Testosterone is protective against impaired glucose metabolism in male intrauterine growth-restricted offspring

Abstract

Placental insufficiency alters the intrauterine environment leading to increased risk for chronic disease including impaired glucose metabolism in low birth weight infants. Using a rat model of low birth weight, we previously reported that placental insufficiency induces a significant increase in circulating testosterone in male intrauterine growth-restricted offspring (mIUGR) in early adulthood that is lost by 12 months of age. Numerous studies indicate testosterone has a positive effect on glucose metabolism in men. Female growth-restricted littermates exhibit glucose intolerance at 6 months of age. Thus, the aim of this paper was to determine whether mIUGR develop impaired glucose metabolism, and whether a decrease in elevated testosterone levels plays a role in its onset. Male growth-restricted offspring were studied at 6 and 12 months of age. No impairment in glucose tolerance was observed at 6 months of age when mIUGR exhibited a 2-fold higher testosterone level compared to age-matched control. Fasting blood glucose was significantly higher and glucose tolerance was impaired with a significant decrease in circulating testosterone in mIUGR at 12 compared with 6 months of age. Castration did not additionally impair fasting blood glucose or glucose tolerance in mIUGR at 12 months of age, but fasting blood glucose was significantly elevated in castrated controls. Restoration of elevated testosterone levels significantly reduced fasting blood glucose and improved glucose tolerance in mIUGR. Thus, our findings suggest that the endogenous increase in circulating testosterone in mIUGR is protective against impaired glucose homeostasis.

Male and Female Intrauterine Growth-Restricted Offspring Differ in Blood Pressure, Renal Function, and Glucose Homeostasis Responses to a Postnatal Diet High in Fat and Sugar

“…As previously reported, fasting blood glucose concentration at 6 months of age did not differ in offspring on regular chow 32,33 ; no differences were observed in offspring exposed to the HFHS diet (Fig 4a , 4b). When challenged with an oral glucose load in the fasted state, only male HFHS control exhibited an impaired glucose tolerance response (Fig 4c…”

“…29 BP remains elevated in male 30 but not female offspring by 6 months of age 31 whereas only female offspring exhibit glucose intolerance at 6 months of age. 32,33 . Therefore, this study tested the hypothesis that poor fetal growth induced by placental insufficiency followed by chronic exposure to a postnatal diet rich in fat and a sugar-sweetened beverage would cause a greater increase in adiposity and fat mass in IUGR offspring exacerbating the developmental programming of increased blood pressure, impaired renal function and metabolic risk established by IUGR.…”

Developmental origins of nonalcoholic fatty liver disease as a risk factor for exaggerated metabolic and cardiovascular-renal disease

“…Fasting hyperglycemia is also detected in male and female IUGR offspring from RUPP rats (93,94). Under standard chow conditions, by 12 mo of age, male IUGR offspring from RUPP dams have an increased area under the curve to glucose tolerance testing without a significant change in insulin secretion in response to a fasting blood glucose challenge (94). Interestingly, these male IUGR offspring had increased fasting glucose (Fig.…”

“…Prevention of reductions in ␤-cell vascularity and islet number and increased inflammation by treatment in early life with IL-4-neutralizing antibodies reduced T-helper 2 lymphocytes and macrophages and abolished fasting hyperglycemia, but assessments of hepatic insulin signaling were not reported. Fasting hyperglycemia is also detected in male and female IUGR offspring from RUPP rats (93,94). Under standard chow conditions, by 12 mo of age, male IUGR offspring from RUPP dams have an increased area under the curve to glucose tolerance testing without a significant change in insulin secretion in response to a fasting blood glucose challenge (94).…”

Mechanisms linking exposure to preeclampsia in utero and the risk for cardiovascular disease

“…37,[41][42][43][44][45][46][47][48][49][50][51] Development of obesity is variable, with obesity reported in adult female, but not male, RUPP rats with ageing, 52,53 but normal body and central fat abundance in adult progeny of sFlt1-transduced mice of both sexes. 54 Likewise, effects of in utero exposure to a preeclamptic phenotype on postnatal glucose tolerance are sex-and agedependent in the RUPP rat, 53,55 L-NAME-treated rat 56 and sFlt1-transduced mice 51 models of PE. Progeny cardiac dysfunction is common to all of these models, although with some variation in phenotype and different sets of outcomes studied in each model.…”