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

Yuji Uchizono, Masanori Iwase, Udai Nakamura, Nobuhiro Sasaki, Daisuke Goto, Mitsuo Iida

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62 Citations (Scopus)


Tacrolimus causes posttransplant diabetes mellitus, although 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 μmol/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 α-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 Ca 2+. Under stringent Ca2+-free conditions, tacrolimus did not affect mastoparaninduced 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.

Original languageEnglish
Pages (from-to)2264-2272
Number of pages9
Issue number5
Publication statusPublished - May 2004
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Endocrinology


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