Effects of overexpression of human GLUT4 gene on maternal diabetes and fetal growth in spontaneous gestational diabetic C57BLKS/J Lepr(db/+) mice

During gestation, heterozygous C57BLKS/J-Lepr(db/+) mice develop spontaneou s gestational diabetes mellitus (GDM), and the newborn fetuses are macrosom ic compared with offspring from wild-type (+/+) mothers. To investigate the effects of the leptin receptor mutation on maternal metabolism and fetal g rowth during pregnancy, we studied +/+, db/+, and db/+ transgenic mice that overexpress the human GLUT4 gene two- to threefold (db/+TG6). During pregn ancy, fasting plasma glucose and hepatic glucose production were twofold gr eater in db/+ than +/+ mice, despite similar insulin levels. In skeletal mu scle, insulin-stimulated tyrosine phosphorylation was decreased in pregnant +/+ mice, and even more so in db/+ mice: insulin receptor beta (IR-beta), +/+ 34%, db/+ 57% decrease, P < 0.05; insulin receptor substrate 1 (IRS-1), +/+ 44%, db/+ 61% decrease, P < 0.05; and phosphoinositol (PI) 3-kinase (p 85 alpha), +/+ 33%, db/+ 65% decrease, P < 0.05. Overexpression of GLUT4 in db/+TG6 mice markedly improved glucose-stimulated insulin secretion, by 25 0%, and increased IR beta, IRS-1, and p85 alpha phosphorylation twofold, de spite no change in concentration of these proteins. Plasma leptin concentra tion increased 40-fold during pregnancy, from 2.2 +/- 0.5 to 92 +/- 11 ng/m l and 3.6 +/- 0.1 to 178 +/- 34 ng/ml in +/+ and db/+ mice, respectively (P < 0.01), but was increased to only 23 +/- 3 ng/ml in pregnant db/+TG6 mice (P < 0.001). Maternal fat mass and energy intake were greater in db/+ mice , and fat mass was reduced by GLUT4 overexpression, independent of food int ake. Fetal body weight was increased by 8.1 and 7.9% in db/+ and db/+TG6 mo thers, respectively (P < 0.05), regardless of fetal genotype, whereas fetus es from db/+TG8 mothers (four- to fivefold overexpression) weighed signific antly less compared with pups from +/+ or db/+ mothers (P < 0.05). These re sults suggest that the single mutant db allele effects susceptibility to GD M through abnormalities in insulin receptor signaling, defective insulin se cretion, and greater nutrient availability. GLUT4 overexpression markedly i mproves insulin-signaling in GDM, resulting in increased insulin secretion and improved glycemic control. However, maternal hyperglycemia appears not to be the sole cause of fetal macrosomia. These data suggest that GDM is as sociated with defects in insulin receptor signaling in maternal skeletal mu scle, and this may be an important factor provoking maternal and fetal peri natal complications.