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This version published online on February 12, 2004
Endocrinology, doi:10.1210/en.2003-1152
A more recent version of this article appeared on May 1, 2004
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*CALCIUM, ELEMENTAL
*CARBACHOL CHLORIDE
*GLUCOSE

Submitted on September 3, 2003
Accepted on February 4, 2004

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, and Mitsuo Iida

Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

* To whom correspondence should be addressed. E-mail: iwase{at}intmed2.med.kyushu-u.ac.jp.

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-day culture. Tacrolimus time-dependently suppressed glucose-stimulated insulin secretion, and at therapeutic concentration of 0.01 µmol/liter, it suppressed glucose-stimulated insulin secretion to 32 ± 5% of the control after 7-day 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+ ([Ca2+]i), but altered the rapid frequency oscillations of Ca2+ concentration. Tacrolimus suppressed insulin secretion stimulated by mitochondrial fuel (combination of L-leucine and L-glutamine, alfa-ketoisocaproate) and glibenclamide, but not by L-arginine. Tacrolimus suppressed insulin secretion induced by carbachol, and by a protein kinase C (PKC) 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 [Ca2+]i at insulin exocytosis, and that PKC-mediated (Ca2+-dependent and independent) and Ca2+-independent GTP signaling pathways may be involved. However, tacrolimus-induced impaired insulin secretion was reversed at 3 days after the removal of the drug. Our study demonstrated that tacrolimus impairs insulin secretion at multiple steps in stimulus-secretion coupling.
Key words: Posttransplant diabetes mellitus • insulin secretion • intracellular Ca2+ concentration • tacrolimus • exocytosis




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