The effects of chronic uremia on glucagon binding and action in isolated rat hepatocytes.
Increased liver sensitivity to glucagon has been proposed to play a role in the complex metabolic state of chronic uremia. In order to assess this possibility at the cellular level, we studied basal and glucagon-stimulated alpha-aminoisobutyric acid (AIB) uptake, glucagon binding, and glucagon degradation in isolated hepatocytes from chronic uremic and pair-fed and ad libitum-fed control rats. The uremic rats were euglycemic and hyperglucagonemic when compared with their controls. The basal rate of AIB uptake was enhanced in hepatocytes from both the uremic and pair-fed control rats. Hepatocytes from ad libitum-fed control animals responded significantly to glucagon at concentrations from 1 X 10(-11) to 1 X 10(-7) mol/L, and those from pair-fed control animals at concentrations from 1 X 10(-8) to 1 X 10(-7) mol/L. Hepatocytes from the uremic rats were unresponsive to glucagon with regard to AIB uptake. 125I-labeled glucagon binding was increased in the uremic rats. This increase of glucagon binding appears to be the results of an increase in the number of binding sites rather than a consequence of a change in binding affinity or decreased glucagon degradation. In conclusion, our data are not supportive of the hypothesis that there exists in uremia an increased sensitivity to glucagon in the liver. The uremic liver is resistant to glucagon with regard to AIB uptake. Despite the high level of circulating immunoreactive glucagon, hepatocytes from uremic rats did not show the expected "down regulation" of their 125I-labeled glucagon binding sites. These studies emphasize the primary role of post-binding events in the regulation of glucagon action and binding.
D000621:Aminoisobutyric Acids / Q000378:metabolism; D000818:Animals; D002908:Chronic Disease; D004305:Dose-Response Relationship, Drug; D005934:Glucagon / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D014511:Uremia / Q000378:metabolism*
D000621:Aminoisobutyric Acids; C100049:2-aminoisobutyric acid; D005934:Glucagon