HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 288/2/E365    most recent 00390.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (9) Citing Articles via Google Scholar Google Scholar Articles by Radu, R. G. Articles by Seino, Y. Search for Related Content PubMed PubMed Citation Articles by Radu, R. G. Articles by Seino, Y.

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

¹Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto; and ²Kansai-Denryoku Hospital, Osaka, Japan

Submitted 23 August 2004 ; accepted in final form 9 October 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 ± 0.08 vs. tacrolimus 1.75 ± 0.02 ng·islet^–1·30 min^–1, P < 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 ± 0.99 vs. tacrolimus 6.52 ± 0.40 pmol/islet, P < 0.01; glucose utilization: control 103.8 ± 6.9 vs. tacrolimus 74.4 ± 5.1 pmol·islet^–1·90 min^–1, P < 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 ± 3.4 vs. tacrolimus 49.9 ± 2.8 pmol·islet^–1·60 min^–1, P < 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 5'-triphosphate

This article has been cited by other articles:

				J. Yang, R. K. Wong, M. Park, J. Wu, J. R. Cook, D. A. York, S. Deng, J. Markmann, A. Naji, B. A. Wolf, et al. Leucine Regulation of Glucokinase and ATP Synthase Sensitizes Glucose-Induced Insulin Secretion in Pancreatic {beta}-Cells Diabetes, January 1, 2006; 55(1): 193 - 201. [Abstract] [Full Text] [PDF]