Effect of Spontaneous Gestational Diabetes on Fetal and Postnatal Hepatic Insulin Resistance in Leprdb/+ Mice

Abstract

Infant macrosomia is a classic feature of a gestational diabetes mellitus (GDM) pregnancy and is associated with increased risk of adult obesity and type II diabetes mellitus, however mechanisms linking GDM and later disease remain poorly understood. The heterozygous leptin receptor-deficient (Lepr db/ϩ ) mouse develops spontaneous GDM and the fetuses display characteristics similar to infants of GDM mothers. We examined the effects of GDM on maternal insulin resistance, fetal growth, and postnatal development of hepatic insulin resistance. Fetal body weight on d 18 of gestation was 6.5% greater (p Ͻ 0.05) in pups from ad libitum-fed db/ϩ mothers compared with wild-type (WT) controls. Pair-feeding db/ϩ mothers to the intake of WT mothers normalized fetal weight despite less than normal maternal insulin sensitivity. More stringent caloric restriction reduced insulin and glucose levels below WT controls and resulted in fetal intrauterine growth restriction. The level of hepatic insulin receptor protein was decreased by 28% to 31% in both intrauterine growth restriction and fetuses from ad libitum-fed GDM mothers compared with offspring from WT mothers. In 24-wkold adult offspring from GDM mothers, body weight was similar to WT offspring, however, the females from GDM mothers were fatter and hyperinsulinemic compared with offspring from WT mothers. Insulin-stimulated phosphorylation of Akt, a key intermediate in insulin signaling, was severely decreased in the livers of adult GDM offspring. Hepatic glucose-6-phosphatase activity was also inappropriately increased in the adult offspring from GDM mothers. These results suggest that spontaneous GDM in the pregnant Lepr db/ϩ mouse is triggered by overfeeding, and this effect results in obesity and insulin resistance in the livers of the adult offspring. The specific decrease in Akt phosphorylation in livers of adult offspring suggests that this may be a mechanism for reduced insulin-dependent physiologic events, such as suppression of hepatic glucose production, a defect associated with susceptibility to type II diabetes mellitus. Abbreviations GDM, gestational diabetes mellitus IGT, impaired glucose tolerance Lepr db/؉ , leptin receptor deficient WT, wild-type IUGR, intrauterine growth retardation IR-␣, insulin receptor ␣ IRS-1, insulin receptor substrate-1 GLUT, glucose transporter PI 3-kinase, phosphotidylinositol-3-kinase Akt (c-PkB), related to A kinase, protein kinase B G-6-Pase, glucose-6-phosphatase HGP, hepatic glucose production Fetal growth and development are primarily determined by the fetal genome, however, the genetic regulation of fetal growth is influenced by different maternal factors, which can exert a stimulatory or an inhibitory effect. Epidemiologic studies have revealed strong statistical links between nutritional experiences during pregnancy and later development of diseases such as obesity and type II diabetes in adulthood (1, 2). Most convincing are the studies in Pima Indians demonstrating that, besides a genetic transmission of diabetes, the...

Diet-Induced Obesity in Female Mice Leads to Offspring Hyperphagia, Adiposity, Hypertension, and Insulin Resistance

“…However, not all of these report an increase in offspring fat mass 25 and the fatty acid composition of the fat enriched diet appears critical, with excessive maternal saturated fat intake being key. 16,18 An influence of maternal obesity per se has been suggested by recent studies of Yamashita et al 26 and Lambin et al, 10 which have shown increased fat mass in adult wild-type progeny of obese and insulin resistant heterozygous leptin receptor-deficient (Lepr db/ϩ ) mice. Complex interactions between dietary and obesity related metabolic sequelae are therefore likely to set in train events leading to offspring obesity.…”

Established diet-induced obesity in female rats leads to offspring hyperphagia, adiposity and insulin resistance

“…A direct effect of maternal obesity as such on the development of key features of metabolic syndrome in offspring has been suggested by studies in transgenic animals; adult wild-type progeny of obese and insulin-resistant heterozygous leptin receptor-deficient (Lepr db/+ ) mice showed an increase of fat mass [32,33]. Using an identical diet to that of the present study, we have also recently shown a similar increase in fat mass in the offspring of obese mice, proving commonality of this model in different rodent species [34].…”

“…Ideally, plasma analytes should have been assessed on the same day rather than over a 2 day period (days 10-11), but this is unlikely to have had a major influence on data interpretation. Moreover, adult offspring from a murine model of gestational diabetes (heterozygous C57BL/KsJLepr db/+ ) [32] and from a rat model of diabetes induced by streptozotocin [42] showed hyperphagia, increased adiposity and alterations of the glucose homeostasis.…”

Effect of intrauterine growth retardation on liver and long-term metabolic risk

“…73 Finally, in heterozygous leptin receptor-deficient mice, the exposure to maternal gestational diabetes mellitus induces hepatic insulin resistance in the adult offspring. 74,75 Humans In humans, the impairment of growth during fetal and early postnatal life has been associated with increased plasma concentrations of fibrinogen and factor VII in adulthood. 76 The high plasma concentrations of the two hemostatic factors may predispose to thrombosis and increase the risk of CVD.…”