Diabetes Outfoxed by GLP-1?

George G. Holz^* and Oleg G. Chepurny

Department of Physiology and Neuroscience, New York University School of Medicine, New York, NY 10016, USA.

Summary: Foxo1, a member of the Fox0 subfamily of winged-helix forkhead transcription factors, is a target of insulin and insulin-like growth factor–1 (IGF-1) signal transduction pathways that activate protein kinase B (PKB) in pancreatic ß cells. Foxo1 is a substrate for PKB, and its phosphorylation results in nuclear exclusion with concomitant alterations in gene expression that are important to cellular growth and differentiation. Because activation of PKB can require insulin receptor substrate proteins (IRS-1 and IRS-2) and phosphatidylinositol 3-kinase (PI3K), it is of interest to determine whether the activity of Foxo1 is also regulated by heterotrimeric G protein–coupled receptors (GPCRs) with IRS-1 or -2, PI3K, or PKB signaling potential. Indeed, studies of ß cells have demonstrated that activation of a GPCR for the blood glucose–lowering hormone GLP-1 leads to major alterations of IRS-2, PI3K, and PKB activity. By promoting nuclear exclusion of Foxo1 in a PKB-mediated manner, GLP-1 may up-regulate the expression of a homeodomain transcription factor (PDX-1) that serves as a master regulator of ß-cell growth and differentiation. This STKE Perspective summarizes signaling properties of GLP-1 that may explain its ability to increase ß-cell mass, to increase pancreatic insulin secretory capacity, and to lower levels of blood glucose in type 2 diabetic subjects.

*Corresponding author. MSB 442, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA. Telephone, 212-263-5434; fax, 212-689-9060; e-mail: holzg01{at}popmail.med.nyu.edu

The editors suggest the following Related Resources on Science sites:

In Science Signaling

EDITORS' CHOICE
Aging
Staying Young with p16^INK4a

Elizabeth M. Adler (3 October 2006)
Sci. STKE 2006 (355), tw337. [DOI: 10.1126/stke.3552006tw337]
 |  Abstract »

EDITORIAL GUIDES
Focus Issue: Diabetes—Fighting Fat on Multiple Fronts

Elizabeth M. Adler (25 January 2005)
Sci. STKE 2005 (268), eg2. [DOI: 10.1126/stke.2682005eg2]
 |  Abstract »  |  Full Text »  |  PDF »

REVIEWS
The Many Forks in FOXO's Road

Hien Tran, Anne Brunet, Eric C. Griffith, and Michael E. Greenberg (4 March 2003)
Sci. STKE 2003 (172), re5. [DOI: 10.1126/stke.2003.172.re5]
 |  Gloss »  |  Abstract »  |  Full Text »  |  PDF »

DATABASE OF CELL SIGNALING
Insulin Signaling Pathway

Morris F. White
Sci. Signal. (Connections Map Pathway), http://stke.sciencemag.org/cgi/cm/stkecm;CMP_12069
 |  Canonical Pathway »

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES: