In recent decades, the United States has experienced an unabated rise in the number of individuals diagnosed with diabetes;as a result 23 million people are currently living with type 2 diabetes. The pathogenesis of type 2 diabetes involves a complex interplay between insulin resistance and failure of pancreatic ? cell compensation. ? cell compensation occurs through improved ? cell function and ? cell mass expansion, which are both regulated by the critical pancreatic transcription factor PDXI. Preliminary data show that PDXI deficiency increases ? cell apoptosis during diet induced insulin resistance by increasing susceptibility to endoplasmic reticulum (ER) stress (M. Sachdeva, unpublished data, 2008). The ER of a ? cell processes one million insulin molecules per minute, and ER stress has been associated with type 2 diabetes in mice and humans. High throughput gene expression and promoter occupancy analyses suggest that PDXI regulates several genes involved in maintaining ER homeostasis, including EROlip and GRP170. PDXI regulation of EROlip and GRP170 is hypothesized to be important for insulin biosynthesis and ? cell survival. This hypothesis will be tested in the following specific aims: I. Determine the role of DX1 in insulin biosynthesis, II. Determine the role of PDXI in the regulation of ER homeostasis and p cell survival. Insulin secretion will be studied in mouse insulinoma cells with shRNA silenced EROlip and GRP170. The role of EROlip in insulin disulfide bond formation and the function of GRP170 as a ? cell chaperone will be analyzed. To determine the effects of EROlip and GRP170 deficiency on ER homeostasis, ER stress markers such as BiP and CHOP will be measured, and Annexin V and TUNEL staining will be used to quantify ? cell apoptosis. Overexpression of EROlip and GRP170 may partially rescue the PDXI deficiency phenotype suggesting that they are important mediators of the effects of PDXI on insulin secretion and ? cell survival. Relevance: Failure of ? cells to sufficiently secrete insulin and death of these insulin-producing cells results in diabetes. Studying the mechanism for PDXI regulation of insulin secretion and ? cell survival may lead to targets for treatment of type 2 diabetes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZDK1-GRB-W (O1))
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Castle, Arthur
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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Khoo, Cynthia; Yang, Juxiang; Weinrott, Samuel A et al. (2012) Research resource: the pdx1 cistrome of pancreatic islets. Mol Endocrinol 26:521-33
Khoo, Cynthia; Yang, Juxiang; Rajpal, Gautam et al. (2011) Endoplasmic reticulum oxidoreductin-1-like ? (ERO1l?) regulates susceptibility to endoplasmic reticulum stress and is induced by insulin flux in ?-cells. Endocrinology 152:2599-608