Tacrolimus suppresses glucose-induced insulin release from pancreatic islets by reducing glucokinase activity

Abstract

. 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

The direct effects of tacrolimus and cyclosporin A on isolated human islets: A functional, survival and gene expression study

“…After seven days, the inhibition of insulin release was further enhanced, but equivalently with 0.01, 0.1 and 1.0 μmol/l tacrolimus. A dose-dependent reduction of insulin secretion from rodent islets was observed by Radu and colleagues, 19 who used 3 to 30 nmol/l tacrolimus concentrations for 24 h. Furthermore, to investigate the effects of calcineurin inhibitors on human b-cells at the molecular level, we profiled gene expression with Affymetrix chips by using three human islet preparations. We are aware that the use of more preparations would have allowed more stringent statistical analysis.…”

“…In isolated rodent and human islets, tacrolimus and cyclosporin A were usually found to reduce insulin gene expression. 12,19,20 In human lymphocytes, cyclosporin A increased Bcl-2 transcription. 21 Interestingly, the calcineurin and the calcineurin NFAT signaling gene sets were similarly affected by both tacrolimus and cyclosporin A.…”

Src activation generates reactive oxygen species and impairs metabolism–secretion coupling in diabetic Goto–Kakizaki and ouabain-treated rat pancreatic islets

“…Since depletion of mitochondrial DNA abolishes the glucose-induced ATP elevation, mitochondria clearly are a major source of ATP production in pancreatic beta cells [2,3]. Glucose-induced insulin secretion from beta cells is often impaired by exposure to high concentrations of fuels including glucose, NEFAs and ketone bodies, and by administration of diabetogenic pharmacological agents, all of which involve impaired glucose-induced ATP elevation in beta cells [4][5][6][7][8][9][10][11]. Thus, reduced mitochondrial ATP production plays an important role in impaired glucoseinduced insulin secretion.…”

Prevalence of Metabolic Syndrome in Organ Transplantation: A Review of the Literature

“…Sirolimus at therapeutic concentrations was reported to significantly increase insulin secretion in both basal (50%) and stimulated (40%) states in mini pigs in vivo [131]. Sirolimus also increases insulin content in human islets [134].…”

“…Moreover, both tacrolimus and cyclosporine were reported to induce defective glucose-stimulated insulin secretion by inhibiting the closure of the ATP-sensitive potassium channel [130]. Tacrolimus may also reduce glucokinase activity and affect insulin exocytosis downstream of the rise in intracellular Ca 2 + , resulting in decreased glucose-stimulated insulin secretion [129][130][131][132].…”