INSULIN RECEPTOR (IR) DEVELOPMENT IN NORMAL (N) AND DIABETIC (D) PREGNANCIES: DOES INSULIN (I) UP REGULATE THE RECEPTOR?

Abstract

Offspring of D pregnancies have increased concentrations of IR on plasma membranes associated with differences in membrane lipid composition and physical structure. We have previously suggested that increased [I] occurring in human and animal offspring of D pregnancies caused up-regulation of IR. Since ambient [I] is the difference between its secretion by the pancreas and its degradation, we have studied these factors in rat fetuses from both N and D pregnancies. Twenty nine pregnant rats of timed gestation received either saline (N, n=13) or streptozotocin 60 mg/kg (D, n=16) on d 7 of pregnancy, and were sacrificed on d 21. Pooled fetal serum I levels were comparable (47 ± 8 vs. 34 ± 2μU/ml), whereas blood glucose levels were markedly elevated in offspring of D, (39 ± 13 vs. 321 ± 63 mg/dl, p < 0.001). Tracer I binding was also elevated on liver plasma membranes from D (5.3 ± 1.0 vs. 2.1 ± 0.3%/100μ g protein, p <0.02) due to increased high and low affinity receptors. I content of fetal pancreatic islets, quantitated by immunoperoxidase staining, was significantly lower in D offspring. I degradation was significantly higher in fetal liver homogenates from D offspring compared to N, (34 ± 1.7 vs. 26 ± 1.2% degradated/30 min/100μg protein, p<0.001).Conclusions: Elevation in IR concentrations on fetal liver membranes in D pregnancies appears to occur independently of I presented to the liver. The data support the concept that I degradation and IR regulation occur by separate pathways. A causal relationship between fetal hyperglycemia and/or hyperlipidemia and alterations of membrane structure increasing IR exposure cannot be excluded.