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Proc Natl Acad Sci U S A. 2014 Jun 3;111(22):E2319-28. doi: 10.1073/pnas.1323066111. Epub 2014 May 19.

Insulin regulates carboxypeptidase E by modulating translation initiation scaffolding protein eIF4G1 in pancreatic β cells.

Author information

  • 1Joslin Diabetes Center and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215;Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612; rohit.kulkarni@joslin.harvard.edu cwliew@uic.edu.
  • 2Joslin Diabetes Center and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215;
  • 3Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN 46202;
  • 4Department of Medicine/Endocrinology, Diabetes, and Metabolism and the Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104;
  • 5Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA 01605;
  • 6Department of Medicine, The University of Chicago, Chicago, IL 60637;
  • 7Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612;
  • 8Department of Anatomy and Neurobiology, University of Maryland, Baltimore, MD 21201;
  • 9Department of Biochemistry, McGill University, Montreal, QC, Canada H3A 1A3; and.
  • 10Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110.
  • 11Joslin Diabetes Center and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215; rohit.kulkarni@joslin.harvard.edu cwliew@uic.edu.

Abstract

Insulin resistance, hyperinsulinemia, and hyperproinsulinemia occur early in the pathogenesis of type 2 diabetes (T2D). Elevated levels of proinsulin and proinsulin intermediates are markers of β-cell dysfunction and are strongly associated with development of T2D in humans. However, the mechanism(s) underlying β-cell dysfunction leading to hyperproinsulinemia is poorly understood. Here, we show that disruption of insulin receptor (IR) expression in β cells has a direct impact on the expression of the convertase enzyme carboxypeptidase E (CPE) by inhibition of the eukaryotic translation initiation factor 4 gamma 1 translation initiation complex scaffolding protein that is mediated by the key transcription factors pancreatic and duodenal homeobox 1 and sterol regulatory element-binding protein 1, together leading to poor proinsulin processing. Reexpression of IR or restoring CPE expression each independently reverses the phenotype. Our results reveal the identity of key players that establish a previously unknown link between insulin signaling, translation initiation, and proinsulin processing, and provide previously unidentified mechanistic insight into the development of hyperproinsulinemia in insulin-resistant states.

KEYWORDS:

ER stress; GWAS; bIRKO; prohormone

PMID:
24843127
[PubMed - indexed for MEDLINE]
PMCID:
PMC4050564
Free PMC Article

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