Exendin-4 uses Irs2 signaling to mediate pancreatic beta cell growth and function.
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.
Park
Sunmin
S
Howard Hughes Medical Institute, Division of Endocrinology, Department of Medicine, Children's Hospital Boston, MA 02215, USA.
Dong
Xiaocheng
X
Fisher
Tracy L
TL
Dunn
Sarah
S
Omer
A Kadir
AK
Weir
Gordon
G
White
Morris F
MF
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D000077270:Exenatide; D005838:Genotype; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D007515:Islets of Langerhans / Q000166:cytology; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D008956:Models, Chemical; D010179:Pancreas / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D018027:Receptors, Glucagon / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014688:Venoms / Q000737:chemistry
D001786:Blood Glucose; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; C526297:IRS2 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526298:Irs2 protein, mouse; D010455:Peptides; D010750:Phosphoproteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018027:Receptors, Glucagon; D014688:Venoms; D000077270:Exenatide; D000242:Cyclic AMP; D011972:Receptor, Insulin; D005947:Glucose