Mechanism of oestrogen and progesterone effects on lipid and carbohydrate metabolism: alteration in the insulin: glucagon molar ratio and hepatic enzyme activity

Abstract

As in women receiving oestrogens the administration of 17beta-oestradiol to ovariectomized female rats caused a rise in fasting plasma triglycerides and a fall in plasma glucose. Progesterone, on the other hand, had no significant effects. In the oestradiol treated rats, the portal vein basal insulin levels were slightly reduced. Oestradiol, however, had a marked suppressive effect on the alpha cells of the pancreas resulting in a greater reduction in basal glucagon and impaired glucagon response to alanine infusions. The relative insulin to glucagon (I/G) molar concentration ratio in portal vein blood was increased. Oestradiol also produced a dose dependent increase in the activity of the liver lipogenic enzymes, acetyl CoA carboxylase and fatty acid synthetase. On the other hand, the activity of the gluconeogenic rate limiting enzyme phosphoenol-pyruvate carboxykinase (PEPCK) was inhibited. The cross-over pattern of gluconeogenic intermediates confirmed inhibition of gluconeogenesis at this step, an effect which is similar to that induced by relative insulin 'excess'. Progesterone produced an increase in the portal vein insulin concentrations. Both the basal and the alanine-stimulated glucagon levels were also increased. The I/G molar ratio in portal vein blood of progesterone treated rats remained unaltered and the hepatic lipogenic and gluconeogenic enzyme activities were similar to control animals. These data suggest that insulin activity is increased relative to glucagon in the liver of oestradiol-treated rats due to the rise in portal vein I/G ratio. The changes in liver lipogenic and gluconeogenic enzymes and the alterations in fasting plasma triglycerides and glucose in response to oestrogens could be secondary to this effect.

PIP: The effects of 17beta-estradiol (E2) and progesterone (P) on the portal vein blood levels of insulin and glucagon in female ovariectomized (OVX) rats were studied and the simultaneous status of both the rate-limiting enzymes and metabolic intermediates of hepatic lipogenesis and gluconeogenesis were examined. Administration of E2 to OVX rats caused a rise in plasma triglycerides and a fall in plasma glucose. P was without this effect. E2-treated rats had slightly reduced portal vein basal insulin levels and a marked suppression in basal glucagon response with impaired glucagon response to alanine infusions. E2 caused an increase in the relative insulin to glucagon (I/G) molar concentration in portal vein blood and a dose-dependent increase in the activity of acetyl CoA carboxylase and fatty acid synthetase. The activity of the gluconeogenic rate limiting enzyme phosphoenal-pyruvate carboxykinase was inhibited. The inhibition of gluconeogenesis at this point is similar to what occurs with insulin excess. P produced insulin increases in the portal vein and increases in both basal and alanine-stimulated glucagon levels. The I/G ratio remained unchanged, and hepatic lipogenic and gluconeogenic activity were similar to controls. These results suggest that in the liver of E2-treated rats, insulin is increased relative to glucagon due to the rise in portal vein I/G. Other changes could be secondary to this effect.