which may play an important role in pancreatic islet function but whose biology is, to date, relatively unexplored in this tissue. Loss of Atf6 has been linked to human diabetes risk, and experiments in mice suggest that beta cell Atf6 activity protects against diabetogenic insults. Current understanding of Atf6 biology suggests several possible mechanisms by which Atf6 may be beneficial for beta cell health, including not only proliferation but also insulin production and secretion, maintenance of beta cell differentiation status, and promoting beta cell survival. Experiments in this project will explore Atf6 roles in healthy beta cell adaptation to insulin demand, assessing both proliferation and function. We will define mechanisms downstream of Atf6, using both candidate and unbiased approaches to identify Atf6 transcription targets in mouse and human islets. Finally, we will determine how Atf6 loss undermines beta cell capacity to stand up to diabetogenic stimuli. To accomplish these studies we have assembled a strong team of beta cell ER stress experts (Peter Arvan, Raghu Mirmira, Fumi Urano) and an Atf6 expert (Luke Wiseman). With technical support from the UMass MMPC (Jason Kim), the Indiana Diabetes Research Center (Raghu Mirmira), and the UMass Deep Sequencing and Bioinformatics cores (Maria Zapp, Alper Kucukural, Nick Merowsky) we have all the tools in hand to move this important work forward.