Exendin-4 uses Irs2 signaling to mediate pancreatic β cell growth and function

Sunmin Park, X. Dong, Tracy L. Fisher, Sarah Dunn, A. Kadir Omer, Gordon Weir, Morris F. White

Research output: Contribution to journalArticle

145 Citations (Scopus)

Abstract

The insulin receptor substrate 2 (Irs2) branch of the insulin/insulin-like growth factor-signaling cascade prevents diabetes in mice because it promotes β cell replication, function, and survival, especially during metabolic stress. Because exendin-4 (Ex4), a long acting glucagon-like peptide 1 receptor agonist, has similar effects upon β cells in rodents and humans, we investigated whether Irs2 signaling was required for Ex4 action in isolated β cells and in Irs2-/- mice. Ex4 increased cAMP levels in human islets and Min6 cells, which promoted Irs2 expression and stimulated Akt phosphorylation. In wild type mice Ex4 administered continuously for 28 days increased β cell mass 2-fold. By contrast, Ex4 failed to arrest the progressive β cell loss in Irs2-/- mice, which culminated in fatal diabetes; however, Ex4 delayed the progression of diabetes by 3 weeks by promoting insulin secretion from the remaining islets. We conclude that some short term therapeutic effects of glucagon-like peptide 1 receptor agonists can be independent of Irs2, but its long term effects upon β cell growth and survival are mediated by the Irs2 branch of the insulin/insulin-like growth factor signaling cascade.

Original languageEnglish (US)
Pages (from-to)1159-1168
Number of pages10
JournalJournal of Biological Chemistry
Volume281
Issue number2
DOIs
StatePublished - Jan 13 2006
Externally publishedYes

Fingerprint

Insulin Receptor Substrate Proteins
Cell growth
Growth
Medical problems
Somatomedins
Insulin
Physiological Stress
Phosphorylation
Therapeutic Uses
exenatide
Islets of Langerhans
Rodentia
Cell Survival
Survival

ASJC Scopus subject areas

  • Biochemistry

Cite this

Exendin-4 uses Irs2 signaling to mediate pancreatic β cell growth and function. / Park, Sunmin; Dong, X.; Fisher, Tracy L.; Dunn, Sarah; Omer, A. Kadir; Weir, Gordon; White, Morris F.

In: Journal of Biological Chemistry, Vol. 281, No. 2, 13.01.2006, p. 1159-1168.

Research output: Contribution to journalArticle

Park, Sunmin ; Dong, X. ; Fisher, Tracy L. ; Dunn, Sarah ; Omer, A. Kadir ; Weir, Gordon ; White, Morris F. / Exendin-4 uses Irs2 signaling to mediate pancreatic β cell growth and function. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 2. pp. 1159-1168.
@article{3eecdb3f429b492e9683cdade191b24c,
title = "Exendin-4 uses Irs2 signaling to mediate pancreatic β cell growth and function",
abstract = "The insulin receptor substrate 2 (Irs2) branch of the insulin/insulin-like growth factor-signaling cascade prevents diabetes in mice because it promotes β cell replication, function, and survival, especially during metabolic stress. Because exendin-4 (Ex4), a long acting glucagon-like peptide 1 receptor agonist, has similar effects upon β cells in rodents and humans, we investigated whether Irs2 signaling was required for Ex4 action in isolated β cells and in Irs2-/- mice. Ex4 increased cAMP levels in human islets and Min6 cells, which promoted Irs2 expression and stimulated Akt phosphorylation. In wild type mice Ex4 administered continuously for 28 days increased β cell mass 2-fold. By contrast, Ex4 failed to arrest the progressive β cell loss in Irs2-/- mice, which culminated in fatal diabetes; however, Ex4 delayed the progression of diabetes by 3 weeks by promoting insulin secretion from the remaining islets. We conclude that some short term therapeutic effects of glucagon-like peptide 1 receptor agonists can be independent of Irs2, but its long term effects upon β cell growth and survival are mediated by the Irs2 branch of the insulin/insulin-like growth factor signaling cascade.",
author = "Sunmin Park and X. Dong and Fisher, {Tracy L.} and Sarah Dunn and Omer, {A. Kadir} and Gordon Weir and White, {Morris F.}",
year = "2006",
month = "1",
day = "13",
doi = "10.1074/jbc.M508307200",
language = "English (US)",
volume = "281",
pages = "1159--1168",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "2",

}

TY - JOUR

T1 - Exendin-4 uses Irs2 signaling to mediate pancreatic β cell growth and function

AU - Park, Sunmin

AU - Dong, X.

AU - Fisher, Tracy L.

AU - Dunn, Sarah

AU - Omer, A. Kadir

AU - Weir, Gordon

AU - White, Morris F.

PY - 2006/1/13

Y1 - 2006/1/13

N2 - The insulin receptor substrate 2 (Irs2) branch of the insulin/insulin-like growth factor-signaling cascade prevents diabetes in mice because it promotes β cell replication, function, and survival, especially during metabolic stress. Because exendin-4 (Ex4), a long acting glucagon-like peptide 1 receptor agonist, has similar effects upon β cells in rodents and humans, we investigated whether Irs2 signaling was required for Ex4 action in isolated β cells and in Irs2-/- mice. Ex4 increased cAMP levels in human islets and Min6 cells, which promoted Irs2 expression and stimulated Akt phosphorylation. In wild type mice Ex4 administered continuously for 28 days increased β cell mass 2-fold. By contrast, Ex4 failed to arrest the progressive β cell loss in Irs2-/- mice, which culminated in fatal diabetes; however, Ex4 delayed the progression of diabetes by 3 weeks by promoting insulin secretion from the remaining islets. We conclude that some short term therapeutic effects of glucagon-like peptide 1 receptor agonists can be independent of Irs2, but its long term effects upon β cell growth and survival are mediated by the Irs2 branch of the insulin/insulin-like growth factor signaling cascade.

AB - The insulin receptor substrate 2 (Irs2) branch of the insulin/insulin-like growth factor-signaling cascade prevents diabetes in mice because it promotes β cell replication, function, and survival, especially during metabolic stress. Because exendin-4 (Ex4), a long acting glucagon-like peptide 1 receptor agonist, has similar effects upon β cells in rodents and humans, we investigated whether Irs2 signaling was required for Ex4 action in isolated β cells and in Irs2-/- mice. Ex4 increased cAMP levels in human islets and Min6 cells, which promoted Irs2 expression and stimulated Akt phosphorylation. In wild type mice Ex4 administered continuously for 28 days increased β cell mass 2-fold. By contrast, Ex4 failed to arrest the progressive β cell loss in Irs2-/- mice, which culminated in fatal diabetes; however, Ex4 delayed the progression of diabetes by 3 weeks by promoting insulin secretion from the remaining islets. We conclude that some short term therapeutic effects of glucagon-like peptide 1 receptor agonists can be independent of Irs2, but its long term effects upon β cell growth and survival are mediated by the Irs2 branch of the insulin/insulin-like growth factor signaling cascade.

UR - http://www.scopus.com/inward/record.url?scp=33644850386&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33644850386&partnerID=8YFLogxK

U2 - 10.1074/jbc.M508307200

DO - 10.1074/jbc.M508307200

M3 - Article

VL - 281

SP - 1159

EP - 1168

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 2

ER -