Increased Glucagon Receptors in Chronically Hypersomatotrophic and Hyperglucagonemic Rats

Abstract

The effect of increased levels of growth hormone on glucagon binding by isolated hepatocytes and on the cellular cyclic AMP response to glucagon was evaluated in rats bearing growth hormone-secreting tumor (Mt-T-W 15) and in rats treated with rat growth hormone. An increased binding, due to an increased number of receptors, was observed in both groups of animals. Glucagon binding did not correlate with plasma glucagon levels, suggesting a failure of down regulation, possibly due to an effect of growth hormone and insulin on the number of receptors. Tumor-bearing and growth hormone-treated rats had larger hepatocytes so that, when hormone binding was expressed in terms of square micrometer of membrane surface, it appeared decreased. When the tumor was removed the increase in the number of glucagon receptors per cell persisted, even though the average cell size returned toward normal. It is suggested that this retention of the receptors may have been the result of continuing hyperinsulinism. Basal cAMP levels were elevated in hepatocytes of tumor-bearing and growth hormone-treated animals, possibly due to cell hypertrophy. On the other hand, the maximum cAMP response to glucagon was not altered by the experimental procedures. A negative effect of insulin on cAMP accumulation may explain this apparent paradox, Indeed, hepatocytes isolated from rats following tumor removal, but with continuing hyperinsulinemia, had a lower maximum cAMP response, even though the glucagon binding per cell or per unit of cell surface Was increased.

Regulation of the Hepatic Response to Glucagon: Role of Insulin, Growth Hormone and Cortisol

“…How ever, we have previously reported that GH increased the size of hepatocytes and increased the number of recep tors per cell and, therefore, increased glucagon binding to hepatocytes in the hyperglucagonemia GH-tumorbearing model [Dunbar et al, 1985] and we have con firmed it in the present studies. The slight but significant increase in glucagon binding in our cortisol-treated model has not been reported.…”

“…The mechanisms associated with glucagon stimulation of gly cogenolysis and gluconeogenesis have been extensively investigated. It is established that this process begins first with receptor binding followed by adenyl-cyclasemediated events [Birnbaumer and Pohl, 1973;Giorgio et al, 1974], In a previous study, it was demonstrated that glucagon binding to hepatocytes and glucagon-stimu lated adenyl cyclase could be influenced by other hor mones or metabolic factors [Walsh and Dunbar, 1984;Dunbar and Cremonesi, 1984;Dunbar et al, 1985]. Also it was demonstrated that the coupling of the events of receptor binding and adenyl cyclase activation was not always consistent.…”

Central Adrenergic Suppression Augments the Insulin and Glucagon Secretory, and the Glycogenolytic Responses in Streptozotocin-Diabetic Rats

“…This phenomenon may have been the result of a restoration of liver glycogen stores or of an increased sensitivity of the glucagon receptors. Although the gluca gon receptors usually are down-regulated in diabetic ani mals [36,37], some of our previous experiments have demonstrated that both the glucagon receptors and the sensitivity to glucagon can be influenced by hormonal and metabolic factors [38,39]. Clonidine treatment clearly enhanced the sensitivity to glucagon stimulation in the diabetic animals.…”