31 Kawamori, D. Kurpad, A. J. Hu, J. Liew, C. W. Shih, J. L. Ford, E. L. Herrera, P. L. Polonsky, K. S. McGuinness, O. P. Kulkarni, R. N. 2009 Cell Metab 9 4 350-61 Apr 1932-7420 (Electronic) 19356716 Animals Arginine/pharmacology Diabetes Mellitus, Experimental Fasting Feeding Behavior/drug effects Gene Expression Regulation/drug effects Glucagon/genetics/*secretion Glucagon-Secreting Cells/drug effects/pathology/*secretion Glucose Intolerance/complications Hyperinsulinism/complications/metabolism Hypoglycemia/complications/metabolism Insulin/genetics/*metabolism Insulin-Secreting Cells/drug effects/metabolism/pathology Mice Mice, Knockout Organ Size/drug effects Organ Specificity/drug effects Receptor, Insulin/deficiency/metabolism *Signal Transduction/drug effects Streptozocin Glucagon plays an important role in glucose homeostasis by regulating hepatic glucose output in both normo- and hypoglycemic conditions. In this study, we created and characterized alpha cell-specific insulin receptor knockout (alphaIRKO) mice to directly explore the role of insulin signaling in the regulation of glucagon secretion in vivo. Adult male alphaIRKO mice exhibited mild glucose intolerance, hyperglycemia, and hyperglucagonemia in the fed state and enhanced glucagon secretion in response to L-arginine stimulation. Hyperinsulinemic-hypoglycemic clamp studies revealed an enhanced glucagon secretory response and an abnormal norepinephrine response to hypoglycemia in alphaIRKO mice. The mutants also exhibited an age-dependent increase in beta cell mass. Furthermore, siRNA-mediated knockdown of insulin receptor in glucagon-secreting InR1G cells promoted enhanced glucagon secretion and complemented our in vivo findings. Together, these data indicate a significant role for intraislet insulin signaling in the regulation of alpha cell function in both normo- and hypoglycemic conditions. 5P30DK36836/DK/NIDDK NIH HHS/United StatesDK20593/DK/NIDDK NIH HHS/United StatesDK31842/DK/NIDDK NIH HHS/United StatesDK56341/DK/NIDDK NIH HHS/United StatesDK59637/DK/NIDDK NIH HHS/United StatesDK67536/DK/NIDDK NIH HHS/United StatesUL1RR024992/RR/NCRR NIH HHS/United StatesJournal ArticleResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov'tUnited States http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19356716