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) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kelly, A. Articles by Matschinsky, F. M. Search for Related Content PubMed PubMed Citation Articles by Kelly, A. Articles by Matschinsky, F. M. Social Bookmarking                What's this?

Glutaminolysis and Insulin Secretion

From Bedside to Bench and Back

¹ Department of Pediatrics, Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
² Department of Pathology, Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
³ Department of Biochemistry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Identification of regulatory mutations of glutamate dehydrogenase (GDH) in a form of congenital hyperinsulinism (GDH-HI) is providing a model for basal insulin secretion (IS) and amino acid (AA)-stimulated insulin secretion (AASIS) in which glutaminolysis plays a key role. Leucine and ADP are activators and GTP is an inhibitor of GDH. GDH-HI mutations impair GDH sensitivity to GTP inhibition, leading to fasting hypoglycemia, leucine hypersensitivity, and protein-induced hypoglycemia, indicating the importance of GDH in basal secretion and AASIS. The proposed model for glutaminolysis in IS is based on GDH providing NADH and -ketoglutarate (-KG) to the Krebs cycle, hence increasing the ß-cell ATP-to-ADP ratio to effect insulin release. The process operates with 1) sufficient lowering of ß-cell phosphate potential (i.e., fasting) and when 2) AAs provide leucine for allosteric activation and glutamate from transaminations. To test this hypothesis, IS studies were performed in rat and GDH-HI mouse models. In the rat study, rat islets were isolated, cultured, and then perifused in Krebs-Ringer bicarbonate buffer with 2 mmol/l glutamine using 10 mmol/l 2-aminobicyclo[2,2,1]-heptane-2-carboxylic acid (BCH) or a BCH ramp after 50 or 120 min of glucose deprivation. In the GDH-HI mouse study, the H454Y GDH-HI mutation driven by the rat insulin promoter was created for H454Y ß-cell-specific expression. Cultured, isolated islets were perifused in leucine 0–10 mmol/l with 2 mmol/l glutamine 0–25 mmol/l, AA 0–10 mmol/l, or glucose 0–25 mmol/l. Rat islets displayed enhanced BCH-stimulated IS after 120 min of glucose deprivation, but not when energized by fuel. H454Y and control islets had similar glucose-stimulated IS, but H454Y mice had lower random blood glucose. Leucine-stimulated IS and AASIS occurred at lower thresholds and were greater in H454Y versus control islets. Glutamine stimulated IS in H454Y but not control islets. The clinical manifestations of GDH-HI and related animal studies suggest that GDH regulates basal IS and AASIS. Energy deprivation enhanced GDH-mediated IS, and H454Y mice were hypoglycemic, substantiating roles for GDH and its regulation by the phosphate potential in basal IS. Excessive IS from H454Y islets upon exposure to GDH substrates or stimuli indicate that regulation of GDH by the ß-cell phosphate potential plays a critical role in AASIS. These findings provide a foundation for defining pathways of basal secretion and AASIS, augmenting our understanding of ß-cell function.

CiteULike

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				T. Anno, S. Uehara, H. Katagiri, Y. Ohta, K. Ueda, H. Mizuguchi, Y. Moriyama, Y. Oka, and Y. Tanizawa Overexpression of constitutively activated glutamate dehydrogenase induces insulin secretion through enhanced glutamate oxidation Am J Physiol Endocrinol Metab, February 1, 2004; 286(2): E280 - E285. [Abstract] [Full Text] [PDF]

				M. J. DUNNE, K. E. COSGROVE, R. M. SHEPHERD, A. AYNSLEY-GREEN, and K. J. LINDLEY Hyperinsulinism in Infancy: From Basic Science to Clinical Disease Physiol Rev, January 1, 2004; 84(1): 239 - 275. [Abstract] [Full Text] [PDF]

				Y.-J. Liu, H. Cheng, H. Drought, M. J. MacDonald, G. W. G. Sharp, and S. G. Straub Activation of the KATP channel-independent signaling pathway by the nonhydrolyzable analog of leucine, BCH Am J Physiol Endocrinol Metab, August 1, 2003; 285(2): E380 - E389. [Abstract] [Full Text] [PDF]