Estrogen deprivation in primate pregnancy leads to insulin resistance in offspring

Abstract

This study tested the hypothesis that estrogen programs mechanisms within the primate fetus that promote insulin sensitivity and glucose homeostasis in offspring. Glucose tolerance tests were performed longitudinally in prepubertal offspring of baboons untreated or treated on days 100 to 165/175 of gestation (term is 184 days) with the aromatase inhibitor letrozole which decreased fetal estradiol levels by 95%. Basal plasma insulin levels were over 2-fold greater in offspring delivered to letrozole-treated than untreated animals. Moreover, the peak 1 min, average of the 1, 3 and 5 min, and area under the curve blood glucose and plasma insulin levels after an iv bolus of glucose were greater (P<0.05 and P<0.01, respectively) in offspring deprived of estrogen in utero than in untreated animals and partially or completely restored in letrozole plus estradiol-treated baboons. The value for the homeostasis model assessment of insulin resistance was 2.5-fold greater (P<0.02) and quantitative insulin sensitivity check index lower (P<0.01) in offspring of letrozole-treated versus untreated animals and returned to almost normal in letrozole plus estradiol-treated animals. The exaggerated rise in glucose and insulin levels after glucose challenge in baboon offspring deprived of estrogen in utero indicates that pancreatic beta cells had the capacity to secrete insulin, but that peripheral glucose uptake and/or metabolism were impaired, indicative of insulin resistance and glucose intolerance. We propose that estrogen normally programs mechanisms in utero within the developing primate fetus that lead to insulin sensitivity, normal glucose tolerance and the capacity to metabolize glucose after birth.

Insulin resistance elicited in postpubertal primate offspring deprived of estrogen in utero

“…An iv glucose tolerance test was performed essentially as described previously [1], according to the established method of Overkamp et al [18], sequentially (1–4 times) on each baboon offspring at 6–12 month intervals after onset of puberty between the ages of 4¼ (females)/5 (males) years and 8 years of age. Intravenous glucose tolerance test results in individual animals did not change between 4¼–8 years of age and thus the data obtained from the individual iv GTT performed was averaged to yield a single value for each animal.…”

“…basal fasting), 1, 3, 5, 10, 20, 40, 60 and 90 min before/after dextrose administration. Blood glucose levels were determined via an iStat Portable Clinical Analyzer (Model #210003, Abbott Labs, East Windsor, NJ) on 0.1 ml of blood and insulin determined in stored (−20 °C) plasma samples using a solid-phase chemiluminescent immunometric assay via an Immulite System (Siemens Healthcare Diagnostics, Tarrytown, NY) as described previously [1]. …”

“…Samples of skeletal muscle were homogenized on ice in phosphate-buffered saline containing 1 % cholic acid, 0.1 % SDS, 1 mM EDTA (Sigma-Aldrich, St Louis, MO) and a protease inhibitor cocktail, as described previously [1]. Briefly, samples (25–50 μg protein) were heated to 95° C in Laemmli buffer, cooled, centrifuged (800 × g), loaded onto 10 % SDS-polyacrylamide gels (PAGE) and electrophoresed using a Bio-Rad Mini-Protean electrophoresis chamber (Bio-Rad Laboratories, Richmond, CA) in 25 mM Tris (pH 8.3), 192 mM glycine and 0.1 % SDS.…”

“…prior to onset of puberty [1]. Thus, the rise in serum glucose and plasma insulin levels induced by intravenous glucose challenge was greater in prepubertal offspring delivered to baboon mothers treated with the aromatase inhibitor letrozole, than in animals exposed in utero to the normal elevation in estrogen.…”

Gonadotropin-releasing hormone receptor (Gnrhr) gene knock out: Normal growth and development of sensory, motor and spatial orientation behavior but altered metabolism in neonatal and prepubertal mice

“…Insulin resistance is implied by the high blood glucose in Gnrhr null pups; this suggests that a decrease in intracellular glucose and fat accumulation would occur in adipose tissue. It has been shown that estrogen deprivation in pregnancy leads to insulin resistance in a primate offspring; this may explain the phenomenon in the Gnrhr pups who are are born at an early stage of development and lack maternal or endogenous estradiol thereafter [64]. This could help to explain the connection between loss of estradiol and implied insulin resistance in young pups.…”