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 31 Evgenov, N. V. Medarova, Z. Dai, G. Bonner-Weir, S. Moore, A. 2006 Nat Med 12 1 144-8 Jan 1078-8956 (Print) 16380717 Time Factors Phantoms, Imaging Microscopy, Fluorescence Microscopy, Electron/methods Microscopy, Confocal/methods Mice, Nude Mice Animals Magnetic Resonance Imaging/methods Islets of Langerhans Transplantation/*pathology Islets of Langerhans/*cytology Hyperglycemia Humans Enzyme-Linked Immunosorbent Assay Disease Models, Animal Diabetes Mellitus, Type 1/*pathology Diabetes Mellitus, Experimental Cell Transplantation Microscopy Fluorescence Disease Models Animal Diabetes Mellitus Phantoms Imaging Electron/methods Confocal/methods Nude Type 1/*pathology Experimental Type 1 diabetes mellitus is characterized by the selective destruction of insulin-producing beta cells, which leads to a deficiency in insulin secretion and, as a result, to hyperglycemia. At present, transplantation of pancreatic islets is an emerging and promising clinical modality, which can render individuals with type 1 diabetes insulin independent without increasing the incidence of hypoglycemic events. To monitor transplantation efficiency and graft survival, reliable noninvasive imaging methods are needed. If such methods were introduced into the clinic, essential information could be obtained repeatedly and noninvasively. Here we report on the in vivo detection of transplanted human pancreatic islets using magnetic resonance imaging (MRI) that allowed noninvasive monitoring of islet grafts in diabetic mice in real time. We anticipate that the information obtained in this study would ultimately result in the ability to detect and monitor islet engraftment in humans, which would greatly aid the clinical management of this disease. DK071225/DK/NIDDK NIH HHS/United StatesJournal ArticleResearch Support, N.I.H., ExtramuralUnited States http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16380717