Estrogen: a master regulator of bioenergetic systems in the brain and body.

Purpose: To review the medications that influence glucose metabolism and to examine the mechanisms of these medications on glucose metabolism. Data Sources: Data were obtained from a MEDLINE search...

Drug-Induced Disorders of Glucose Tolerance

Studies were performed to evaluate the relative importance of enhanced adipose tissue lipolysis and increased insulin levels in modulating hepatic VLDL production in patients with endogenous hypertriglyceridaemia. Eight control subjects and nine patients with hypertriglyceridaemia were investigated. The latter group comprised four patients with idiopathic hypertriglyceridaemia, three maturity onset diabetics, and two siblings with diabetic lipodystrophy. Each individual's plasma VLDL was selectively labelled with I131 in the apoprotein moiety and then reinjected to assess the turnover of these molecules. This was correlated with the insulin response to an oral glucose load and with the plasma FFA flux measured by a continuous infusion of14C palmitate. In the patients with idiopathic hypertriglyceridaemia and in the adult onset diabetics, plasma VLDL-apoprotein turnover was increased suggesting enhanced hepatic production of these molecules. Although the insulin levels in these patients were higher than normal, no significant correlation was demonstrable between the plasma insulin and the turnover of VLDL-B-apoprotein. Furthermore, in the two patients with lipo-dystrophy the turnover of plasma VLDL was within the normal range, whereas the plasma insulin responses were the highest among all the patients. These results suggest that hyperinsulinaemia alone is not sufficient to account for the increased VLDL production seen in some of our patients. The plasma FFA flux was raised in the patients with idiopathic hypertriglyceridaemia and in the maturity onset diabetics, and was within the normal range in the two patients with lipodystrophy. Indeed, in all the subjects studied a significant correlation was observed between the turnover of plasma VLDL-B-apoprotein and the plasma FFA flux. The results thus indicate that the rate of FFA release to plasma constitutes the predominant factor in determining hepatic output of VLDL and that in the majority of patients with endogenous hypertriglyceridaemia the increased FFA flux resulting from insulin resistance in adipose tissue could effectively increase VLDL production. This process appears to be independent of the prevailing insulin levels, and could occur in the presence of insulin resistance in the liver. The latter, however, could be responsible for the impaired glucose tolerance observed in some patients.

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Role of insulin resistance in adipose tissue and liver in the pathogenesis of endogenous hypertriglyceridaemia in man.

There is a persistent perception that oestrogens have an adverse effect on carbohydrate metabolism. It might therefore be expected that their use would result in a corresponding increase in the incidence of diabetes. Recent evidence from clinical trials suggesting that women on postmenopausal oestrogen hormone replacement therapy (HRT) have a reduced incidence of type 2 diabetes therefore appears paradoxical. Short-term supraphysiological oestrogen administration has an adverse effect on glucose tolerance, resulting from suppression of first-phase insulin secretion and increased insulin resistance. Oestrogen-induced increases in glucocorticoid activity could account for these effects. Oestrogen-induced deterioration in glucose tolerance is, however, accompanied by a reduction in fasting glucose, an effect that could be accounted for by glucagon antagonism. These short-term effects contrast with long-term preservation of insulin secretion and glucose homeostasis by oestrogens. In animal studies, ovariectomy is associated with decreased insulin secretion and increased risk of diabetes, whereas oestrogen administration protects against diabetes and increases the insulin response to glucose. The mechanism is uncertain, but direct effects on the pancreas via steroid receptors or indirect effects via oestrogen-induced glucagon antagonism and subclinical increases in glucocorticoids and growth hormone could all contribute. Recent evidence that HRT increases the risk of cardiovascular disease suggests that it should not be used for the prevention of diabetes, but the mechanism responsible for this benefit merits further investigation and might lead to new therapies.

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Oestrogens and insulin secretion

In female animals, energy metabolism and fertility are tightly connected, and reciprocally regulated. However, the relative contributions of metabolic and reproductive pathways have changed over the course of evolution. In oviparous animals, metabolic factors take precedence over fertility, enabling egg production to be inhibited in a nutritionally poor environment. By contrast, in placental mammals, the opposite occurs: the need to feed a developing embryo and neonate forces metabolic pathways to adapt to these reproductive needs. This physiological necessity explains why in female mammals alterations of gonadal activity, including age-dependent cessation of ovarian functions, are associated with a disruption of metabolic homeostasis and consequent inflammatory reactions that trigger the onset of metabolic, cardiovascular, skeletal and neural pathologies. This Review discusses how metabolic homeostasis and reproductive functions interact to optimize female fertility and explains the pathogenic mechanisms underlying the disordered energy metabolism associated with human ovarian dysfunction owing to menopause, polycystic ovary syndrome and Turner syndrome. Finally, this article highlights how hormone replacement therapy might aid the restoration of metabolic homeostasis in women with ovarian dysfunction.

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J W H Doar

Papers

Some Effects of Oral Contraceptives on Carbohydrate Metabolism