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Peroxisome Proliferator–Activated Receptor- and Glucocorticoids Interactively Regulate Insulin Secretion During Pregnancy

From the Centre for Diabetes and Metabolic Medicine, Institute of Cell and Molecular Science, St. Bartholomew’s and the Royal London School of Medicine and Dentistry, Queen Mary, University of London, London, U.K

Address correspondence and reprint requests to Professor Mary C. Sugden, Centre for Diabetes and Metabolic Medicine, Institute of Cell and Molecular Science, 4 Newark St., Whitechapel, London E1 2AT, U.K. E-mail: m.c.sugden{at}qmul.ac.uk

Abbreviations: GSIS, glucose-stimulated insulin secretion; I, incremental plasma insulin values integrated over the period of increased glucose; PDK, pyruvate dehydrogenase kinase; PPAR, peroxisome proliferator-activated receptor

We evaluated the impact of peroxisome proliferator–activated receptor (PPAR) activation and dexamethasone treatment on islet adaptations to the distinct metabolic challenges of fasting and pregnancy, situations where lipid handling is modified to conserve glucose. PPAR activation (24 h) in vivo did not affect glucose-stimulated insulin secretion (GSIS) in nonpregnant female rats in the fasted state, although fasting suppressed GSIS. Dexamethasone treatment (5 days) of nonpregnant rats lowered the glucose threshold and augmented GSIS at high glucose; the former effect was selectively opposed by PPAR activation. Pregnancy-induced changes in GSIS were opposed by PPAR activation at day 19 of pregnancy. Dexamethasone treatment from day 14 to 19 of pregnancy did not modify the GSIS profile of perifused islets from 19-day pregnant rats but rendered the islet GSIS profile refractory to PPAR activation. During sustained hyperglycemia in vivo, dexamethasone treatment augmented GSIS in nonpregnant rats but limited further modification of GSIS by pregnancy. We propose that the effect of PPAR activation to oppose lowering of the glucose threshold for GSIS by glucocorticoids is important as part of the fasting adaptation, and modulation of the islet GSIS profile by glucocorticoids toward term facilitates the transition of maternal islet function from the metabolic demands of pregnancy to those imposed after parturition.

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