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

Abstract

One of the hallmarks of the hyperglycemic-hyperinsulinemic infant of the diabetic mother (IDM) is macrosomia and selective organomegaly. Primary hyperinsulinemia, with insulin levels similar to those observed in human IDMs at delivery, was produced in the fetal rhesus monkey during the last third of gestation. The effects of this physiologically relevant hyperinsulinemia, in the absence of hyperglycemia, on fetal growth were studied. Fetal macrosomia, with a 23% increase in total body weight, was observed in physiologically hyperinsulinemic fetuses. A similar 27% increase in weight was produced by fetal insulin levels that were 10 times higher. A logarithmic correlation was observed between fetal birth weight ratio and fetal plasma insulin concentration. In contrast to this increase in weight, skeletal growth, as measured by crown-heel length and head circumference, was not affected by hyperinsulinemia. Only cardiomegaly was found in the low-dose hyperinsulinemic fetuses, whereas cardiomegaly, hepatomegaly, and splenomegaly were produced by hyperinsulinemia in which insulin levels were in the highest range. Compositional analysis of heart and skeletal muscle indicated no differences in the protein, RNA and DNA concentration, or in the protein-to-DNA ratio in hyperinsulinemic fetuses. We interpret these data as indicating that fetal insulin plays the predominant role in controlling the normal, as well as the augmented, fetal weight characteristic of the human infant of the diabetic mother.

Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study

“…Pedersen documented increased body weight in infants of diabetic mothers compared with control subjects. Fetal hyperinsulinemia, in the absence of maternal diabetes, has been demonstrated to cause "diabetes-like" fetopathy in rhesus monkey offspring (4). At least some of the increased fetal weight has been shown to be attributable to increased fat accretion (5).…”

Effects of intravenous insulin-like growth factor-I and insulin administration on insulin-like growth factor-binding proteins in the ovine fetus

“…Insulin has long been considered an important fetal metabolic hormone (Susa et al 1984), and several extensive studies of insulin regulation of fetal glucose and protein metabolism have been performed (Hay & Meznarich 1986, Liechty et al 1992. In addition, insulin-like growth factor (IGF)-I and IGF-II are potent metabolic, mitogenic and differentiative factors, and considered to be important regulators of fetal growth (D'Ercole 1991, Iwamoto et al 1992, Liechty et al 1996.…”

Differences in umbilical cord insulin and birth weight in non-diabetic pregnancies of women from different ethnic groups in New Zealand

“…Although the ethnic differences in insulin disappeared on adjusting for birth weight, this cross sectional design cannot be used to assess whether the low insulin or the low birth weight came first. However, as insulin stimulates growth [19] it is possible that the babies were small because of their lower insulin concentration.…”