Mechanisms of Beta Cell Failure

Columbia University Health Sciences, New York NY

Investigators

Linked publications, trials & patents

Abstract

DESCRIPTION (provided by applicant): ¿ cell failure plays a key role in the pathogenesis of type 2 diabetes. Targeted mutagenesis in mice has suggested that altered function of the ¿ cell's insulin signaling pathway partly contributes to this defect. In studies supported by this grant, the PI's laboratory has shown that: (i) ¿ cell compensation to insulin resistance occurs primarily via increased ¿ cell replication; (ii) decreased ¿ cell function (insulin secretion) can be compensated for by increased proliferation and vice versa, but (iii) any abnormality of the mechanism coupling insulin secretion with proliferation will shorten ¿ cell life and accelerate ¿ cell failure. Moreover, (iv) the PI has defined a pathway, comprised of the transcription factors Foxo1 and Pml and of the histone deacetylase Sirt1, that protects ¿ cells against hyperglycemia-induced glucose toxicity through the induction of metabolic diapause. Finally, (v) the PI has shown that conditional Foxo1 ablation in pancreatic progenitor cells, but not in terminally differentiated ¿ cells, gives rise to numerous insulin-positive cells in pancreatic ducts. Based on these accomplishments, as well as unpublished preliminary data, the PI proposes that a moderate reduction of metabolic activity and sparing use of cell replication are conducive to preserving ¿ cell function in the metabolic syndrome. The PI seeks continuing support to investigate critical aspects of this hypothesis, including: (Aim 1) does induction of premature senescence protect against ¿ cell failure? (Aim 2) is the decision between ¿ cell life (premature senescence) and death (apoptosis) dependent on Foxo1 transcriptional vs. coregulatory functions? (Aim 3) does Foxo1 fine-tune glycolysis via the ChREBP/Nif3l1 pathway? (Aim 4) Can ¿-like endocrine cells be isolated from pancreatic ducts of flPdx-Foxo1 knockout mice? To achieve these goals, the PI proposes studies in which signaling pathways linking insulin secretion to ¿ cell proliferation will be altered by gene targeting, and their effects on ¿ cell performance studied in various models of type 2 diabetes. The mainstay of this proposal rests on the PI's longstanding experience in introducing mutations in mice and analyzing the consequences by extensive metabolic phenotyping. PUBLIC HEALTH RELEVANCE: Prevention of ¿ cell dysfunction is a critical goal of diabetes treatment. Studies supported by this grant have defined mechanisms that we believe to be new, linking insulin secretion with ¿ cell differentiation, proliferation and hyperplasia, as well as new biochemical and molecular circuitries that can be exploited for ¿ cell replacement in diabetes. These studies have delineated a role for the forkhead protein Foxo1 as a biochemical linchpin among diverse ¿ cell functions. We envision that the molecular signature imparted by Foxo1 activation illustrates the concerted regulation of ¿ cell function one ought to achieve to prevent ¿ cell failure. Thus, the studies outlined in this proposal, while building on the lessons of the past funding cycle, aim to explore the contribution of the identified pathways to the ¿ cell's metabolic adaptation in type 2 diabetes. The driving theme of the proposed work is to define cellular pathways that can be enlisted in the clinic against ¿ cell dysfunction.