Differential Effects of Short and Long Durations of Insulin-Induced Maternal Hypoglycemia upon Fetal Rat Tissue Growth and Glucose Utilization

Abstract

ABSTRACI'. We studied the effects of short and long durations of insulin-induced maternal hypoglycemia upon in vivo glucose utilization of several fetal tissues in the rat. Osmotic minipumps filled with insulin were implanted in pregnant rats on d 15 or 18 of gestation (term 21.5 d), and radiolabeled 2-deoxyglucose was used to measure relative glucose utilization rates (rCU) of fetal liver, lung, muscle, kidney, heart, placenta, and brain on d 20 of gestation after 2 or 5 d of hypoglycemia. Maternal plasma glucose concentrations decreased within 24 h of pump placement and remained less than controls throughout gestation. Fetal plasma glucose and insulin concentrations on d 20 were equally reduced after 2 and 5 d of hypoglycemia. Both 2 and 5 d of hypoglycemia were associated with significant reductions in the rCU of fetal liver, lung, and muscle. Reductions in fetal kidney rCU also occurred after 2 and 5 d of hypoglycemia but to a smaller degree. rGU of fetal heart was reduced after 2 d of hypoglycemia, but was normal after 5 d of hypoglycemia. Both 2 and 5 d of hypoglycemia were associated with increased rCU of fetal brain. Five d, but not 2 d of hypoglycemia resulted in decreased fetal weight on d 20 of gestation. However, at term, newborn pups delivered of hypoglycemic mothers weighed significantly less than controls regardless of the timing of minipump placement. Liver, lung, and carcass of these growth-retarded pups weighed less than control tissues, whereas kidney, heart, and brain weights were not affected. We speculate that fetal tissue growth and glucose utilization are influenced by common mechanisms and that glucose utilization may be an important determinant of fetal tissue growth. (Pediatr Res 32: 436-440, 1992) Abbreviations rCU, relative glucose utilization IUGR, intrauterine growth retardation 2DG, 2-deoxyglucose 2DG6P, 2-deoxyglucose-6-phosphate Pk, placental discrimination constant IUGR is a frequently occurring obstetrical problem associated with an increased incidence of perinatal mortality and morbidity. Limited metabolic fuel availability to the fetus is an important factor in the development of IUGR. Decreased availability of maternally derived glucose is responsible for diminished plasma glucose and insulin concentrations in growth-retarded human fetuses (l,2). Fetal hypoglycemia and hypoinsulinemia, in turn, are major factors retarding fetal growth; glucose is a primary fetal metabolic substrate and insulin is a key growth-stimulating hormone that has mitogenic and numerous anabolic effects.The effects of limited glucose availability upon fetal growth is apparently tissue-specific because IUGR often results in asymmetric fetal growth, i.e. limited somatic but normal brain growth. The mechanisms for this phenomenon are not completely understood. Whether glucose utilization of specific tissues reflects these differential growth patterns under conditions of limited glucose availability is not known and is the focus of this study.We previously studied the effects of maternal uterine arter...

Embryonic mortality and intrauterine growth retardation (IUGR) associated with placental alterations in pregnant rats treated with methyl methanesulfonate (MMS) at the peri-implantation stage

“…The glycogen store and GLUT1 expression remaining in the JZ of the placenta of MMS-treated rats at term may thus be the result of reduced glucose consumption by the placenta associated with the observed placental hypoplasia (especially of the JZ). Long-term insulin-induced maternal hypoglycemia results in growth retardation of both the fetus and placenta (Lueder et al, 1992;Carver and Hay, 1995). However, MMS had no effect on the plasma glucose level of dams throughout gestation in the present study.…”

“…Such factors of the maternal environment include nutrient restriction (Woodall et al, 1996;Rudge et al, 1999;Redmer et al, 2004;Wu et al, 2006), oxidative stress (Maranghi et al, 1998;Nash et al, 2005;Myatt, 2006;Burdon et al, 2007), anemia (Crowe et al, 1995), hypoxia (Robinson et al, 1979(Robinson et al, , 1985Owens et al, 1987aOwens et al, , 2007Lynch and Bruce, 1989;Myatt, 2006), and hypoglycemia (Robinson et al, 1979;Lueder et al, 1992;Carver and Hay, 1995;Owens et al, 1987bOwens et al, , 2007. Nutrient restriction affects the development of the blastocyst, its implantation, and the subsequent development of the placenta (Cross and Mickelson, 2006).…”

Effect of Acute Insulin-Induced Hypoglycemia on Fetal versus Adult Brain Fuel Utilization, Assessed by ¹³C MRS Isotopomer Analysis of [U-¹³C]Glucose Metabolites

“…Changes in cerebral glucose utilization rates and glucose transport have been observed only after 2-5 days of maternal hypoglycemia induced by a continuous insulin infusion into maternal circulation (using an insulin mini-pump) [12]. Since our experimental conditions were most similar to those of Bissonnette et al [13], we assumed that no changes in cerebral glucose transport or metabolic rate occurred during the short duration of our experiment.…”

“…The multiplet 13 C resonances are the result of superposition of doublets and singlets. The doublets arise from molecules containing two adjacent 13 C carbon atoms, and the singlets from molecules where the 13 C carbons are adjacent to 12 C. Singlet resonances also arise from natural abundance of 13 C (1.1%). Thus, the ratio of d/s at a specific carbon atom reflects either the double ( 13 C-13 C)-labeled molecules versus monolabeled ( 13 C-12 C) molecules or the 13 C enrichment of double-labeled ( 13 C-13 C) molecules when the singlet resonances arise only from natural abundance, 1.1%.…”

“…The effect of insulin-induced maternal hypoglycemia in late gestation on the fetal brain has also been studied, although the information available is scarce and inconclusive. In one report, both short-term and long-term hypoglycemia resulted in an increase in glucose utilization rate, although the mechanism for this remained speculative [12]. In another study, acute insulin-induced hypoglycemia did not result in any change in fetal cerebral metabolic rate or cerebral glucose uptake [13].…”