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Effects of ornithine α-ketoglutarate on insulin secretion in rat pancreatic islets: implication of nitric oxide synthase and glutamine synthetase pathways*

Published online by Cambridge University Press:  09 March 2007

Christina Schneid ,
Sylviane Darquy ,
Luc Cynober ,
Gérard Reach  and
Jean-Pascal De Bandt
Christina Schneid
Affiliation:
INSERM U-341, Service de Diabètologie, Hôpital Hôtel-Dieu, Paris, France Laboratoire de Biologie de la Nutrition EA 2498, Faculté de Pharmacie-Paris 5, Paris, France
Sylviane Darquy
Affiliation:
INSERM U-341, Service de Diabètologie, Hôpital Hôtel-Dieu, Paris, France Laboratoire de Biologie de la Nutrition EA 2498, Faculté de Pharmacie-Paris 5, Paris, France
Luc Cynober
Affiliation:
INSERM U-341, Service de Diabètologie, Hôpital Hôtel-Dieu, Paris, France Laboratoire de Biologie de la Nutrition EA 2498, Faculté de Pharmacie-Paris 5, Paris, France
Gérard Reach
Affiliation:
INSERM U-341, Service de Diabètologie, Hôpital Hôtel-Dieu, Paris, France
Jean-Pascal De Bandt*
Affiliation:
INSERM U-341, Service de Diabètologie, Hôpital Hôtel-Dieu, Paris, France Laboratoire de Biologie de la Nutrition EA 2498, Faculté de Pharmacie-Paris 5, Paris, France
*
†Corresponding author:Dr J.-P. De Bandt, fax +33 1 42 34 86 12, email jp.debandt@htd.ap-hop-paris.fr
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Abstract

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Ornithine α-ketoglutarate (OKG) administration in human subjects elicits insulin secretion. We investigated whether this action was related to an effect of OKG on islets of Langerhans, and addressed the underlying mechanisms of action. For this purpose the influence of OKG on insulin secretion was measured in isolated rat islets of Langerhans under two different conditions. In incubated islets, OKG (0·25 to 2·5 mmol/l) significantly and dose-relatedly increased insulin secretion (1·7- to 4·2-fold; P<0·05 v. basal). To study the kinetics of OKG-stimulated insulin secretion, perifusion experiments were performed, which showed that OKG affected insulin secretion in both initial and later phases. Experiments using α-ketoglutarate (α-KG) (1 mmol/l) or ornithine (Orn) (2 mmol/l) alone, in concentrations equal to that of OKG, showed that the OKG-induced insulin secretion could not be obtained by either component alone, suggesting that an α-KG–Orn interaction is mandatory for the insulin-secreting effect to occur. Since data obtained in vivo suggest that effects of OKG may depend on the synthesis of NO, glutamine and/or polyamines, three metabolic pathways potentially involved in insulin secretion, we then evaluated their contribution by means of their respective inhibitors: α-NG-nitroarginine methyl ester (l-NAME), methionine sulfoximine (MSO) and difluoromethylornithine (DFMO). Both l-NAME and MSO were able significantly to reduce OKG-induced insulin secretion (30 and 40 % respectively; P<0·05), while DFMO was ineffective. Thus OKG is an effective stimulator of insulin secretion, requiring the joint presence of both Orn and α-KG, and acting mainly via the synthesis of NO and glutamine. A better understanding of OKG insulino-secretory properties and its mechanisms of action are a prerequisite for its use in insulin-compromised situations.

Keywords

Nitric oxidePolyaminesGlutamine
Type
Research Article
Information
British Journal of Nutrition , Volume 89 , Issue 2 , February 2003 , pp. 249 - 257
Copyright
Copyright © The Nutrition Society 2003

Footnotes

*

Parts of this work have been published in abstract form: Schneid C, Darquy S, Reach G, Cynober L &De Bandt JP (2000) In vitro insulin stimulation in pancreatic islets by ornithine-α-ketoglutarate. Diabetologia43, Suppl. 1, A134; Schneid C, Darquy S, Reach G, Cynober L &De Bandt JP (2000) α-Cétoglutarate d'ornithine et sécrétion d'insuline par les îlots de Langerhans: Rôle de l'ornithine et de l'α-cétoglutarate. Nutrition Clinique et Métabolisme14, Suppl. 2, S131; Schneid C, Darquy S, Reach G, Cynober L &De Bandt JP (2000) 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 &Metabolism27, Suppl. 1, 1S61.

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