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.

A multiwalled carbon nanotube/dihydropyran composite film electrode for insulin detection in a microphysiometer chamber

“…Samples of the media outflow are collected throughout the experiment, every one to two minutes, and the insulin content is then determined to obtain a rate of insulin release. The number of islets used in perifusion experiments varies from 5 to as many as 50 [5][6][7][8][9]. In perifusion experiments, the concentration vs. time profile of secreted insulin can be compared to the expected glucose stimulated insulin response for healthy islets [10,11].…”

Hyperthyroidism impairs pancreatic beta cell adaptations to late pregnancy and maternal liporegulation in the rat

“…This is normally accompanied by a lowered glucose threshold for insulin secretion and increased insulin secretion at high glucose concentration [5,36,37], which compensates for the development of insulin resistance so that glucose tolerance is maintained. We found that hyperthyroidism during late gestation targeted both of these stable pancreatic beta cell adaptations to pregnancy.…”

“…Isolated islets were collected into HEPESbuffered Hanks' balanced salts solution containing 5% BSA. Insulin release was measured in a perifusion system, as described previously [5,33]. In this system, 50 islets were housed in small chambers on Millicell culture plate inserts (Sigma, Poole, Dorset, UK).…”

“…Inadequate compensatory hypersecretion of insulin to counter insulin resistance is critical to the pathology of type 2 diabetes [3]. Pregnancy is a progressive state of maternal insulin resistance [4][5][6] (reviewed in [7]), which in healthy pregnancies is accompanied by reciprocal increases in insulin secretion (see [5,8]). Gestational diabetes occurs in women who secrete insufficient insulin to compensate for lowered in-sulin sensitivity during the third trimester [9] (reviewed in [3]).…”

“…Despite maternal hyperinsulinaemia, pregnancy is also associated with hypertriacylglycerolaemia [16][17][18][19]. Insulin hypersecretion is reduced in concert with normalisation of maternal TAG levels by the administration of the fibrate WY14,643 in pregnancy [5]. Hyperthyroidism, which elicits adipocyte insulin resistance with regard to anti-lipolysis [20], can cause glucose intolerance in susceptible individuals [21] and has deleterious effects on pregnancy outcome [22].…”