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Tacrolimus Impairment of Insulin Secretion in Isolated Rat Islets Occurs at Multiple Distal Sites in Stimulus-Secretion Coupling

Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka City 812-8582, Japan

Address all correspondence and requests for reprints to: Dr. Masanori Iwase, Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka City 812-8582, Japan. 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-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 -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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