Delineation of glutamate pathways and secretory responses in pancreatic islets with β-cell–specific abrogation of the glutamate dehydrogenase

Molecular Biology of the Cell - Tập 23 Số 19 - Trang 3851-3862 - 2012
Laurène Vetterli1, Stefania Carobbio2, Shirin Pournourmohammadi2, Rafael Martín-del-Río3, Dorte M. Skytt4, Helle S. Waagepetersen4, Jorge Tamarit‐Rodriguez3, Pierre Maechler2
1Department of Cell Physiology and Metabolism, University of Geneva Medical Center, 1211 Geneva, Switzerland
2aDepartment of Cell Physiology and Metabolism, University of Geneva Medical Center, 1211 Geneva, Switzerland
3bDepartment of Biochemistry, Complutense University, 28040 Madrid, Spain
4cDepartment of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark

Tóm tắt

In pancreatic β-cells, glutamate dehydrogenase (GDH) modulates insulin secretion, although its function regarding specific secretagogues is unclear. This study investigated the role of GDH using a β-cell–specific GDH knockout mouse model, called βGlud1−/−. The absence of GDH in islets isolated from βGlud1–/–mice resulted in abrogation of insulin release evoked by glutamine combined with 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid or l-leucine. Reintroduction of GDH in βGlud1–/–islets fully restored the secretory response. Regarding glucose stimulation, insulin secretion in islets isolated from βGlud1–/–mice exhibited half of the response measured in control islets. The amplifying pathway, tested at stimulatory glucose concentrations in the presence of KCl and diazoxide, was markedly inhibited in βGlud1–/–islets. On glucose stimulation, net synthesis of glutamate from α-ketoglutarate was impaired in GDH-deficient islets. Accordingly, glucose-induced elevation of glutamate levels observed in control islets was absent in βGlud1–/–islets. Parallel biochemical pathways, namely alanine and aspartate aminotransferases, could not compensate for the lack of GDH. However, the secretory response to glucose was fully restored by the provision of cellular glutamate when βGlud1–/–islets were exposed to dimethyl glutamate. This shows that permissive levels of glutamate are required for the full development of glucose-stimulated insulin secretion and that GDH plays an indispensable role in this process.

Từ khóa


Tài liệu tham khảo

Ahuja N, 2007, J Biol Chem, 282, 33583, 10.1074/jbc.M705488200

Bertrand G, 2002, J Biol Chem, 277, 32883, 10.1074/jbc.M205326200

Braun M, 2010, Diabetes, 59, 1694, 10.2337/db09-0797

Bryla J, 1994, Metabolism, 43, 1187, 10.1016/0026-0495(94)90064-7

Bustamante J, 2001, Am J Physiol Endocrinol Metab, 281, E1275, 10.1152/ajpendo.2001.281.6.E1275

Carobbio S, 2009, J Biol Chem, 284, 921, 10.1074/jbc.M806295200

Carobbio S, 2004, Diabetologia, 47, 266, 10.1007/s00125-003-1306-2

Casimir M, 2009, J Biol Chem, 284, 25004, 10.1074/jbc.M109.015495

Casimir M, 2009, Biochem J, 424, 459, 10.1042/BJ20090729

Eto K, 1999, Science, 283, 981, 10.1126/science.283.5404.981

Eto K, 2003, Am J Physiol Endocrinol Metab, 285, E262, 10.1152/ajpendo.00542.2002

Fahien LA, 1988, J Biol Chem, 263, 13610, 10.1016/S0021-9258(18)68285-7

Fernandez-Pascual S, 2004, Biochem J, 379, 721, 10.1042/bj20031826

Fisher HF, 1985, Methods Enzymol, 113, 16, 10.1016/S0076-6879(85)13006-5

Frigerio F, 2008, Biochim Biophys Acta, 1777, 965, 10.1016/j.bbabio.2008.04.031

Gammelsaeter R, 2011, PLoS One, 6, e22960, 10.1371/journal.pone.0022960

Gao ZY, 1999, Diabetes, 48, 1535, 10.2337/diabetes.48.8.1535

Gembal M, 1992, J Clin Invest, 89, 1288, 10.1172/JCI115714

Gilon P, 1991, Endocrinology, 129, 2521, 10.1210/endo-129-5-2521

Haigis MC, 2006, Cell, 126, 941, 10.1016/j.cell.2006.06.057

Herrera PL, 2000, Development, 127, 2317, 10.1242/dev.127.11.2317

Hoy M, 2002, FEBS Lett, 531, 199, 10.1016/S0014-5793(02)03500-7

Hudson RC, 1993, Comp Biochem Physiol B, 106, 767, 10.1016/0305-0491(93)90031-Y

Li C, 2006, J Biol Chem, 281, 15064, 10.1074/jbc.M600994200

Li C, 2003, J Biol Chem, 278, 2853, 10.1074/jbc.M210577200

MacDonald MJ, 1982, Arch Biochem Biophys, 213, 643, 10.1016/0003-9861(82)90594-X

Maechler P, 2006, Int J Biochem Cell Biol, 38, 696, 10.1016/j.biocel.2005.12.006

Maechler P, 2002, Diabetes, 51, S99, 10.2337/diabetes.51.2007.S99

Maechler P, 1999, Nature, 402, 685, 10.1038/45280

Malaisse WJ, 1982, Endocrinology, 111, 392, 10.1210/endo-111-2-392

Malaisse WJ, 1980, Mol Cell Endocrinol, 20, 171, 10.1016/0303-7207(80)90080-5

Mawhinney TP, 1986, J Chromatogr, 358, 231, 10.1016/S0021-9673(01)90333-4

Michaelidis TM, 1993, Genomics, 16, 150, 10.1006/geno.1993.1152

Owen OE, 2002, J Biol Chem, 277, 30409, 10.1074/jbc.R200006200

Panten U, 1984, Biochem J, 219, 189, 10.1042/bj2190189

Pizarro-Delgado J, 2010, Biochem J, 431, 381, 10.1042/BJ20100714

Pizarro-Delgado J, 2009, Biochem J, 419, 359, 10.1042/BJ20081731

Pralong WF, 1994, J Biol Chem, 269, 27310, 10.1016/S0021-9258(18)46986-4

Pullen TJ, 2010, Islets, 2, 89, 10.4161/isl.2.2.11025

Ravier MA, 2000, J Biol Chem, 275, 1587, 10.1074/jbc.275.3.1587

Rubi B, 2001, J Biol Chem, 276, 36391, 10.1074/jbc.M104999200

Sener A, 1981, Biochim Biophys Acta, 677, 32, 10.1016/0304-4165(81)90142-2

Sener A, 1980, Nature, 288, 187, 10.1038/288187a0

Sener A, 1981, Proc Natl Acad Sci USA, 78, 5460, 10.1073/pnas.78.9.5460

Sener A, 1982, Horm Metab Res, 14, 405, 10.1055/s-2007-1019030

Smith TJ, 2001, J Mol Biol, 307, 707, 10.1006/jmbi.2001.4499

Stanley CA, 1998, N Engl J Med, 338, 1352, 10.1056/NEJM199805073381904

Storto M, 2006, Mol Pharmacol, 69, 1234, 10.1124/mol.105.018390

Yang SJ, 2003, Biochimie, 85, 581, 10.1016/S0300-9084(03)00092-0

Zhou Y, 2010, J Biol Chem, 285, 33718, 10.1074/jbc.M110.136846

Thông tin
Thông tin xuất bản

Molecular Biology of the Cell

Tập 23 Số 19

3851-3862

Thông tin tác giả