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

被引:119
作者
BRAND, CL
ROLIN, B
JORGENSEN, PN
SVENDSEN, I
KRISTENSEN, JS
HOLST, JJ
机构
[1] UNIV COPENHAGEN,PANUM INST,DEPT MED PHYSIOL C,DK-2200 COPENHAGEN N,DENMARK
[2] NOVO NORDISK AS,DIABET PHARMACOL,BAGSVAERD,DENMARK
[3] NOVO NORDISK AS,DEPT IMMUNOCHEM,BAGSVAERD,DENMARK
[4] NOVO NORDISK AS,HYBRIDOMA LAB,BAGSVAERD,DENMARK
关键词
IMMUNONEUTRALIZATION; MONOCLONAL ANTIBODY; GLUCAGON; INSULIN; STREPTOZOTOCIN; RAT;
D O I
10.1007/s001250050208
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 . 10(11) 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; crossover: 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.
引用
收藏
页码:985 / 993
页数:9
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