Effects of ornithine α-ketoglutarate on insulin secretion in rat pancreatic islets

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Volume 89, Issue 2, February (2003), pp. 249-257 © The Author 2003

doi:10.1079/BJN2002761

 

Medline/PubMed Citation | Related Articles in PubMed | Download to Citation

Matcher Effects of ornithine #945;-ketoglutarate on insulin secretion in rat

pancreatic islets: implication of nitric oxide synthase and glutamine synthetase

pathways

Christina Schneid1,2, Sylviane Darquy1,2, Luc Cynober1,2, Gérard Reach1 and

Jean-Pascal De Bandt1,2†

1INSERM U-341, Service de Diabètologie, Hôpital Hôtel-Dieu, Paris, France

2Laboratoire de Biologie de la Nutrition EA 2498, Faculté de Pharmacie-Paris 5,

Paris, France

(Received 5 November 2001–Revised 1 July 2002–Accepted 5 September 2002)

Abstract

Ornithine #945;-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 #945;-ketoglutarate (#945;-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 #945;-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:

L-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 #945;-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.

 

 

Abbreviations: Arg; arginine; DFMO; difluoromethylornithine; Glc; glucose; Gln;

glutamine; #945;-KG; #945;-ketoglutarate; KRB; Krebs–Ringer buffer; L-NAME;

L-nitroarginine methyl ester; MSO; methionine sulfoximine; OKG; ornithine

#945;-ketoglutarate; Orn; ornithine

Nitric oxide: Polyamines: Glutamine

 

 

 

 

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