1. Department of Developmental Biology,
2. Program in Immunology,
3. Department of Microbiology and Immunology,
4. Department of Pathology and Howard Hughes Medical Institute,
5. Department of Medicine (Oncology Division), Stanford University, Stanford, California 94305, USA
6. †Present address: MRC Centre for Developmental Neurobiology, King's College London, London WC2R 2LS, UK

Correspondence to: Seung K. Kim^1,5 Correspondence and requests for materials should be addressed to S.K.K. (Email: seungkim@stanford.edu).

Abstract

The growth and function of organs such as pancreatic islets adapt to meet physiological challenges and maintain metabolic balance, but the mechanisms controlling these facultative responses are unclear^{1, 2}. Diabetes in patients treated with calcineurin inhibitors such as cyclosporin A indicates that calcineurin/nuclear factor of activated T-cells (NFAT) signalling might control adaptive islet responses³, but the roles of this pathway in -cells in vivo are not understood. Here we show that mice with a -cell-specific deletion of the calcineurin phosphatase regulatory subunit, calcineurin b1 (Cnb1), develop age-dependent diabetes characterized by decreased -cell proliferation and mass, reduced pancreatic insulin content and hypoinsulinaemia. Moreover, -cells lacking Cnb1 have a reduced expression of established regulators of -cell proliferation^{1, 4, 5}. Conditional expression of active NFATc1 in Cnb1-deficient -cells rescues these defects and prevents diabetes. In normal adult -cells, conditional NFAT activation promotes the expression of cell-cycle regulators and increases -cell proliferation and mass, resulting in hyperinsulinaemia. Conditional NFAT activation also induces the expression of genes critical for -cell endocrine function, including all six genes mutated in hereditary forms of monogenic type 2 diabetes. Thus, calcineurin/NFAT signalling regulates multiple factors that control growth and hallmark -cell functions, revealing unique models for the pathogenesis and therapy of diabetes.

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