Imidazoline compounds stimulate insulin release by inhibition of K-ATP channels and interaction with the exocytotic machinery

被引:94
作者
Zaitsev, SV
Efanov, AM
Efanova, IB
Larsson, O
Ostenson, CG
Gold, G
Berggren, PO
Efendic, S
机构
[1] KAROLINSKA HOSP,KAROLINSKA INST,DEPT MOL MED,ROLF LUFT CTR DIABET RES,S-17176 STOCKHOLM,SWEDEN
[2] MOSCOW MV LOMONOSOV STATE UNIV,BELOZERSKY INST PHYSICOCHEM BIOL,MOSCOW,RUSSIA
[3] ELI LILLY & CO,LILLY CORP CTR,LILLY RES LABS,INDIANAPOLIS,IN 46285
关键词
D O I
10.2337/diabetes.45.11.1610
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
A novel imidazoline compound, RX871024, was used to investigate the mechanisms by which imidazoline derivatives promote insulin secretion in rat pancreatic beta-cells and HIT T15 cells, RX871024 stimulated insulin release from rat pancreatic beta-cells and HIT T15 cells in a glucose-dependent way, This effect was not related to alpha(2)-adrenergic, I-1-, and I-2-imidazoline receptors. RX871024 promoted insulin release by at least two modes of action, One included an increase in cytoplasmic free Ca2+ concentration ([Ca2+](i)), subsequent to blocking of ATP-dependent K+ channels, membrane depolarization, and activation of voltage-dependent Ca2+ channels. The other, a more distal effect of imidazoline, affected the exocytotic machinery and was unrelated to changes in membrane potential and [Ca2+](i). The mechanism of RX871024-induced insulin release was dependent on protein kinases A and C. The sensitizing effect of a low dose of RX871024 on glucose-induced insulin secretion suggests that imidazoline compounds of this kind may constitute the basis for development of a new class of oral hypoglycemic agents.
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页码:1610 / 1618
页数:9
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