Effects of overexpression of human GLUT4 gene on maternal diabetes and fetal growth in spontaneous gestational diabetic C57BLKS/J Lepr(db/+) mice
Effects of overexpression of human GLUT4 gene on maternal diabetes and fetal growth in spontaneous gestational diabetic C57BLKS/J Lepr(db/+) mice. T Ishizuka , P Klepcyk , S Liu , L Panko , S Liu , E M Gibbs and J E Friedman Department of Nutrition, Case Western Reserve University School of Medicine...
Saved in:
Published in | Diabetes (New York, N.Y.) Vol. 48; no. 5; pp. 1061 - 1069 |
---|---|
Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Diabetes Association
01.05.1999
|
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | Effects of overexpression of human GLUT4 gene on maternal diabetes and fetal growth in spontaneous gestational diabetic C57BLKS/J
Lepr(db/+) mice.
T Ishizuka ,
P Klepcyk ,
S Liu ,
L Panko ,
S Liu ,
E M Gibbs and
J E Friedman
Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4935, USA.
Abstract
During gestation, heterozygous C57BLKS/J-Lepr(db/+) mice develop spontaneous gestational diabetes mellitus (GDM), and the
newborn fetuses are macrosomic compared with offspring from wild-type (+/+) mothers. To investigate the effects of the leptin
receptor mutation on maternal metabolism and fetal growth during pregnancy, we studied +/+, db/+, and db/+ transgenic mice
that overexpress the human GLUT4 gene two- to three-fold (db/+TG6). During pregnancy, fasting plasma glucose and hepatic glucose
production were twofold greater in db/+ than +/+ mice, despite similar insulin levels. In skeletal muscle, 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 (p85alpha), +/+ 33%, db/+ 65% decrease, P<0.05. Overexpression of GLUT4 in db/+TG6 mice markedly improved glucose-stimulated
insulin secretion, by 250%, and increased IRbeta, IRS-1, and p85alpha phosphorylation twofold, despite no change in concentration
of these proteins. Plasma leptin concentration increased 40-fold during pregnancy, from 2.2+/-0.5 to 92+/-11 ng/ml 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 intake. Fetal body weight was increased by 8.1 and 7.9% in db/+ and db/+TG6 mothers, respectively (P<0.05),
regardless of fetal genotype, whereas fetuses from db/+TG8 mothers (four- to fivefold overexpression) weighed significantly
less compared with pups from +/+ or db/+ mothers (P<0.05). These results suggest that the single mutant db allele effects
susceptibility to GDM through abnormalities in insulin receptor signaling, defective insulin secretion, and greater nutrient
availability. GLUT4 overexpression markedly improves 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 associated with defects in insulin receptor signaling in maternal skeletal muscle, and this may be an
important factor provoking maternal and fetal perinatal complications. |
---|---|
Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0012-1797 1939-327X |
DOI: | 10.2337/diabetes.48.5.1061 |