In vivo induction of insulin secretion by ornithine alpha-ketoglutarate: involvement of nitric oxide and glutamine.

We previously demonstrated that ornithine alpha-ketoglutarate (OKG), known for its anabolic properties, induces insulin secretion in vitro. The present study was undertaken to further characterize this effect in vivo and investigate a possible interaction with glucose both in vivo and in vitro. Male Wistar rats received an intravenous bolus of OKG (25 mg/kg) and/or glucose (0.8 g/kg) or saline, and their plasma insulin and glucose levels were monitored for 30 minutes. OKG alone increased plasma insulin to a similar extent to glucose. In combination with glucose, OKG significantly increased glucose-induced insulin secretion in vivo and in vitro, and led to a significant increase in glucose utilization in vivo. The absence of significant variations in plasma arginine and glutamine suggests a direct effect of OKG on the pancreas. To assess the involvement of the synthesis of nitric oxide and glutamine in OKG-induced insulin secretion, the experiments were repeated in the presence of inhibitors of these 2 pathways, respectively L-nitroarginine-methylester (L-NAME) and methionine sulfoximine (MSO). Both inhibitors were able significantly to reduce OKG-induced insulin secretion without affecting either basal or glucose-induced insulin release. Thus OKG acts directly with glucose on islets to induce insulin secretion via mechanisms involving NO and glutamine synthesis. In addition, our results suggest that OKG and glucose act via separate pathways.