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Abstract

Diabetes mellitus is a chronic disease that leads to complications including heart disease, stroke, kidney failure, blindness and nerve damage. Type 2 diabetes, characterized by target-tissue resistance to insulin, is epidemic in industrialized societies and is strongly associated with obesity; however, the mechanism by which increased adiposity causes insulin resistance is unclear. Here we show that adipocytes secrete a unique signalling molecule, which we have named resistin (for resistance to insulin). Circulating resistin levels are decreased by the anti-diabetic drug rosiglitazone, and increased in diet-induced and genetic forms of obesity. Administration of anti-resistin antibody improves blood sugar and insulin action in mice with diet-induced obesity. Moreover, treatment of normal mice with recombinant resistin impairs glucose tolerance and insulin action. Insulin-stimulated glucose uptake by adipocytes is enhanced by neutralization of resistin and is reduced by resistin treatment. Resistin is thus a hormone that potentially links obesity to diabetes.

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Acknowledgements

We thank D. Shao for help with the early stages of this project, and M. Brown, M. S. Brown, J. Cunningham, T. Lawrence, M. Birnbaum, J. Stephens, A. Swick and the Lazar laboratory for discussions. We acknowledge D. Reim and D. Speicher of the Wistar Protein Microchemistry/MS Facility for sequence analysis; H. Collins and the Radioimmunoassay Core of the Penn Diabetes Center and J. Moffett; and G. Swain, and the Morphology Core of the Penn Center for the Molecular Study of Digestive Diseases. This work was supported by NIDDK grants to M.A.L., and by the Penn Diabetes Center. C.M.S. was supported by an unrestricted postdoctoral research fellowship from Pfizer. E.J.B. was supported by a student research fellowship from the American Diabetes Association. R.R.B. is a trainee of the Medical Scientist Training Program.

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  1. Division of Endocrinology, Departments of Medicine and Genetics, Diabetes, and Metabolism, and The Penn Diabetes Center, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, USA

    • Claire M. Steppan
    • , Shannon T. Bailey
    • , Savitha Bhat
    • , Elizabeth J. Brown
    • , Ronadip R. Banerjee
    • , Christopher M. Wright
    • , Hiralben R. Patel
    • , Rexford S. Ahima
    •  & Mitchell A. Lazar

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Correspondence to Mitchell A. Lazar.

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https://doi.org/10.1038/35053000

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