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Obesitycausesdiabetes,Sci.,2005

Obesitycausesdiabetes,Sci.,2005 - TYPE 2 DIABETES S PECIAL...

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earnest. To paraphrase Winston Churchill, in the area of common disease genetics we are certainly not at the end, nor are we even at the beginning of the end, but we may, per- haps, be at the end of the beginning. References and Notes 1. M. I. McCarthy, P. Froguel, Am. J. Physiol. Endocrinol. Metab. 283 , E217 (2002). 2. J. Tuomilehto et al. , N. Engl. J. Med. 344 , 1343 (2001). 3. C. N. Hales, D. J. Barker, Br. Med. Bull. 60 , 5 (2001). 4. A. T. Hattersley et al. , Nature Genet. 19 , 268 (1998). 5. H. Beck-Nielsen, A. Vaag, P. Poulsen, M. Gaster, Best Pract. Res. Clin. Endocrinol. Metab. 17 , 445 (2003). 6. A. Stride, A. T. Hattersley, Ann. Med. 34 , 207 (2002). 7. S. O’Rahilly, Eur. J. Endocrinol. 147 , 435 (2002). 8. D. Altshuler et al. , Nature Genet. 26 , 76 (2000). 9. I. Barroso et al. , Nature 402 , 880 (1999). 10. J. M. Friedman, Nature Med. 10 , 563 (2004). 11. S. O’Rahilly, I. S. Farooqi, G. S. Yeo, B. G. Challis, Endocrinology 144 , 3757 (2003). 12. D. Accili et al. , Nature Genet. 12 , 106 (1996). 13. Y. S. Tsai et al. , J. Clin. Invest. 114 , 240 (2004). 14. L. A. Sargeant, N. J. Wareham, K. T. Khaw, Int. J. Obes. Relat. Metab. Disord. 24 , 1333 (2000). 15. J. P. Hugot et al. , Nature 411 , 599 (2001). 16. Y. Horikawa et al. , Nature Genet. 26 , 163 (2000); erratum in Nature Genet. 26 , 502 (2000). 17. J. C. Cohen et al. , Science 305 , 869 (2004). 18. A. L. Gloyn et al. , Diabetes 52 , 568 (2003). 19. L. Love-Gregory et al. , Diabetologia 46 , 136 (2003). 20. I. Barroso et al. , PLoS Biol. 1 , 41 (2003). 21. Q. Zhu et al. , Diabetologia 46 , 567 (2003). 22. K. Silander et al. , Diabetes 53 , 1141 (2004). 23. L. D. Love-Gregory et al. , Diabetes 53 , 1134 (2004). 24. J. Poulton et al. , Hum. Mol. Genet. 11 , 1581 (2002). 25. R. A. Hegele, H. Cao, S. B. Harris, A. J. Hanley, B. Zinman, Diabetes Care 22 , 524 (1999). 26. S. J. Huxtable et al. , Diabetes 49 , 126 (2000). 27. L. M. Hart et al. , J. Clin. Endocrinol. Metab. 84 , 1002 (1999). 28. We thank the Wellcome Trust (S.O’R., I.B., and N.J.W.), the Medical Research Council UK (S.O’R. and N.J.W.), and the European Union Framework Pro- gramme (S.O’R., I.B., and N.J.W.) for their continuing support. S.O’R. has a financial relationship with and is a member of the Scientific Advisory Boards of Prosidion Ltd. and Biovitrum AB. He is a member of the Scientific Advisory Boards of Cambridge Antibody Technology, Cambridge Biotechnology Ltd., Paradigm Therapeutics PLC, and Xcellsyz Ltd. He is a consul- tant for Merck & Co. Inc., Unilever PLC, and Ingenium Pharmaceuticals AG. 10.1126/science.1104346 V I E W P O I N T How Obesity Causes Diabetes: Not a Tall Tale Mitchell A. Lazar The epidemic of obesity-associated diabetes is a major crisis in modern societies, in which food is plentiful and exercise is optional. The biological basis of this problem has been explored from evolutionary and mechanistic perspectives. Evolutionary theories, focusing on the potential survival advantages of ‘‘thrifty’’ genes that are now maladaptive, are of great interest but are inherently speculative and difficult to prove. Mechanistic studies have revealed numerous fat-derived molecules and a link to inflammation that, together, are hypothesized to underlie the obesity-diabetes connection and thereby represent prospective targets for therapeutic intervention.
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