? 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 Based on these accomplishments, as well as unpublished preliminary data, the PI proposes that a moderate reduction of metabolic activity and sparing use of cell replication are conducive to preserving ?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.
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.
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|Giannulis, I; Mondini, E; Cinti, F et al. (2014) Increased density of inhibitory noradrenergic parenchymal nerve fibers in hypertrophic islets of Langerhans of obese mice. Nutr Metab Cardiovasc Dis 24:384-92|
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|Qiang, Li; Accili, Domenico (2012) FGF21 and the second coming of PPAR?. Cell 148:397-8|
|Talchai, Chutima; Xuan, Shouhong; Kitamura, Tadahiro et al. (2012) Generation of functional insulin-producing cells in the gut by Foxo1 ablation. Nat Genet 44:406-12, S1|
|Tsunekawa, Shin; Demozay, Damien; Briaud, Isabelle et al. (2011) FoxO feedback control of basal IRS-2 expression in pancreatic ?-cells is distinct from that in hepatocytes. Diabetes 60:2883-91|
|Kitamura, Tadahiro; Kitamura, Yukari Ido; Kobayashi, Masaki et al. (2009) Regulation of pancreatic juxtaductal endocrine cell formation by FoxO1. Mol Cell Biol 29:4417-30|
|Banks, Alexander S; Kon, Ning; Knight, Colette et al. (2008) SirT1 gain of function increases energy efficiency and prevents diabetes in mice. Cell Metab 8:333-41|
|Kitamura, Tadahiro; Kitamura, Yukari Ido; Funahashi, Yasuhiro et al. (2007) A Foxo/Notch pathway controls myogenic differentiation and fiber type specification. J Clin Invest 117:2477-85|
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