Role of glucagon as a contributor to glucose intolerance in acute and chronic uremia.
It has been suggested that increased sensitivity to glucagon may contribute to glucose intolerance in uremia. In order to evaluate this possibility systematically, we have assessed the effect of glucagon on hepatic glucose outflow, formation of cAMP, and activation of adenylate cyclase by livers obtained from acutely and chronically uremic rats and their respective sham operated controls. Glucagon infused at rates of 6 ng/min/kg rat resulted in minimal and equivalent increases in hepatic glucose outflow and cAMP accumulation when livers from acutely uremic and control rats were perfused for 30 min. However, at glucagon infusion rates of 18 ng/min/kg, glucose efflux from perfused livers of acutely uremic rats was significantly reduced (p less than 0.001) compared to perfused livers of control rats (4.64 +/- .9 vs 12.7 +/- 2.4 mumol/g liver) and cAMP accumulation was also significantly lower (p less than 0.01) (1352 +/- 222 vs 3100 +/- 348 pmol/g liver). Basal adenylate cyclase activity of hepatic membranes obtained from uremic and control rats was similar, and was stimulated by glucagon concentrations ranging from 10(-8) to 10(-6) at equivalent rates in both groups. In livers from chronically uremic rats, glucagon infused at rates of 6 ng/kg/min significantly increased hepatic glucose outflow (32.5 +/- 6.9 mumol/g liver). However this was not greater than that of control animals (37.6 +/- 9.2). Furthermore, cAMP accumulation was significantly lower (p less than .02) in chronically uremic rats than in controls, and activation of adenylate cyclase by glucagon was similar in both groups. These findings indicate that glucagon does not increase glucose efflux, cAMP accumulation or enhance activation of adenylate cyclase by isolated perfused livers from either acutely or chronically uremic rats. Thus, glucose intolerance in uremic rats does not appear to be due to increase hepatic glucose output resulting from increased sensitivity to glucagon.
D000208:Acute Disease; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002908:Chronic Disease; D004789:Enzyme Activation; D005934:Glucagon; D005947:Glucose / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000503:physiopathology*; D008297:Male; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains; D014511:Uremia / Q000503:physiopathology*
D005934:Glucagon; D000262:Adenylyl Cyclases; D005947:Glucose