31 Ueki, K. Okada, T. Hu, J. Liew, C. W. Assmann, A. Dahlgren, G. M. Peters, J. L. Shackman, J. G. Zhang, M. Artner, I. Satin, L. S. Stein, R. Holzenberger, M. Kennedy, R. T. Kahn, C. R. Kulkarni, R. N. 2006 Nat Genet 38 5 583-8 May 1061-4036 (Print) 16642022 Humans Diabetes Mellitus, Experimental/etiology/*physiopathology Animals Receptor, Insulin/genetics/physiology Receptor, IGF Type 1/genetics/physiology Mice, Knockout Mice Mass Spectrometry Islets of Langerhans/*physiopathology Insulin-Like Growth Factor I/*physiology Insulin/*physiology Diabetes Mellitus Receptor Knockout Experimental/etiology/*physiopathology Insulin/genetics/physiology IGF Type 1/genetics/physiology An appropriate beta cell mass is pivotal for the maintenance of glucose homeostasis. Both insulin and IGF-1 are important in regulation of beta cell growth and function (reviewed in ref. 2). To define the roles of these hormones directly, we created a mouse model lacking functional receptors for both insulin and IGF-1 only in beta cells (betaDKO), as the hormones have overlapping mechanisms of action and activate common downstream proteins. Notably, betaDKO mice were born with a normal complement of islet cells, but 3 weeks after birth, they developed diabetes, in contrast to mild phenotypes observed in single mutants. Normoglycemic 2-week-old betaDKO mice manifest reduced beta cell mass, reduced expression of phosphorylated Akt and the transcription factor MafA, increased apoptosis in islets and severely compromised beta cell function. Analyses of compound knockouts showed a dominant role for insulin signaling in regulating beta cell mass. Together, these data provide compelling genetic evidence that insulin and IGF-I-dependent pathways are not critical for development of beta cells but that a loss of action of these hormones in beta cells leads to diabetes. We propose that therapeutic improvement of insulin and IGF-I signaling in beta cells might protect against type 2 diabetes. P01 DK042502/DK/NIDDK NIH HHS/United StatesR01 DK046409/DK/NIDDK NIH HHS/United StatesR01 DK046960/DK/NIDDK NIH HHS/United StatesR01 DK066207/DK/NIDDK NIH HHS/United StatesR01 DK067536/DK/NIDDK NIH HHS/United StatesJournal ArticleResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov'tValidation StudiesUnited States http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16642022