Summary
The role of glucagon in diabetic hyperglycaemia has been a matter of controversy because of difficulties in the production of selective glucagon deficiency. We developed a high-capacity (40 nmol/ ml), high-affinity (0.6·1011 l/mol) monoclonal glucagon antibody (Glu-mAb) and gave i.v. injections (4 ml/kg) to rats in order to study the effect of selective glucagon deficiency on blood glucose. Controls received a mAb against trinitrophenyl. Glu-mAb completely abolished the hyperglycaemic effect of 2.86 nmol/kg glucagon in normal rats (p<0.05, n=6). In moderately hyperglycaemic rats injected with streptozotocin as neonates (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; cross-over: n=6, p<0.05). No significant effect of Glu-mAb treatment was observed in more hyperglycaemic N-STZ rats (cross-over, n=4) and in severely hyperglycaemic rats 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-diabetic hyperglycaemia, but glucagon neutralization only leads to normoglycaemia in the presence of insulin.
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Abbreviations
- A-STZ rats:
-
Adult streptozotocin injected rats
- AUC:
-
area under the curve
- BW:
-
body weight
- Con-mAb:
-
monoclonal control antibody
- Glu-mAb:
-
monoclonal anti-glucagon antibody
- Ka :
-
constant of association
- NIDDM:
-
non-insulin-dependent diabetes mellitus
- N-STZ rats:
-
neonatal streptozotocin-injected rats
- OGTT:
-
oral glucose tolerance test
- STZ:
-
streptozotocin
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Brand, C.L., Rolin, B., JØrgensen, P.N. et al. Immunoneutralization of endogenous glucagon with monoclonal glucagon antibody normalizes hyperglycaemia in moderately streptozotocin-diabetic rats. Diabetologia 37, 985–993 (1994). https://doi.org/10.1007/BF00400461
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DOI: https://doi.org/10.1007/BF00400461