Endocrine Abstracts (2002) 3 OC33

The role of the PPAR gamma in thyroid eye disease: Possible contra-indication for thiazolidenedione therapy

KJ Starkey1, AE Heufelder2, LM Evans1, JS Davies1, G Baker1 & M Ludgate1

1Department of Medicine, UWCM, Cardiff, UK; 2Endocrinology & Molecular Medicine, Munich, Germany.

A male patient treated with a thiazolidenedione (TZD) PPAR gamma agonist for Type 2 diabetes had a dramatic worsening of his thyroid eye disease (TED), which had been stable and inactive for more then two years. Expansion of the orbital fat seemed to be the underlying cause and we have investigated the effects of a PPAR gamma agonist (and subsequently an antagonist) on the adipogenesis of preadipocytes from 10 different patients, representing several fat depots, including TED orbits.

The percentage of differentiating cells, assessed by oil red O staining, morphological changes and PPAR gamma transcript expression levels, was determined for preadipocytes in a hormone induced model of adipogenesis supplemented or not with PPAR gamma agonist or antagonist.

Adipogenesis was induced in 1 to 25% of the preadipocytes in the un-modified protocol, with male fat samples having the highest levels. The PPAR gamma agonist resulted in a 2 to 10 fold increase and a PPAR gamma antagonist produced a 2 to 7 fold reduction in adipogenesis in the hormone induced model. The effects of the PPAR gamma agonist and antagonist were dose dependent and maximal at 10uM but displayed no correlation with the fat depot analysed or the age/gender of the patient providing the sample.

We suggest that care should be exercised when selecting patients for treatment with PPAR gamma agonists such as TZD and that they may be contra-indicated in individuals with a previous or family history of autoimmune thyroid or eye diseases. Our work also suggests that PPAR gamma antagonists could provide a novel and effective therapy for TED patients in the active stage of disease.

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