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Diabetes 52:910-917, 2003
© 2003 by the American Diabetes Association, Inc.

Human Metabolic Syndrome Resulting From Dominant-Negative Mutations in the Nuclear Receptor Peroxisome Proliferator-Activated Receptor-{gamma}

David B. Savage1,2, Garry D. Tan3, Carlo L. Acerini4, Susan A. Jebb5, Maura Agostini1, Mark Gurnell1, Rachel L. Williams4, A. Margot Umpleby6, E. Louise Thomas7, Jimmy D. Bell7, Adrian K. Dixon8, Fidelma Dunne9, Romina Boiani10, Saverio Cinti10, Antonio Vidal-Puig1,2, Fredrik Karpe3, V. Krishna K. Chatterjee1, and Stephen O’Rahilly1,2

1 Department of Medicine, Addenbrooke’s Hospital, Cambridge, U.K
2 Department of Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge, U.K
3 Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Infirmary, Oxford, U.K
4 Department of Paediatrics, Addenbrooke’s Hospital, Cambridge, U.K
5 Medical Research Council Human Nutrition Research, Cambridge, U.K
6 Department of Diabetes and Endocrinology, GKT School of Medicine, St Thomas’s Hospital, London, U.K
7 Robert Steiner MRI Unit, Medical Research Council Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, London, U.K
8 Department of Radiology, Addenbrooke’s Hospital, Cambridge, U.K
9 Department of Medicine, University Hospital Trust (Selly Oak), Raddlebarn Road, Birmingham, U.K
10 Institute of Normal Human Morphology, Faculty of Medicine, Ancona University, Ancona, Italy

We previously reported a syndrome of severe hyperinsulinemia and early-onset hypertension in three patients with dominant-negative mutations in the nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR)-{gamma}. We now report the results of further detailed pathophysiological evaluation of these subjects, the identification of affected prepubertal children within one of the original families, and the effects of thiazolidinedione therapy in two subjects. These studies 1) definitively demonstrate the presence of severe peripheral and hepatic insulin resistance in the affected subjects; 2) describe a stereotyped pattern of partial lipodystrophy associated with all the features of the metabolic syndrome and nonalcoholic steatohepatitis; 3) document abnormalities in the in vivo function of remaining adipose tissue, including the inability of subcutaneous abdominal adipose tissue to trap and store free fatty acids postprandially and the presence of very low circulating levels of adiponectin; 4) document the presence of severe hyperinsulinemia in prepubertal carriers of the proline-467-leucine (P467L) PPAR-{gamma} mutation; 5) provide the first direct evidence of cellular resistance to PPAR-{gamma} agonists in mononuclear cells derived from the patients; and 6) report on the metabolic response to thiazolidinedione therapy in two affected subjects. Although the condition is rare, the study of humans with dominant-negative mutations in PPAR-{gamma} can provide important insight into the roles of this nuclear receptor in human metabolism.


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