Chronic Hyperinsulinemia in the Fetal Rhesus Monkey: Effects on Fetal Growth and Composition

Abstract

The delivery of 19 U of insulin a day for 21 days to the rhesus monkey fetus, coupled with the permeability properties of the placenta, has made it possible to produce fetal hyperinsulinemia in the presence of euglycemia. Fetal plasma insulin concentrations of 3525 /All/ml were attained with no apparent effects on the mother. In fetal macrosomia, a 34% increase in body weight was observed above the expected weight for gestational age (466 vs. 348 g). Relative organomegaly, matched for gestational age of fetal weight, was seen in the hyperinsulinemic fetuses with enlarged livers, placentas, hearts, and spleens. Liver composition in the fetuses was only slightly affected by hyperinsulinemia. Glycogen concentration was elevated, but not sufficiently, to explain the relative hepatomegaly produced. The lipid, protein, DNA, and RNA concentrations were not affected by hyperinsulinemia. Based on the similar DNA concentrations and protein/DNA ratios observed in hyperinsulinemic and control groups, the hepatomegaly appears to be the result of insulin-stimulated hyperplasia and not of hypertrophy. In the presence of normal plasma concentrations of growth substrates, insulin in the subhuman fetus has been shown to be a growth-promoting hormone that has specific growth-stimulating effects. DIABETES 28:1058-1063, December 1979. experimental and clinical data implicate insulin as having a specific growth-promoting influence in the mammalian fetus. Pedersen formulated the hyperglycemia-hyperinsulinism hypothesis in 1954 to explain the characteristic features of infants of diabetic mothers. 1 This hypothesis, simply stated, is that maternal hyperglycemia results in fetal hyperglycemia and, as a result, in hypertrophy of fetal islet tissue with insulin hypersecretion and, hence, greater fetal utilization of glucose and amino acids and enhanced fetal growth. The evidence available to support this hypothesis has been most recently re-reviewed by Pedersen. 2 Other clinical examples of pathology associated with excessive fetal growth and fetal hyperinsulinism are the Beckwith-Wiedeman syndrome, infant giants or fetopathia diabetica, and yQ-cell hyperplasia, adenoma, and nesidioblastosis. In contrast, fetal growth retardation and insulinopenia are associated with transient neonatal diabetes mellitus and pancreatic agenesis. 3 Direct experimental evidence that insulin promotes growth in the mammalian fetus has been difficult to obtain. Significantly larger rat fetuses have been produced by the daily subcutaneous (s.c.) injection of 0.2 U insulin to near term fetuses. 4 Aside from this highly stressed fetal rat model, all other animal models have attempted to produce fetal hyperinsulinism as the consequence of experimentally induced maternal diabetes.Maternal diabetes has been successfully produced by streptozotocin in the rhesus {Macaca mulatta) monkey. 5 " 7 The infants of these diabetic monkeys have been macrosomic and have exhibited the selective organomegaly characteristic of infants of diabetic mothers. 7 The fetuses have been docu...

Reduced Plasma Somatomedin Activity and Costal Cartilage Sulfate Incorporation Activity during Experimental Growth Retardation in the Fetal Rat

“…Insulin had no direct action at physiological concentrations on the uptake of either ['Hlthymidine or ["S]sulfate by fetal rat costal cartilage in vitro (2,18). The administration of pharmacological concentrations of insulin to the fetal rat and monkey led to enhanced body growth (29,30), but this may have been mediated by an increase in circulating somatomedin since somatomedin activity was enhanced in the fetal rabbit and pig following treatment with insulin in utero (3 1, 32). In the postnatal rat, insulin was shown to stimulate somatomedin production directly from liver during perfusion and tissue slice incubation (33,34).…”

“…Group 1. The mean gestational age was 33.5 wk (range, [28][29][30][31][32][33][34][35][36]. The mean birth weight was 2244 g (range, 12 .…”

Insulin as a Growth Factor

“…(120) implanted osmotic minipumps containing insulin into monkey fetuses. Three weeks of pharmacological hyperinsulinemia resulted in a 34% increase in fetal body weight associated with enlargement of the heart.…”

Does being an infant of Gestational Diabetic Mother Affect Cerebellar Size?

“…Glukoz, beyin için primer metabolittir ve insülinin ise büyümeyi arttırıcı etkisi bilinmektedir 13 . Diyabetik rhesus maymunlarla yapıl-mış çalışmalarda, iç organlar, yağ dokusu ve tüm vü-cut ağırlığında önemli ölçüde artış saptanırken, beyin ağırlığında değişiklik saptanmamıştır 19,20 .…”