The role of insulin receptor substrate 2 in hypothalamic and β cell function

Agharul I. Choudhury, Helen Heffron, Mark A. Smith, Hind Al-Qassab, Allison W. Xu, Colin Selman, Marcus Simmgen, Melanie Clements, Marc Claret, Gavin MacColl, David C. Bedford, Kazunari Hisadome, Ivan Diakonov, Vazira Moosajee, Jimmy D. Bell, John R. Speakman, Rachel L. Batterham, Gregory S. Barsh, Michael L.J. Ashford, Dominic J. Withers*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

214 Citations (Scopus)


Insulin receptor substrate 2 (Irs2) plays complex roles in energy homeostasis. We generated mice lacking Irs2 in β cells and a population of hypothalamic neurons (RIPCreIrs2KO), in all neurons (NesCreIrs2KO), and in proopiomelanocortin neurons (POMCCreIrs2KO) to determine the role of Irs2 in the CNS and β cell. RIPCreIrs2KO mice displayed impaired glucose tolerance and reduced β cell mass. Overt diabetes did not ensue, because β cells escaping Cre-mediated recombination progressively populated islets. RIPCreIrs2KO and NesCreIrs2KO mice displayed hyperphagia, obesity, and increased body length, which suggests altered melanocorrin action. POMCCreIrs2KO mice did not display this phenotype. RIPCreIrs2KO and NesCreIrs2KO mice retained leptin sensitivity, which suggests that CNS Irs2 pathways are not required for leptin action. NesCreIrs2KO and POMCCreIrs2KO mice did not display reduced β cell mass, but NesCreIrs2KO mice displayed mild abnormalities of glucose homeostasis. RIPCre neurons did not express POMC or neuropeptide Y. Insulin and a melanocortin agonist depolarized RIPCre neurons, whereas leptin was ineffective. Insulin hyperpolarized and leptin depolarized POMC neurons. Our findings demonstrate a critical role for IRS2 in β cell and hypothalamic function and provide insights into the role of RIPCre neurons, a distinct hypothalamic neuronal population, in growth and energy homeostasis.

Original languageEnglish
Pages (from-to)940-950
Number of pages11
JournalJournal of Clinical Investigation
Issue number4
Publication statusPublished - 1 Jan 2005

Bibliographical note

We thank Jonathan Godwin for blastocyst injections, Corinne Lobe for providing ZEG mice, Marika Charalambous for advice and discussion, Steven Lingard for technical assistance, and Andrew Tinker and Matthew Glyn for assistance with confocal microscopy. We thank the Biological Imaging Centre (BIC), Imaging Sciences Department, Imperial College London, for assistance with the MRI studies. The work was supported by grants from the Wellcome Trust (to A. Choudhury, C. Selman, M.A. Smith, M. Simmgen, K. Hisadome, M.L.J. Ashford, and D.J. Withers); the Biotechnology and Biological Sciences Research Council (BBSRC) (to M. Claret); the Medical Research Council (MRC; to H. Al-Qassab, I. Diakonov, J.D. Bell, R.L. Batterham, and D.J. Withers); Diabetes UK (to A. Choudhury and D.C. Bedford); the NIH (DK-48506, to G.S. Barsh); the Stanford Bio-X Interdisciplinary Initiatives Program (to G.S. Barsh); and by an AstraZeneca BBSRC CASE award (to H. Heffron). Part of this work was conducted within the BetaCellTherapy consortium that is supported as an integrated project by the sixth European Union–framework program. R.L. Batterham is an MRC Clinician Scientist. D.J. Withers is an MRC Senior Clinical Fellow.


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