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and Its Therapeutic Modulation
Departments of Medicine (M.G., D.B.S., V.K.K.C., S.O.) and Clinical Biochemistry (D.B.S., S.O.), University of Cambridge, Addenbrooke’s Hospital, Cambridge CB2 2QQ, United Kingdom
Address all correspondence and requests for reprints to: Prof. V. K. K. Chatterjee, Department of Medicine, University of Cambridge, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, United Kingdom. E-mail: kkc1{at}mole.bio.cam.ac.uk; or Prof. S. O’Rahilly, Department of Clinical Biochemistry, University of Cambridge, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, United Kingdom. E-mail: sorahill{at}hgmp.mrc.ac.uk.
By the end of this decade, it has been estimated that between 200 million and 300 million people worldwide will meet World Health Organization diagnostic criteria for diabetes mellitus. This epidemic of predominantly type 2 diabetes has largely been mediated by our shift toward a more sedentary lifestyle predisposing to obesity and insulin resistance. Affected individuals can also exhibit an array of associated undesirable traits such as hypertension, dyslipidemia, and hypercoagulability, leading to morbidity and mortality from atherosclerotic vascular disease. The coexistence of several of these traits with insulin resistance constitutes the metabolic syndrome. Accordingly, improving insulin sensitivity in this group, and thereby potentially ameliorating the excess vascular risk, is a primary goal of treatment. Recent interest has focused on the thiazolidinediones, a novel class of antidiabetic agents, which act as insulin sensitizers and, therefore, potentially target the underlying metabolic disturbance. These agents are high-affinity ligands for the nuclear receptor peroxisome proliferator-activated receptor 
, and a large body of in vitro and in vivo data has evolved to support their increasing clinical use. Importantly, clinical and laboratory findings in human subjects harboring natural mutations and polymorphisms within the receptor have provided additional insights. Here, we focus on the consequences of inherited variation in the human peroxisome proliferator-activated receptor gene, linking this receptor to disordered glucose homeostasis, adipogenesis, lipid metabolism, and blood pressure regulation. These studies provide further support for the future development of more selective receptor modulators, targeting specific pathways to ameliorate facets of the metabolic syndrome.
This work was supported by the Wellcome Trust.
M.G. and D.B.S. contributed equally to this work.
Abbreviations: BMI, Body mass index; FFA, free fatty acid; HDL, high-density lipoprotein; HODE, hydroxyoctadecadienoic acid; LBD, ligand-binding domain; LDL, low-density lipoprotein; PPAR, peroxisome proliferator-activated receptor; RXR, retinoid X receptor; T2DM, type 2 diabetes mellitus; TZD, thiazolidinedione.
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