Failure of beta (B) cell compensation for insulin resistance in humans leads to the progression to overt diabetes and its associated kidney, eye, vasculature and nervous system complications. During the previous funding period, we discovered that Pdxl, a pancreatic homeodomain transcription factor mutated in human type 2 diabetes, is required for li cell compensation for diet-induced insulin resistance in mice. Pdx1*''mice stressed by a high fat diet fail to increase insulin secretion or to expand B cell mass due to increased Q>cell death and decreased li cell hypertrophy. We determined genome wide Pdxl occupancy and transcriptional targets in primary islets, leading to the identification of a number of Pdxl targets involved in maintaining critical functions of and potentially the biogenesis of the endoplasmic reticulum (ER), the subcellular organelle responsible for the facilitation of protein folding, disulfide bond formation and the transport to the Golgi of proteins destined for secretion. Optimal function of the ER and coordination of its capacity with protein synthesis and the load of unfolded and misfolded proteins is critically important in highly secretory cells such as B cells. Impairment of ER function results in impaired insulin secretion, "ER stress", and eventually programmed cell death if the stress cannot be resolved through proper activation of the unfolded protein response (UPR). We hypothesize that Pdx1 regulates ER biogenesis and translation and that Pdx1 overexpression can promote islet compensation in animal models of diet-induced insulin resistance and diabetes. We further postulate that Pdx1 partners with the TALE homeodomain factor Meis3 to regulate at least a subset ofPdxl target genes involved in lineage allocation and beta cell survival and function.
Our Specific Aims are: (1) To determine whether Pdxl regulates ER biogenesis and mRNA translation, (2) To determine if Pdxl over-expression preserves beta cell survival and function in models of insulin resistance and diabetes, and (3) To determine whether the Pdxl partner, Meis3, regulates islet development and function. Addressing these Aims will provide critical insight into the process of islet compensation that goes awry during the progression of type 2 diabetes.
Diabetes affects over 23 million individuals in the US and well over 150 million woridwide, with complications involving multiple organ systems, making it a formidable medical and public health issue. The natural history of diabetes depends in large part on the adaptation of pancreatic li-cells to meet the increased demand for insulin that results from insulin resistance. Targeting beta cell growth and/or function represents an important approach to develop novel therapies for diabetes.
|Park, Hyeong-Kyu; Ahima, Rexford S (2015) Physiology of leptin: energy homeostasis, neuroendocrine function and metabolism. Metabolism 64:24-34|
|Soleimanpour, Scott A; Gupta, Aditi; Bakay, Marina et al. (2014) The diabetes susceptibility gene Clec16a regulates mitophagy. Cell 157:1577-90|
|Jiang, Shaoning; Park, Dae Won; Tadie, Jean-Marc et al. (2014) Human resistin promotes neutrophil proinflammatory activation and neutrophil extracellular trap formation and increases severity of acute lung injury. J Immunol 192:4795-803|
|Lee, Dolim; Le Lay, John; Kaestner, Klaus H (2014) The transcription factor CREB has no non-redundant functions in hepatic glucose metabolism in mice. Diabetologia 57:1242-8|
|Lee, Sahmin; Lee, Hyun-Chae; Kwon, Yoo-Wook et al. (2014) Adenylyl cyclase-associated protein 1 is a receptor for human resistin and mediates inflammatory actions of human monocytes. Cell Metab 19:484-97|
|Baur, Joseph A; Birnbaum, Morris J (2014) Control of gluconeogenesis by metformin: does redox trump energy charge? Cell Metab 20:197-9|
|Shin, Soona; Kaestner, Klaus H (2014) The origin, biology, and therapeutic potential of facultative adult hepatic progenitor cells. Curr Top Dev Biol 107:269-92|
|Roat, Regan; Rao, Vandana; Doliba, Nicolai M et al. (2014) Alterations of pancreatic islet structure, metabolism and gene expression in diet-induced obese C57BL/6J mice. PLoS One 9:e86815|
|Liew, Chong Wee; Assmann, Anke; Templin, Andrew T et al. (2014) Insulin regulates carboxypeptidase E by modulating translation initiation scaffolding protein eIF4G1 in pancreatic ? cells. Proc Natl Acad Sci U S A 111:E2319-28|
|Carr, Rotonya M; Peralta, Giselle; Yin, Xiaoyan et al. (2014) Absence of perilipin 2 prevents hepatic steatosis, glucose intolerance and ceramide accumulation in alcohol-fed mice. PLoS One 9:e97118|
Showing the most recent 10 out of 167 publications