Exendin-4 Uses Irs2 Signaling to Mediate Pancreatic β Cell Growth and Function

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

doi:10.1074/jbc.m508307200

Sunmin Park, Xiaocheng Dong + Show 5 more

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https://doi.org/10.1074/jbc.m508307200

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Abstract

The insulin receptor substrate 2 (Irs2) branch of the insulin/insulin-like growth factor-signaling cascade prevents diabetes in mice because it promotes beta 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 beta cells in rodents and humans, we investigated whether Irs2 signaling was required for Ex4 action in isolated beta 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 beta cell mass 2-fold. By contrast, Ex4 failed to arrest the progressive beta 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 beta cell growth and survival are mediated by the Irs2 branch of the insulin/insulin-like growth factor signaling cascade.

Highlights

Mote peripheral insulin sensitivity and satiety in type 2 diabetics [5,6,7,8,9]
Ex4 Increases insulin receptor substrate 2 (Irs2) Levels in Isolated Human Islets—Previous experiments demonstrated that activation of cAMP 3 cAMP response element-binding protein (CREB) signaling for 4 –10 h with Ex4 increased the expression of Irs2 in Min6 cells and murine pancreatic ␤ cells [26, 27]
This is consistent with the presence of several half-cre elements in the 5Ј-untranslated region of the murine Irs2 gene where CREB binds during cAMP-stimulated phosphorylation [26]

Summary

Introduction

Mote peripheral insulin sensitivity and satiety in type 2 diabetics [5,6,7,8,9]. During a meal, GLP1 is secreted into the circulation from L cells located in the intestine [10]; GLP1 is quickly inactivated by circulating dipeptidyl-peptidase IV, which diminishing its usefulness as an injectable therapeutic. Protein kinase A activates the transcription factor cAMP response element-binding protein (CREB) in ␤ cells, which stimulates the expression of various genes that play a direct role in glucose sensing (GLUT2 and glucokinase) and insulin secretion (PDX1 and insulin itself) [21, 22]. Recent reports suggest that exendin-4 activates various protein kinases that promote cell growth and survival, including Akt, Jak, protein kinase C, cSrc, or the epidermal growth factor receptor [7, 21, 23]. Foxo1.3 the IRS2 branch of the insulin/insulin-like growth factor signaling pathway strongly promotes ␤ cell growth and survival, which is essential for compensatory ␤ cell function during physiological or metabolic stress (29 –31).

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