Endocrine Abstracts (2001) 2 SP6

PPAR gamma and human insulin resistance

VKK Chatterjee

Department of Medicine, University of Cambridge, Level 5, Addenbrooke's Hospital, Hills Rd, Cambridge, CB2 2QQ, UK

Adiposity is a major risk factor for insulin resistance and type 2 diabetes. PPAR gamma, an orphan nuclear receptor, is highly expressed in adipose tissue. Paradoxically, synthetic PPAR gamma ligands including thiazolidinedones (TZDs), which activate PPAR gamma induce adipogenesis yet improve insulin sensitivity. We have shown that TZDs selectively induce human subcutaneous but not omental preadipocyte differentiation in vitro, correlating with the observation that treatment with rosiglitazone increases subcutaneous but not omental fat deposition in vivo.

In collaboration with S O'Rahilly and Incyte Genetics, we have identified heterozygous loss-of-function mutations in PPAR gamma in patients with severe insulin resistance, type 2 diabetes and early-onset hypertension. The mutant receptors inhibit the function of wild type PPAR gamma in a dominant negative manner and silence transcription via recruitment of corepressors. A tyrosine-based PPAR gamma agonist (farglitazar) reverses dominant negative inhibition and activates gene expression in patient blood mononuclear cells more effectively than rosiglitazone, suggesting that it may have greater therapeutic potential in these subjects. Resistin and adiponectin are PPAR gamma-related mediators derived from adipocytes which increase and reduce insulin resistance respectively. Resistin expression is low in patient and control adipose tissue, whereas circulating adiponectin levels are markedly lower in patients than controls, suggesting that the latter may contribute to insulin resistance.

Most recently, we have identified a frameshift/premature stop mutation in PPAR gamma in a third family. Together with a frameshift/stop mutation in a second gene which controls skeletal muscle glycogen synthesis, the compound genetic abnormalities segregate with severe insulin resistance, whereas heterozygosity for either gene defect alone is associated with normal insulin sensitivity.

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