Tacrolimus impairment of insulin secretion in isolated rat islets occurs at multiple distal sites in stimulus-secretion coupling

被引:54
作者
Uchizono, Y [1 ]
Iwase, M [1 ]
Nakamura, U [1 ]
Sasaki, N [1 ]
Goto, D [1 ]
Iida, M [1 ]
机构
[1] Kyushu Univ, Grad Sch Med Sci, Dept Med & Clin Sci, Higashi Ku, Fukuoka 8128582, Japan
关键词
D O I
10.1210/en.2003-1152
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
the pathogenetic mechanisms remain controversial. We studied the mechanism of tacrolimus-induced impairment of insulin secretion using isolated rat pancreatic islets. Tacrolimus caused reductions in DNA and insulin contents per islet during 7-d culture. Tacrolimus time-dependently suppressed glucose-stimulated insulin secretion, and at a therapeutic concentration of 0.01 mumol/liter, it suppressed glucose-stimulated insulin secretion to 32 +/- 5% of the control value after 7-d incubation. Tacrolimus did not change islet glucose utilization and oxidation, ATP production, insulin mRNA expression, or the capacity for high glucose to increase intracellular Ca2+, but altered the rapid frequency oscillations of Ca2+ concentration. Tacrolimus suppressed insulin secretion stimulated by mitochondrial fuel ( combination of L-leucine and L-glutamine, and alpha-ketoisocaproate) and glibenclamide, but not by L-arginine. Tacrolimus suppressed insulin secretion induced by carbachol and by a protein kinase C agonist in the presence or absence of extracellular Ca2+. Under stringent Ca2+-free conditions, tacrolimus did not affect mastoparan-induced insulin secretion, but suppressed its glucose augmentation. Our results suggest that tacrolimus impairs glucose-stimulated insulin secretion downstream of the rise in intracellular Ca2+ at insulin exocytosis, and that protein kinase C-mediated (Ca2+-dependent and independent) and Ca2+-independent GTP signaling pathways may be involved. However, tacrolimus-induced impaired insulin secretion was reversed 3 d after removal of the drug. Our study demonstrated that tacrolimus impairs insulin secretion at multiple steps in stimulus-secretion coupling.
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收藏
页码:2264 / 2272
页数:9
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