Diabetes outfoxed by GLP-1?
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 beta 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 beta 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 beta-cell growth and differentiation. This STKE Perspective summarizes signaling properties of GLP-1 that may explain its ability to increase beta-cell mass, to increase pancreatic insulin secretory capacity, and to lower levels of blood glucose in type 2 diabetic subjects.
Holz
George G
GG
Department of Physiology and Neuroscience, New York University School of Medicine, New York, NY 10016, USA. holzg01@popmail.med.nyu.edu <holzg01@popmail.med.nyu.edu>
Chepurny
Oleg G
OG
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology / Q000502:physiology*; D000067757:Glucagon-Like Peptide-1 Receptor; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology; D006801:Humans; D006965:Hyperplasia; D007328:Insulin / Q000096:biosynthesis / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins; D000078790:Insulin Secretion; D047908:Intracellular Signaling Peptides and Proteins; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D051381:Rats; D018027:Receptors, Glucagon / Q000502:physiology; D012636:Secretory Rate / Q000187:drug effects; D015398:Signal Transduction; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000502:physiology
C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D018398:Homeodomain Proteins; C526297:IRS2 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526298:Irs2 protein, mouse; C526299:Irs2 protein, rat; D010750:Phosphoproteins; D018027:Receptors, Glucagon; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D052216:Glucagon-Like Peptide 1; D051057:Proto-Oncogene Proteins c-akt