Metabolism - Clinical and Experimental
Volume 52, Issue 3 , Pages 344-350 , March 2003

In vivo induction of insulin secretion by ornithine α-ketoglutarate: Involvement of nitric oxide and glutamine

Received 3 June 2002 ,Accepted 26 September 2002.

References 

  1. Gay G, Villaume C, Beaufrand MJ, et al.  Effects of ornithine alpha-ketoglutarate on blood insulin, glucagon and amino acids in alcoholic cirrhosis. Biomedicine. 1979;30:173–177
  2. Leander U, Fürst P, Vesterberg K, et al.  Nitrogen sparing effect of Ornicetil in the immediate postoperative state. Clinical biochemistry and nitrogen balance. Clin Nutr. 1985;4:43–51
  3. Cynober L, Saizy R, Nguyen Dinh F, et al.  Effect of enterally administered ornithine alpha-ketoglutarate on plasma and urinary amino acid levels after burn injury. J Trauma. 1984;24:590–596
  4. Cynober L, Blondé F, Lioret N, et al.  Arterio-venous differences in amino acids, glucose, lactate and fatty acids in burn patients: Effect of ornithine-alpha-ketoglutarate. Clin Nutr. 1986;5:221–226
  5. Cynober L. Ornithine alpha-ketoglutarate. In:  Cynober L editors. Amino Acid Metabolism and Therapy in Health and Nutritional Disease. Boca Raton, FL: CRC Press; 1995;p. 385–395
  6. De Bandt JP, Cynober L. Amino acids with anabolic properties. Curr Opin Clin Nutr Metab Care. 1998;1:263–272
  7. Vaubourdolle M, Cynober L, Lioret N, et al.  Influence of enterally administered ornithine alpha-ketoglutarate on hormonal patterns in burn patients. Burns. 1987;13:349–356
  8. Krassowski J, Rousselle J, Maeder E, et al.  The effect of ornithine alpha-ketoglutarate on insulin and glucagon secretion in normal subjects. Acta Endocrinol. 1981;98:252–255
  9. Cynober L, Coudray-Lucas C, De Bandt JP, et al.  Action of ornithine alpha-ketoglutarate, ornithine hydrochloride, and calcium alpha-ketoglutarate on plasma amino acid and hormonal patterns in healthy subjects. J Am Coll Nutr. 1990;9:2–12
  10. Schneid C, Darquy S, Cynober L, et al.  Ornithine 2-oxoglutarate and insulin secretion by rat pancreatic islets. Clin Nutr. 2000;19:S11; (suppl 1, abstr)
  11. Schneid C, Darquy S, Reach G, et al.  Etude des mécanismes impliqués dans la sécrétion d'insuline induite par l'α-cétoglutarate d'ornithine dans un modèle d'îlots de Langerhans de rat. Diabetes Metab. 2001;27:1561; (suppl 1, abstr)
  12. Schneid C, Darquy S, Cynober L, Reach G, De Bandt JP. α-cétoglutarate d'ornithine et sécrétion d'insuline par les îlots de Langerhans: Rôle de l'ornithine et de l'α-cétoglutarate. Nutr Clin Metab. 2000;47:130S; (suppl 2, abstr)
  13. Le Boucher J, Farges MC, Minet R, et al.  Modulation of immune response with ornithine α-ketoglutarate in burn injury: An arginine or glutamine dependency?. Nutrition. 1999;15:773–777
  14. Floyd J, Fajans S, Conn J, et al.  Stimulation of insulin secretion by amino acids. J Clin Invest. 1966;45:1487–1502
  15. Malaisse WJ, Malaisse-Lagae F, Sener A. The stimulus-secretion coupling of glucose-induced insulin release: Effect of aminooxyacetate upon nutrient-stimulated insulin secretion. Endocrinology. 1982;111:392–397
  16. Opara EC, Burch WM, Akwari OE. Characterization of glutamine-regulated pancreatic islet hormone release. Surg Forum. 1990;41:16–19
  17. Michalik M, Nelson J, Erecinska M. Glutamate production in islets of Langerhans: Properties of phosphate-activated glutaminase. Metabolism. 1992;41:1319–1326
  18. Malaisse W. Metabolic factors influencing synthesis and secretion of pancreatic islet hormones. In:  Samoles E editors. The Endocrine Pancreas. New York, NY: Raven; 1991;p. 73–92
  19. Maechler P, Wollheim CB. Mitochondrial glutamate acts as a messenger in glucose-induced insulin exocytosis. Nature. 1999;402:685–689
  20. Gerich J, Charles M, Grodsky G. Characterization of the effect of arginine and glucose on glucagon and insulin release from perfused rat pancreas. J Clin Invest. 1974;54:833–841
  21. Levin S, Karam J, Hane S, et al.  Enhancement of arginine-induced insulin secretion in man by prior administration of glucose. Diabetes. 1971;20:171–176
  22. Cynober L, Vaubourdolle M, Dore A, et al.  Kinetics and metabolic effects of orally administered ornithine alpha-ketoglutarate in healthy subjects fed with a standardized regimen. Am J Clin Nutr. 1984;39:514–519
  23. Assan R, Attali J, Ballerio G, et al.  Glucagon secretion induced by natural and artificial amino acids in the perfused rat pancreas. Diabetes. 1977;26:300–307
  24. Lacy PE, Kostianovsky M. Method for the isolation of intact islets of Langerhans from the rat pancreas. Diabetes. 1967;16:35–39
  25. Kilbourn RG, Szabo C, Traber DL. Beneficial versus detrimental effects of nitric oxide synthase inhibitors in circulatory shock: Lessons learned from experimental and clinical and clinical studies. Shock. 1997;7:235–246
  26. Southan GJ, Szabo C. Selective pharmacological inhibition of distinct nitric oxide synthase isoforms. Biochem Pharmacol. 1996;51:383–394
  27. Minet R, Villie F, Marcollet M, et al.  Measurement of glutamine synthetase activity in rat muscle by a colorimetric assay. Clin Chim Acta. 1997;268:121–132
  28. Tourrel C, Bailbé D, Meile MJ, et al.  Glucagon-like-peptide-1 and exendin-4 stimulates b-cell neogenesis in streptozotocin-treated newborn rats resulting in persistently improved glucose homeostasis at adult age. Diabetes. 2001;50:1562–1570
  29. Cynober L. The use of alpha-ketoglutarate salts in clinical nutrition and metabolic care. Curr Opin Clin Nutr Metab Care. 1999;2:33–37
  30. Schmidt HH, Warner TD, Ishii K, et al.  Insulin secretion from pancreatic B cells caused by L-arginine-derived nitrogen oxides. Science. 1992;255:721–723
  31. Gross R, Roye M, Manteghetti M, et al.  Mechanisms involved in the effect of nitric oxide synthase inhibition on L-arginine-induced insulin secretion. Br J Pharmacol. 1997;120:495–501
  32. Blachier F, Mourtada A, Sener A, et al.  Stimulus-secretion coupling of arginine-induced insulin release. Uptake of metabolized and non metabolized cationic amino acids by pancreatic islets. Endocrinology. 1989;124:134–141
  33. Palmer JP, Benson JW, Walter RM. Arginine stimulated acute phase of insulin and glucagon secretion in diabetic subjects. J Clin Invest. 1973;52:870–876
  34. Blachier F, Leclercq-Meyer V, Marchand J, et al.  Stimulus-secretion coupling of arginine-induced insulin release. Functional response of islets to L-arginine and L-ornithine. Biochim Biophys Acta. 1989;1013:144–151
  35. Vaubourdolle M, Coudray-Lucas C, Jardel A, et al.  Action of enterally administered ornithine alpha-ketoglutarate on protein breakdown in skeletal muscle and liver of the burned rat. JPEN J Parenter Enteral Nutr. 1991;15:517–520
  36. Malaisse WJ, Malaisse-Lagae F, Rasschaert J, et al.  The fuel concept for insulin release: Regulation of glucose phosphorylation in pancreatic islets. Biochem Soc Trans. 1990;18:107–108
  37. Jones P, Persaud S, Bjaaland T, et al.  Nitric oxide is not involved in the initiation of insulin secretion from rat islets of Langerhans. Diabetologia. 1992;35:1020–1027
  38. Moinard C, Caldefie F, Walrand S, et al.  Involvement of glutamine, arginine, and polyamines in the action of ornithine alpha-ketoglutarate on macrophage functions in stressed rats. J Leuk Biol. 2000;67:834–840
  39. Malaisse WJ, Blachier F, Mourtada A, et al.  Stimulus-secretion coupling of arginine-induced insulin release. Metabolism of L-arginine and L-ornithine in pancreatic islets. Biochim Biophys Acta. 1989;1013:133–143
  40. Maechler P, Kennedy ED, Sebo E, et al.  Secretagogues modulate the calcium concentration in the endoplasmic reticulum of insulin-secreting cells. Studies in aequorin-expressing intact and permeabilized ins-1 cells. J Biol Chem. 1999;274:12583–12592
  41. Le Boucher J, Cynober L. Ornithine alpha-ketoglutarate: The puzzle. Nutrition. 1998;14:870–873
  42. Rorsman P, Renström E. Cell biology: Glutamate primes the pump. Nature. 1999;402:595–596

 Supported in part by a research grant from Chiesi, SA, Courbevoie, France. C.S. is a recipient of a grant from the “Fondation pour la Recherche Médicale.” Portions of this work have been previously published in abstract form.

☆☆ Address reprint requests to Dr Jean-Pascal De Bandt, Service de Biochimie A, Hôpital Hôtel-Dieu 1, place du Parvis Notre-Dame, F-75181 Paris cedex 04, France.

PII: S0026-0495(02)05270-8

doi: 10.1053/meta.2003.50054

Metabolism - Clinical and Experimental
Volume 52, Issue 3 , Pages 344-350 , March 2003