Deficits in Pituitary and Brain Cell Nuclear Retention of (³H)Estradiol in Diabetic Rats Deprived of Insulin: Time Course and Metabolic Correlates

Abstract

Withdrawal of exogenous insulin for 24 h in ovariectomized, streptozotocin-diabetic rats significantly impairs estradiol uptake in whole homogenate fractions of hypothalamus-preoptic area and pituitary gland. Significant reductions in cell nuclear fractions from the same tissues are seen after 36 h of insulin deprivation. Subsequent reinstatement of insulin treatment does not yield full recovery of estradiol uptake after 24 h of insulin replacement. Fat content of the diet has no effect on brain or pituitary estradiol uptake in diabetic animals deprived of insulin for 36 h. Circulating levels of triglycerides, ketones, glucose, glycerol and free fatty acids were found to predict uptake levels to a significant extent, but no single metabolite is reliably predictive across tissues. These data demonstrate that insulin-dependent changes in brain and pituitary uptake of estradiol in rats are slow to develop, and they support the hypothesis that at least some of the reproductive dysfunctions observed in diabetic rats may be the result of impaired cell nuclear estradiol binding in hypothalamus and pituitary.

Diabetes-Induced Alterations of Reproductive and Adrenal Function in the Female Rat

“…The reduced uterine to body weight ratios were consistent with the impaired ovarian steroidogenesis reported here and by Liu et al [14]. Another reported abnormality in diabetic rats is decreased estrogen and/or estrogen receptor translocation in the hypothalamus and pituitaiy [38,39], The proestrus LH surge was observed in our control and insulin-treated animals, but was absent in our diabetics as has been well documented in previous studies |4 , 6,7], One explanation for the absent LH surge in the diabetic female is insufficient estradiol levels or estrogen effect to trigger this pituitary response. Insulin therapy restored uterine weight and improved glucose and glycohemoglobin to control levels.…”

Estrogenic Stimulation of Hypothalamic-Limbic System Metabolism in Ageing Diabetic C57BL/KsJ Mice

“…These studies suggest that estrogenic compounds may serve as regionally specific CNS metabolic stimulants with respect to such functions as neuronal carbohydrate metabolism in steroid-hormone-responsive loci of the CNS. Thus, the depression of normal neuronal metabolic activity at selected steroid target sites in the CNS may be related to suboptimal neuronal stimulation by ovarian steroids, since the production and release of such compounds is compromised by the concurrent expression of developmental reproductive incompetency and tissue atrophy [26, 27, 30, 31]which occur as a result of the db/db mutation in this species. To date, the ability of E therapy to delay or influence the neuronal degeneration and dysfunction that occurs in association with the exacerbation of the diabetes syndrome in this species remains to be elucidated.…”

Estrous Behavior and Pituitary and Brain Cell Nuclear Retention of [³Η]Estradiol in Chronically Insulin-Deficient Female Rats

“…Bars represent group mean lordosis ratings ± SEM. droxybutyrate), free fatty acid and glucose concentrations were de termined as previously described [4], The data from these assays were examined through multiple regression analyses and Pearson product-moment correlations.…”

“…This idea is supported by data demonstrating that in chronically insulin-deficient rats, dietary supplements of olive oil to a carbohydrate-rich diet can normalize estrous cycles [9] and that increasing dietary fat content can eliminate hyperpha-gia [6]. While high dietary fat does not ameliorate brain es tradiol uptake deficits in female rats acutely deprived of in sulin [4], to date there are no published reports on the effects of fat-enriched diets on estradiol uptake in chronically insu lin-deprived animals. Furthermore, it is not presently known whether fat-enriched diets would alter the sex behav ior deficits reported in diabetic rats.…”

“…Previous research has implicat ed the central nervous system as one of the possible sites of functional disruption, with the demonstration that acute in sulin deficiency leads to reduced estradiol uptake in hypothalamus-preoptic area and pituitary gland [4,7], re duction of cell nuclear estrogen receptor levels in hypothalamus-preoptic area [13], and reduction in lordosis behavior 17.13], Although shifts in plasma constituents reflect rapid met abolic responses to insulin deprivation, deficits in brain up take of estradiol develop relatively slowly in rats. Hypothalamus-preoptic area and pituitary gland whole homogenate fractions show depressed uptake after 24 h of insulin with drawal, and nuclear fractions from these tissues show simi lar reductions after 36 h [4]. These data suggest that chronic insulin deprivation might provide a useful metabolic model for the study of reproductive dysfunction in diabetics.…”