IMMUNONEUTRALIZATION OF ENDOGENOUS GLUCAGON WITH MONOCLONAL GLUCAGON ANTIBODY NORMALIZES HYPERGLYCEMIA IN MODERATELY STREPTOZOTOCIN-DIABETIC RATS

The role of glucagon in diabetic hyperglycaemia has been a matter of c ontroversy because of difficulties in the production of selective gluc agon deficiency. We developed a high-capacity (40 nmol/ml), high-affin ity (0.6 . 10(11) l/mol) monoclonal glucagon antibody (Glu-mAb) and ga ve i.v, injections (4 ml/kg) to rats in order to study the effect of s elective glucagon deficiency on blood glucose. Controls received a mAb against trinitrophenyl. Glu-mAb completely abolished the hyperglycaem ic effect of 2.86 nmol/kg glucagon in normal rats (p<0.05, n = 6). In moderately hyperglycaemic rats injected with streptozotocin as neonate s (N-STZ), Glu-mAb abolished a postprandial increase in blood glucose (from 11.2 +/- 0.7 mmol/l to 17.3 +/- 1.8 mmol/l in controls vs 10.5 /- 0.9 mmol/l to 9.3 +/- 1.0 mmol/l; crossover: n = 6, p < 0.05). No s ignificant effect of Glu-mAb treatment was observed in more hyperglyca emic N-STZ rats (cross-over, n = 4) and in severely hyperglycaemic rat s injected with STZ as adults (n = 6), but after insulin treatment of the latter, at doses partially restoring blood glucose levels (12.7 +/ - 4.3 mmol/l), Glu-mAb administration almost normalized blood glucose (maximal difference: 6.0 +/- 3.8 mmol/l; cross-over: n = 5, p < 0.05). In conclusion, our results provide strong additional evidence for the hypothesis that glucagon is involved in the pathogenesis of diabetes. The hormone plays an important role in the development of STZ-diabeti c hyperglycaemia, but glucagon neutralization only leads to normoglyca emia in the presence of insulin.