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J. Biol. Chem., Vol. 279, Issue 14, 13393-13401, April 2, 2004

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A Signaling Role of Glutamine in Insulin Secretion^*

Changhong Li, Carol Buettger, Jae Kwagh, Andrea Matter, Yevgeny Daikhin¶, Ilana B. Nissim¶, Heather W. Collins, Marc Yudkoff¶, Charles A. Stanley, and Franz M. Matschinsky||

From the Division of Endocrinology, the ^¶Division of Child Development and Pediatric Rehabilitation, Children's Hospital of Philadelphia, and the Department of Biochemistry and Biophysics and Diabetes Center, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Children with hypoglycemia due to recessive loss of function mutations of the -cell ATP-sensitive potassium (K_ATP) channel can develop hypoglycemia in response to protein feeding. We hypothesized that amino acids might stimulate insulin secretion by unknown mechanisms, because the K_ATP channel-dependent pathway of insulin secretion is defective. We therefore investigated the effects of amino acids on insulin secretion and intracellular calcium in islets from normal and sulfonylurea receptor 1 knockout (SUR1–/–) mice. Even though SUR1–/– mice are euglycemic, their islets are considered a suitable model for studies of the human genetic defect. SUR1–/– islets, but not normal islets, released insulin in response to an amino acid mixture ramp. This response to amino acids was decreased by 60% when glutamine was omitted. Insulin release by SUR1–/– islets was also stimulated by a ramp of glutamine alone. Glutamine was more potent than leucine or dimethyl glutamate. Basal intracellular calcium was elevated in SUR1–/– islets and was increased further by glutamine. In normal islets, methionine sulfoximine, a glutamine synthetase inhibitor, suppressed insulin release in response to a glucose ramp. This inhibition was reversed by glutamine or by 6-diazo-5-oxo-L-norleucine, a non-metabolizable glutamine analogue. High glucose doubled glutamine levels of islets. Methionine sulfoximine inhibition of glucose stimulated insulin secretion was associated with accumulation of glutamate and aspartate. We hypothesize that glutamine plays a critical role as a signaling molecule in amino acid- and glucose-stimulated insulin secretion, and that -cell depolarization and subsequent intracellular calcium elevation are required for this glutamine effect to occur.

Received for publication, October 20, 2003 , and in revised form, January 5, 2004.

^* These studies were supported in part by NIDDK, National Institutes of Health Research Grants, RO1 DK 53012, RO1 DK 56268 (to C. A. S.), NIDDK Grant 22122 (to F. M. M.), and National Institutes of Health Grants HD 26979, NS 37915 (to M. Y.) and National Institutes of Health Grant DK 19525 for the RIA and Islets Biology cores. The work was presented in part at the 2003 annual meeting of the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Dept. of Biochemistry and Biophysics and Diabetes Center, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. Tel.: 215-898-1971; Fax: 215-898-2178; E-mail: matsch{at}mail.med.upenn.edu.

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