. Tacrolimus suppresses glucose-induced insulin release from pancreatic islets by reducing glucokinase activity. Am J Physiol Endocrinol Metab 288: E365-E371, 2005. First published October 12, 2004; doi:10.1152/ ajpendo.00390.2004.-Tacrolimus is widely used for immunosuppressant therapy, including various organ transplantations. One of its main side effects is hyperglycemia due to reduced insulin secretion, but the mechanism remains unknown. We have investigated the metabolic effects of tacrolimus on insulin secretion at a concentration that does not influence insulin content. Twenty-four-hour exposure to 3 nM tacrolimus reduced high glucose (16.7 mM)-induced insulin secretion (control 2.14 Ϯ 0.08 vs. tacrolimus 1.75 Ϯ 0.02 ng ⅐ islet Ϫ1 ⅐ 30 min Ϫ1 , P Ͻ 0.01) without affecting insulin content. In dynamic experiments, insulin secretion and NAD(P)H fluorescence during a 20-min period after 10 min of high-glucose exposure were reduced in tacrolimus-treated islets. ATP content and glucose utilization of tacrolimus-treated islets in the presence of 16.7 mM glucose were less than in control (ATP content: control 9.69 Ϯ 0.99 vs. tacrolimus 6.52 Ϯ 0.40 pmol/islet, P Ͻ 0.01; glucose utilization: control 103.8 Ϯ 6.9 vs. tacrolimus 74.4 Ϯ 5.1 pmol ⅐ islet Ϫ1 ⅐ 90 min Ϫ1 , P Ͻ 0.01). However, insulin release from tacrolimus-treated islets was similar to that from control islets in the presence of 16.7 mM ␣-ketoisocaproate, a mitochondrial fuel. Glucokinase activity, which determines glycolytic velocity, was reduced by tacrolimus treatment (control 65.3 Ϯ 3.4 vs. tacrolimus 49.9 Ϯ 2.8 pmol ⅐ islet Ϫ1 ⅐ 60 min Ϫ1 , P Ͻ 0.01), whereas hexokinase activity was not affected. These results indicate that glucose-stimulated insulin release is decreased by chronic exposure to tacrolimus due to reduced ATP production and glycolysis derived from reduced glucokinase activity.islet; adenosine 5Ј-triphosphate TACROLIMUS (FK-506) IS AN IMMUNOSUPPRESSANT widely used in human organ transplantation. Immunosuppression by the agent is due to blocking of antigen-stimulated expression of genes, including interleukin-2 in T lymphocytes, which is required for T-cell proliferation (34). Interleukin-2 gene transcription is activated by dephosphorylation and nuclear translocation of a transcriptional cofactor, the nuclear factor of activated T cells (NFAT). Tacrolimus binds specific intracellular proteins, FK-506-binding proteins (FKBPs), and inhibits calcineurin (protein phosphatase-2B), a Ca 2ϩ

Yamada. Chronic exposure to ␤-hydroxybutyrate inhibits glucoseinduced insulin release from pancreatic islets by decreasing NADH contents. Am J Physiol Endocrinol Metab 288: E372-E380, 2005. First published October 12, 2004 doi:10.1152/ajpendo.00157.2004.-To investigate the effects of chronic exposure to ketone bodies on glucose-induced insulin secretion, we evaluated insulin release, intracellular Ca 2ϩ and metabolism, and Ca 2ϩ efficacy of the exocytotic system in rat pancreatic islets. Fifteen-hour exposure to 5 mM D-␤-hydroxybutyrate (HB) reduced high glucose-induced insulin secretion and augmented basal insulin secretion. Augmentation of basal release was derived from promoting the Ca 2ϩ -independent and ATP-independent component of insulin release, which was suppressed by the GDP analog. Chronic exposure to HB affected mostly the second phase of glucose-induced biphasic secretion. Dynamic experiments showed that insulin release and NAD(P)H fluorescence were lower, although the intracellular Ca 2ϩ concentration ([Ca 2ϩ ]i) was not affected 10 min after exposure to high glucose. Additionally, [Ca 2ϩ ]i efficacy in exocytotic system at clamped concentrations of ATP was not affected. NADH content, ATP content, and ATP-to-ADP ratio in the HB-cultured islets in the presence of high glucose were lower, whereas glucose utilization and oxidation were not affected. Mitochondrial ATP production shows that the respiratory chain downstream of complex II is not affected by chronic exposure to HB, and that the decrease in ATP production is due to decreased NADH content in the mitochondrial matrix. Chronic exposure to HB suppresses glucose-induced insulin secretion by lowering the ATP level, at least partly by inhibiting ATP production by reducing the supply of NADH to the respiratory chain. Glucose-induced insulin release in the presence of aminooxyacetate was not reduced, which implies that chronic exposure to HB affects the malate/aspartate shuttle and thus reduces NADH supply to mitochondria. islet; reduced nicotinamide adenine dinucleotide; adenosine 5Ј-triphosphate

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