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

Research output: Contribution to journalArticle

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Abstract

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
JournalEndocrinology
Volume145
Issue number5
DOIs
Publication statusPublished - May 1 2004

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Tacrolimus
Insulin
Glucose
Protein Kinase C
Glyburide
Exocytosis
Carbachol
Guanosine Triphosphate
Glutamine
Islets of Langerhans
Leucine
Arginine
Diabetes Mellitus
Adenosine Triphosphate

All Science Journal Classification (ASJC) codes

  • Endocrinology

Cite this

Tacrolimus impairment of insulin secretion in isolated rat islets occurs at multiple distal sites in stimulus-secretion coupling. / Uchizono, Yuji; Iwase, Masanori; Nakamura, Udai; Sasaki, Nobuhiro; Goto, Daisuke; Iida, Mitsuo.

In: Endocrinology, Vol. 145, No. 5, 01.05.2004, p. 2264-2272.

Research output: Contribution to journalArticle

Uchizono, Yuji ; Iwase, Masanori ; Nakamura, Udai ; Sasaki, Nobuhiro ; Goto, Daisuke ; Iida, Mitsuo. / Tacrolimus impairment of insulin secretion in isolated rat islets occurs at multiple distal sites in stimulus-secretion coupling. In: Endocrinology. 2004 ; Vol. 145, No. 5. pp. 2264-2272.
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