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Am J Physiol Endocrinol Metab 295: E1380-E1389, 2008. First published October 14, 2008; doi:10.1152/ajpendo.90700.2008
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PPAR{alpha} activation and increased dietary lipid oppose thyroid hormone signaling and rescue impaired glucose-stimulated insulin secretion in hyperthyroidism

Mark J. Holness, Gemma K. Greenwood, Nicholas D. Smith, and Mary C. Sugden

Centre for Diabetes and Metabolic Medicine, Institute of Cell and Molecular Science, St. Bartholomew's and Royal London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom

Submitted 18 August 2008 ; accepted in final form 9 October 2008

The aim of the study was to investigate the impact of hyperthyroidism on the characteristics of the islet insulin secretory response to glucose, particularly the consequences of competition between thyroid hormone and peroxisome proliferator-activated receptor (PPAR){alpha} in the regulation of islet adaptations to starvation and dietary lipid-induced insulin resistance. Rats maintained on standard (low-fat/high-carbohydrate) diet or high-fat/low-carbohydrate diet were rendered hyperthyroid (HT) by triiodothyronine (T3) administration (1 mg·kg body wt–1·day–1 sc, 3 days). The PPAR{alpha} agonist WY14643 (50 mg/kg body wt ip) was administered 24 h before sampling. Glucose-stimulated insulin secretion (GSIS) was assessed during hyperglycemic clamps or after acute glucose bolus injection in vivo and with step-up and step-down islet perifusions. Hyperthyroidism decreased the glucose responsiveness of GSIS, precluding sufficient enhancement of insulin secretion for the degree of insulin resistance, in rats fed either standard diet or high-fat diet. Hyperthyroidism partially opposed the starvation-induced increase in the glucose threshold for GSIS and decrease in glucose responsiveness. WY14643 administration restored glucose tolerance by enhancing GSIS in fed HT rats and relieved the impact of hyperthyroidism to partially oppose islet starvation adaptations. Competition between thyroid hormone receptor (TR) and PPAR{alpha} influences the characteristics of GSIS, such that hyperthyroidism impairs GSIS while PPAR{alpha} activation (and increased dietary lipid) opposes TR signaling and restores GSIS in the fed hyperthyroid state. Increased islet PPAR{alpha} signaling and decreased TR signaling during starvation facilitates appropriate modification of islet function.

islet function; thyroid hormone action; peroxisome proliferator-activated receptor-{alpha}; fasting; fat feeding


Address for reprint requests and other correspondence: M. J. Holness, Centre for Diabetes and Metabolic Medicine, Inst. of Cell and Molecular Science, 4 Newark St., Whitechapel, London E1 2AT, UK (e-mail: m.j.holness{at}qmul.ac.uk)






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