The function of the pancreatic β-cell is the storage and release of insulin, the main hormone involved in blood glucose homeostasis. The results in this article show that the widespread environmental contaminant bisphenol-A (BPA) imitates 17β-estradiol (E2) effects in vivo on blood glucose homeostasis through genomic and nongenomic pathways. The exposure of adult mice to a single low dose (10 μg/kg) of either E2 or BPA induces a rapid decrease in glycemia that correlates with a rise of plasma insulin. Longer exposures to E2 and BPA induce an increase in pancreatic β-cell insulin content in an estrogen-receptor–dependent manner. This effect is visible after 2 days of treatment and starting at doses as low as 10 μg/kg/day. After 4 days of treatment with either E2 or BPA, these mice developed chronic hyperinsulinemia, and their glucose and insulin tolerance tests were altered. These experiments unveil the link between environmental estrogens and insulin resistance. Therefore, either abnormal levels of endogenous estrogens or environmental estrogen exposure enhances the risk of developing type 2 diabetes mellitus, hypertension, and dyslipidemia.

The Estrogenic Effect of Bisphenol A Disrupts Pancreatic β-Cell Function In Vivo and Induces Insulin Resistance

Gonadal effects on food intake and adiposity: a metabolic hypothesis.

To elucidate the temporal profile of adaptive changes of the islets of Langerhans to the increased insulin demands of pregnancy, we have studied islet cell proliferation and insulin secretion during gestation in the rat. 5-Bromo-2'- deoxyuridine incorporation into dividing islet cells was signifi- cantly (P < 0.05) increased over age-matched controls by day 10, rose continuously to a peak at day 14, and then returned to control levels by day 18. By day 20, cell division was significantly inhibited (P < 0.05). The pattern of changes in insulin secretory profiles observed with perfused pancreata of pregnant animals was similar to that obtained for islet cell proliferation. Both the threshold of glucose-stimulated insulin secretion and the amount of above threshold insulin secretion began to diverge from con- trols by day 10. By day 12, the glucose-stimulation threshold was significantly decreased from 5.7 mM glucose to 3.3 mM (P < 0.05), remained at this low level through day 15, and returned toward normal by day 20. Concomitant with the increased sen- sitivity of B cells to glucose, the above threshold insulin secretion was significantly increased by day 12 (P < 0.05), peaked at day 15, and returned to control levels by day 20. This insulin secre- tory data demonstrates that the increased sensitivity of B cells to glucose is an important component of the adaptation of islets during pregnancy to the increased demand for insulin at phys- iological concentrations of plasma glucose. To correlate the above changes in islet cell proliferation and insulin secretion with levels of placental iactogen (PL), serum lactogenic hormone activity was measured by Nb2 lymphoma cell replication assays. This analysis revealed the expected bi- phasic pattern: a midpregnancy peak at day 12, followed by a nadir at day 14, and then continuously elevated levels until term. The bioassay data agreed with the known secretory profiles of rat (r) PL-I (midpregnancy) and rPL-II (late pregnancy). Our results provide the first systematic evaluation of changes in islet function during pregnancy in the rat. In addition, they provide evidence that rPL-I may be the critical hormonal signal which triggers the primary adaptive changes in islet function characteristic of pregnancy. The return to normal values of insulin secretion and inhibition of cell division observed at day 20 in the presence of high concentrations of rPL-II suggests that other inhibitory influences become dominant in the later stages of rat pregnancy. These observations suggest that complex in- teractions exist among lactogens and other pregnancy hormones in the regulation of islet function during late pregnancy. (En- docrinology 130: 1459-1466, 1992)

Adaptation of Islets of Langerhans to Pregnancy: Increased Islet Cell Proliferation

Pregnancy is associated with insulin resistance. We studied insulin binding and postbinding function in isolated adipocytes from pregnant and nonpregnant rats. We also used a primary culture system for female virgin rat adipocytes to assess the effects of gestational hormones in vitro on insulin binding and postbinding function. Insulin binding to adipocytes was normal during pregnancy, but [14C]3-O-methylglucose transport was reduced. When hCG or estradiol was added to the culture medium, no change in maximum [14C]3-O-methylglucose transport was found; however, maximum insulin binding was increased with estradiol. Progesterone and cortisol both decreased maximum insulin binding and [14C]3-O-methylglucose transport. PRL and placental lactogen decreased maximum [14C]3-O-methylglucose transport, but did not change insulin binding. When these hormones were added concurrently no change in insulin binding was found, but maximum [14C]3-O-methylglucose transport was reduced. We conclude that the insulin resistance of pregnancy is associated with a postbinding defect in insulin action. Estradiol increased insulin receptor binding, but during pregnancy this effect may be offset by the reduction in insulin binding induced by progesterone and cortisol. The postbinding defect in insulin action during pregnancy is probably related to increasing amounts of progesterone, cortisol, PRL, and placental lactogen.

Role of Gestational Hormones in the Induction of Insulin Resistance

During pregnancy, the mother must adapt her body systems to support nutrient and oxygen supply for growth of the baby in utero and during the subsequent lactation. These include changes in the cardiovascular, pulmonary, immune and metabolic systems of the mother. Failure to appropriately adjust maternal physiology to the pregnant state may result in pregnancy complications, including gestational diabetes and abnormal birth weight, which can further lead to a range of medically significant complications for the mother and baby. The placenta, which forms the functional interface separating the maternal and fetal circulations, is important for mediating adaptations in maternal physiology. It secretes a plethora of hormones into the maternal circulation which modulate her physiology and transfers the oxygen and nutrients available to the fetus for growth. Among these placental hormones, the prolactin-growth hormone family, steroids and neuropeptides play critical roles in driving maternal physiological adaptations during pregnancy. This review examines the changes that occur in maternal physiology in response to pregnancy and the significance of placental hormone production in mediating such changes.

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The Role of Placental Hormones in Mediating Maternal Adaptations to Support Pregnancy and Lactation

A B S T R A C T Influences of estrogen and progesterone on the development of hyperinsulinemia and augmented pancreatic islet insulin secretion during pregnancy were assessed in this study. Groups of female rats were injected subcutaneously for 21 days with varying daily dosages of estradiol benzoate or progesterone in oil. On day 21, pancreatic islets were isolated by a collagenase method. Total insulin secretion was measured after 90min incubations of 10 islets in buffered medium containing glucose. Higher physiologic dosages of estradiol or progesterone, singly or in combination, significantly increased islet secretion above values of untreated control rats and were comparable to augmented islet responses of term, 3-wk pregnant rats. Diameter and protein content of islets obtained from steroid-treated and pregnant rats exceeded control measurements in these instances. However, 2-hr preincubations of control islets with 1 or 10 /g/ml of either steroid did not influence subsequent glucose-stimulated insulin output. In related studies, plasma insulin responses during 30 min intravenous glucose tolerance tests were significantly above control responses in term-pregnant rats and animals receiving comparable dosages of steroids for 3 wk. Unlike pregnancy or progesterone treatment, estradiol administration alone or with progesterone significantly lowered postchallenge plasma glucose concentrations.

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R. K. Kalkhoff

Papers

Relative Effects of Pregnancy, Estradiol, and Progesterone on Plasma Insulin and Pancreatic