Insulin regulates carboxypeptidase E by modulating translation initiation scaffolding protein eIF4G1 in pancreatic β cells.
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.
Joslin 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.
Chong Wee
CW
Liew
Joslin Diabetes Center and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215;
Anke
A
Assmann
Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN 46202;
Andrew T
AT
Templin
Department 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;
Jeffrey C
JC
Raum
Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA 01605;
Kathryn L
KL
Lipson
Department of Medicine, The University of Chicago, Chicago, IL 60637;
Sindhu
S
Rajan
Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612;
Guifen
G
Qiang
Joslin Diabetes Center and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215;
Jiang
J
Hu
Joslin Diabetes Center and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215;
Dan
D
Kawamori
Department of Anatomy and Neurobiology, University of Maryland, Baltimore, MD 21201;
Iris
I
Lindberg
Department of Medicine, The University of Chicago, Chicago, IL 60637;
Louis H
LH
Philipson
Department of Biochemistry, McGill University, Montreal, QC, Canada H3A 1A3; and.
Nahum
N
Sonenberg
Joslin Diabetes Center and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215;
Allison B
AB
Goldfine
Department 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;
Doris A
DA
Stoffers
Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN 46202;
Raghavendra G
RG
Mirmira
Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110.
Fumihiko
F
Urano
Joslin 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.
Rohit N
RN
Kulkarni
D000818:Animals; D043423:Carboxypeptidase H / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D039603:Eukaryotic Initiation Factor-4G / Q000235:genetics / Q000378:metabolism*; D055106:Genome-Wide Association Study; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014176:Protein Biosynthesis / Q000502:physiology; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism
C113920:EIF4G1 protein, human; C491908:Eif4g1 protein, mouse; D039603:Eukaryotic Initiation Factor-4G; D018398:Homeodomain Proteins; D007328:Insulin; C497387:SREBF1 protein, human; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D011972:Receptor, Insulin; D043423:Carboxypeptidase H
ER stress; GWAS; bIRKO; prohormone