Peroxisome Proliferator-Activated Receptor-α Activation during Pregnancy Attenuates Glucose-Stimulated Insulin Hypersecretion in Vivo by Increasing Insulin Sensitivity, without Impairing Pregnancy-Induced Increases in β-Cell Glucose Sensing and Responsiveness

Abstract

We investigated the effects of acute (24-h) peroxisome proliferator-activated receptor (PPAR)alpha activation by WY14,643 (pirinixic acid) treatment on glucose-stimulated insulin secretion (GSIS) during pregnancy, in the rat, in relation to insulin sensitivity. GSIS after iv glucose challenge (500 mg/kg) was increased at d 15 of pregnancy but was attenuated by WY14,643 treatment in vivo, with decreases in acute insulin response (51%; P < 0.001) and total suprabasal 30-min area under the insulin curve (deltaI) (55%; P < 0.001). GSIS was unaffected by WY14,643 treatment in unmated rats. Islet perifusions were employed to identify persistent effects of PPARalpha activation. GSIS was enhanced, and the glucose threshold was reduced in perifused islets from pregnant rats, but WY14,643 treatment failed to reverse these effects. WY14,643 treatment of 15-d-pregnant rats significantly lowered (by 63%; P < 0.01) the insulin resistance index [total suprabasal 30-min area under insulin curve x suprabasal 30-min area under glucose curve (deltaI x deltaG)]. A strong positive linear relationship (r = 0.92) between acute insulin response and deltaI x deltaG was evident between groups. Our studies show that acute PPARalpha activation reverses the augmented GSIS evoked by pregnancy in vivo, whereas the isolated islets retain pregnancy-induced enhancement of beta-cell glucose sensing and responsiveness. Normalization of maternal GSIS to that found in the nonpregnant state is observed in association with alleviation of maternal insulin resistance.