EVIDENCE FOR A MAJOR ROLE FOR GLUCAGON IN REGULATION OF PLASMA-GLUCOSE IN CONSCIOUS, NONDIABETIC, AND ALLOXAN-INDUCED DIABETIC RABBITS

Effects of glucagon immunoneutralization on plasma glucose, insulin, a nd glucagon were studied 2-4 h after intravenous injection of a high-a ffinity, monoclonal glucagon antibody into normal as well as moderatel y and severely alloxan (ALX)-induced diabetic rabbits (n = 5-7). A mon oclonal trinitrophenyl antibody was used in control studies. Endogenou s glucagon was completely neutralized as evidenced by undetectable lev els of free glucagon and high plasma glucagon-binding capacities. In p ostabsorbtive normal rabbits, glucagon neutralization decreased plasma glucose by 2.2 +/- 0.3 mmol/l, and the resulting plasma levels of ins ulin and glucagon (indirectly measured) were 8 +/- 3 and 640 +/- 129% of baseline, respectively. However, when euglycemia was maintained by means of glucose infusion (steady-state plasma glucose and glucose inf usion rate: 6.6 +/- 0.1 mmol/l and 3.0 +/- 0.4 mg . kg(-1) . min(-1)), both plasma insulin and glucagon remained unaltered. Thus, the glucos e infusion rate accurately reflects glucagon's contribution to postabs orbtive glucose production. In both moderately and severely diabetic r abbits, immunoneutralization of glucagon decreased plasma glucose by s imilar to 8 mmol/l, leading to euglycemia (7.3 +/- 1.1 mmol/l) and red uced hyperinsulinemia (41 +/- 9% of baseline) in the former and to par tial restoration of euglycemia (12.7 +/- 1.8 mmol/l) and unchanged ins ulin levels in the latter group of diabetic rabbits (P < 0.05 vs, cont rols in all studies). No significant changes were observed in control studies. In conclusion, glucagon is an important regulator of postabso rbtive glucose production in normal rabbits and plays an important rol e in the maintenance of hyperglycemia in ALX-induced diabetic rabbits.