Pdx1 (MODY4) regulates pancreatic beta cell susceptibility to ER stress

Mira M. Sachdeva, Kathryn C. Claiborn, Cynthia Khoo, Juxiang Yang, David N. Groff, Raghavendra G. Mirmira, Doris A. Stoffers

Research output: Contribution to journalArticle

129 Scopus citations

Abstract

Type 2 diabetes mellitus (T2DM) results from pancreatic β cell failure in the setting of insulin resistance. Heterozygous mutations in the gene encoding the β cell transcription factor pancreatic duodenal homeobox 1 (Pdx1) are associated with both T2DM and maturity onset diabetes of the young (MODY4), and low levels of Pdx1 accompany β cell dysfunction in experimental models of glucotoxicity and diabetes. Here, we find that Pdx1 is required for compensatory β cell mass expansion in response to diet-induced insulin resistance through its roles in promoting βcell survival and compensatory hypertrophy. Pdx1-deficient β cells show evidence of endoplasmic reticulum (ER) stress both in the complex metabolic milieu of high-fat feeding as well as in the setting of acutely reduced Pdx1 expression in the Min6 mouse insulinoma cell line. Further, Pdx1 deficiency enhances βcell susceptibility to ER stressassociated apoptosis. The results of high throughput expression microarray and chromatin occupancy analyses reveal that Pdx1 regulates a broad array of genes involved in diverse functions of the ER, including proper disulfide bond formation, protein folding, and the unfolded protein response. These findings suggest that Pdx1 deficiency leads to a failure of βcell compensation for insulin resistance at least in part by impairing critical functions of the ER.

Original languageEnglish (US)
Pages (from-to)19090-19095
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number45
DOIs
StatePublished - Nov 10 2009

Keywords

  • Chromatin occupancy
  • Diabetes
  • Gene regulation
  • Islet compensation

ASJC Scopus subject areas

  • General

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