Glucagon binding and adenylate cyclase activity in liver membranes from untreated and insulin-treated diabetic rats.
To investigate the role of hepatic glucagon receptors in the hypersensitivity to glucagon observed in insulin-deprived diabetics, liver plasma membranes were prepared from control rats and from streptozotocin-induced diabetic rats some of whom were treated with high-dose and low-dose insulin. The untreated diabetic animals exhibited hyperglycemia, weight loss, hypoinsulinemia, and hyperglucagonemia. High-dose insulin treatment (2 U Protamine-zinc-insulin/100 g per day) resulted in normoglycemia, normal weight gain, mild hyperinsulinemia, and return of glucagon levels toward base line. The low-dose (1 U protamine-zinc-insulin/100 g per day) insulin-treated diabetic group demonstrated chemical changes intermediate between the untreated and the high-dose insulin-treated animals. In liver plasma membranes from the untreated diabetic rats, specific binding of (125)I-glucagon was increased by 95%. Analysis of binding data suggested that the changes in glucagon binding were a consequence of alterations in binding capacity rather than changes in binding affinity. Furthermore, in the untreated diabetic rats, both basal and glucagon (2 muM)-stimulated adenylate cyclase activity were twofold higher than in controls. In the high-dose insulin-treated diabetic rats, glucagon binding and basal and glucagon-stimulated adenylate cyclase activity were normalized to control values, whereas low-dose insulin treatment resulted in changes intermediate between control and untreated diabetic rats. In contrast to glucagon-stimulated adenylate cyclase activity, fluoride-stimulated adenylate cyclase activity was similar in all groups of rats. Liver plasma membranes from untreated and insulin-treated diabetic animals degraded (125)I-glucagon to the same extent as control rats. The specific binding of (125)I-insulin in the untreated diabetic animals was 40% higher than in control rats. In low-dose insulin-treated diabetic rats, insulin binding was not significantly different from that of control rats, whereas in the high-dose insulin-treated group in whom plasma insulin was 70% above control levels, insulin binding was 30% lower than in control rats. These findings suggest that alterations in glucagon receptors may contribute to the augmented glycemic and ketonemic response to glucagon observed in insulin-deprived diabetics.
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D001835:Body Weight; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005934:Glucagon / Q000378:metabolism*; D007328:Insulin / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D011506:Proteins / Q000378:metabolism; D051381:Rats; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism
D007328:Insulin; D011506:Proteins; D011956:Receptors, Cell Surface; D005934:Glucagon; D000262:Adenylyl Cyclases