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Anaplerotic input is sufficient to induce time-dependent potentiation of insulin release in rat pancreatic islets

¹Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853; and ²University of Wisconsin Children's Diabetes Center, Madison, Wisconsin 53706

Submitted 22 August 2003 ; accepted in final form 18 June 2004

Nutrients that induce biphasic insulin release, such as glucose and leucine, provide acetyl-CoA and anaplerotic input in the -cell. The first phase of release requires increased ATP production leading to increased intracellular Ca²⁺ concentration ([Ca²⁺]_i). The second phase requires increased [Ca²⁺]_i and anaplerosis. There is strong evidence to indicate that the second phase is due to augmentation of Ca²⁺-stimulated release via the K_ATP channel-independent pathway. To test whether the phenomenon of time-dependent potentiation (TDP) has similar properties to the ATP-sensitive K⁺ channel-independent pathway, we monitored the ability of different agents that provide acetyl-CoA and anaplerotic input or both of these inputs to induce TDP. The results show that anaplerotic input is sufficient to induce TDP. Interestingly, among the agents tested, the nonsecretagogue glutamine, the nonhydrolyzable analog of leucine aminobicyclo[2.2.1]heptane-2-carboxylic acid, and succinic acid methyl ester all induced TDP, and all significantly increased -ketoglutarate levels in the islets. In conclusion, anaplerosis that enhances the supply and utilization of -ketoglutarate in the tricarboxylic acid cycle appears to play an essential role in the generation of TDP.

insulin secretion; anaplerosis; -ketoglutarate

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