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

Chong Wee Liew, Anke Assmann, Andrew T. Templin, Jeffrey C. Raum, Kathryn L. Lipson, Sindhu Rajan, Guifen Qiang, Jiang Hu, Dan Kawamori, Iris Lindberg, Louis H. Philipson, Nahum Sonenberg, Allison B. Goldfine, Doris A. Stoffers, Raghu Mirmira, Fumihiko Urano, Rohit N. Kulkarni

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number22
DOIs
StatePublished - Jun 3 2014

Fingerprint

Translational Peptide Chain Initiation
Carboxypeptidase H
Proinsulin
Insulin
Insulin Receptor
Type 2 Diabetes Mellitus
Eukaryotic Initiation Factor-4G
Sterol Regulatory Element Binding Protein 1
Homeobox Genes
Hyperinsulinism
Insulin Resistance
Transcription Factors
Phenotype
Enzymes
Hyperproinsulinemia
Proteins

Keywords

  • bIRKO
  • ER stress
  • GWAS
  • Prohormone

ASJC Scopus subject areas

  • General

Cite this

Insulin regulates carboxypeptidase E by modulating translation initiation scaffolding protein eIF4G1 in pancreatic β cells. / Liew, Chong Wee; Assmann, Anke; Templin, Andrew T.; Raum, Jeffrey C.; Lipson, Kathryn L.; Rajan, Sindhu; Qiang, Guifen; Hu, Jiang; Kawamori, Dan; Lindberg, Iris; Philipson, Louis H.; Sonenberg, Nahum; Goldfine, Allison B.; Stoffers, Doris A.; Mirmira, Raghu; Urano, Fumihiko; Kulkarni, Rohit N.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 22, 03.06.2014.

Research output: Contribution to journalArticle

Liew, CW, Assmann, A, Templin, AT, Raum, JC, Lipson, KL, Rajan, S, Qiang, G, Hu, J, Kawamori, D, Lindberg, I, Philipson, LH, Sonenberg, N, Goldfine, AB, Stoffers, DA, Mirmira, R, Urano, F & Kulkarni, RN 2014, 'Insulin regulates carboxypeptidase E by modulating translation initiation scaffolding protein eIF4G1 in pancreatic β cells', Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 22. https://doi.org/10.1073/pnas.1323066111
Liew, Chong Wee ; Assmann, Anke ; Templin, Andrew T. ; Raum, Jeffrey C. ; Lipson, Kathryn L. ; Rajan, Sindhu ; Qiang, Guifen ; Hu, Jiang ; Kawamori, Dan ; Lindberg, Iris ; Philipson, Louis H. ; Sonenberg, Nahum ; Goldfine, Allison B. ; Stoffers, Doris A. ; Mirmira, Raghu ; Urano, Fumihiko ; Kulkarni, Rohit N. / Insulin regulates carboxypeptidase E by modulating translation initiation scaffolding protein eIF4G1 in pancreatic β cells. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 22.
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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.",
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