Maternal diabetes does not alter postnatal development of the hepatic glucagon receptor-adenylate cyclase system in the rat.

Abstract

Summary: We examined the postnatal maturation of the glucagon receptor-adenylate cyclase system of liver plasma membrane from rats born to normal or streptozotocin-induced diabetic mothers and compared results to those of nonpregnant adult. Diabetes in mothers was confirmed by hyperglycemia (458 ± 41 versus 128 ± 13 mg/dl; mean ± S.E.) and relative hypoinsulinemia (4.3 ± 1.0 versus 7.4 ± 1.0 ng/ml) when compared to controls. Pups born to diabetic mothers (IDM) were hyperglycemic (59 ± 6 versus 23 ± 5 mg/dl) but not significantly hyperinsulinemic (4.3 ± 0.5 versus 3.5 ± 0.6 ng/ml) when compared to control pups on day 1; by day 7 and on day 21 glucose and insulin were similar in IDM and control pups. Binding of [125I]-glucagon to liver plasma membrane was markedly reduced in both IDM and control newborns corresponding to 20, 25, and 30% of normal adult values on days 1, 7, and 21 of life. Resolution of the curvilinear Scatchard plots of binding data by the two-site model (high affinity-low capacity; low affinity-high capacity) revealed a progressive increase in receptor number (X 1011/mg protein) of the high affinity sites from 0.9 on day 1 to 1.7 on day 7 and 2.2 on day 21; normal adult was 6.1. Neither the affinity constants of the high or low affinity components, nor the number of low affinity sites differed substantially between adult or newborns at any postnatal age. Basal cAMP production (pM/mg protein/10 min) was similar in adult and newborn. But cAMP production in response to 10–9 to 10–6 M glucagon was always greater in adult than newborn until day 21. Whereas adult liver plasma membrane increased cAMP production with 10–9 M glucagon, the minimum concentration of glucagon capable of consistently and significantly increasing cAMP in newborn on day 1 and 7 was 10–7 M. cAMP production above basal in response to glucagon correlated with glucagon binding and with the number of high affinity glucagon receptors. Adequacy of neonatal liver adenylate cyclase activity was demonstrated by the equivalent responses in cAMP in adult or newborn at any ages after stimulation with 15 mM sodium fluoride; thus, the reduction in number of glucagon receptors in the newborn was specifically responsible for decreased cAMP production after glucagon stimulation. No difference in this pattern of postnatal maturation of glucagon receptors-cAMP production was apparent in liver plasma membrane from controls or IDM pups.