RT Journal Article
SR Electronic
T1 Diabetes Outfoxed by GLP-1?
JF Science's STKE
JO Sci. STKE
FD American Association for the Advancement of Science
SP pe2
OP pe2
DO 10.1126/stke.2682005pe2
VO 2005
IS 268
A1 Holz, George G.
A1 Chepurny, Oleg G.
YR 2005
UL http://stke.sciencemag.org/content/2005/268/pe2.abstract
AB 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 β 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 β 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 β-cell growth and differentiation. This STKE Perspective summarizes signaling properties of GLP-1 that may explain its ability to increase β-cell mass, to increase pancreatic insulin secretory capacity, and to lower levels of blood glucose in type 2 diabetic subjects.