Insulin-Receptor Development in Normal and Diabetic Pregnancies: Role of Membrane Fluidity

In the hyperinsulinemic offspring of the diabetic mother, both significant macrosomia and postnatal hypoglycemia are thought to be due to increased insulin sensitivity. The purpose of this study is to characterize changes in insulin-receptor development in fetal offspring of an experimental model of diabetic pregnancy. Two groups of Sprague-Dawley female rats were studied after timed mating. Both groups received injections of either vehicle (controls) or streptozocin (diabetic), 40 mg/100 g body wt, on day 7 of pregnancy and were killed at either 17, 20, or 21 days of gestation. Maternal and fetal blood were assayed for glucose and insulin, and fetal liver membranes were prepared for 125I-labeled insulin binding, lipid composition, and fluorescence polarization studies with the probe 1,6-diphenyl-1,3,5-hexatriene (DPH). Maternal and pooled fetal glucose levels were elevated in streptozocin-treated rats; however, pooled fetal insulin values were not elevated in the offspring of diabetic animals compared with controls (33 ± 1 vs. 50 ± 5 μU/ml). 125I-insulin binding was greater in fetal offspring of diabetic (FO) rat membranes at each gestational age studied [P < .001 by analysis of variance (ANOVA)] due to significantly greater numbers of both high- and low-affinity receptors. The highest insulinbinding capacity was seen on membranes obtained from FD rats at day 21 (9.92 M · L1 · 100 μg membranes1 vs. 6.38 M · L1 · 100 μg protein1 in fetal control (FC) rats. At each gestational age, membranes from FDs had lower values for fluorescence polarization (using the probe DPH) than did gestational-age-matched controls. These values suggest that membrane fluidity was lower in membranes from the FD group. Lipid analyses of plasma membranes showed significantly higher levels of phospholipid-to-protein ratios in samples from 20- and 21-day FD rats than in matched controls (0.297 ± 0.032 and 0.0547 ± 0.116 vs. 0.193 ± 0.001 and 0.261 ± 0.016, P < .05 by ANOVA). Significant correlations existed between insulin tracer binding and fluorescence polarization (FP) (r = −.82, P < .05) and between insulin-binding capacity and flow activation energy, a measurement derived from FP data obtained over a range of temperatures (r = − .95, P < .005). In summary, experimental diabetic pregnancy was associated with increased expression of insulin receptors on hepatic plasma membranes. This could be correlated with certain physical properties of the membrane related to lipid content and composition. The data did not exclude the possibility that other factors such as different rates of receptor synthesis and/or degradation could be operative in fetal development in diabetic pregnancy.