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.