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Activation of the K_ATP channel-independent signaling pathway by the nonhydrolyzable analog of leucine, BCH

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 7 January 2003 ; accepted in final form 18 April 2003

Leucine and glutamine were used to elicit biphasic insulin release in rat pancreatic islets. Leucine did not mimic the full biphasic response of glucose. Glutamine was without effect. However, the combination of the two did mimic the biphasic response. When the ATP-sensitive K⁺ (K_ATP) channel-independent pathway was studied in the presence of diazoxide and KCl, leucine and its nonmetabolizable analog 2-aminobicyclo[2,2,1]heptane-2-carboxylic acid (BCH) both stimulated insulin secretion to a greater extent than glucose. Glutamine and dimethyl glutamate had no effect. Because the only known action of BCH is stimulation of glutamate dehydrogenase, this is sufficient to develop the full effect of the K_ATP channel-independent pathway. Glucose, leucine, and BCH had no effect on intracellular citrate levels. Leucine and BCH both decreased glutamate levels, whereas glucose was without effect. Glucose and leucine decreased palmitate oxidation and increased esterification. Strikingly, BCH had no effect on palmitate oxidation or esterification. Thus BCH activates the K_ATP channel-independent pathway of glucose signaling without raising citrate levels, without decreasing fatty acid oxidation, and without mimicking the effects of glucose and leucine on esterification. The results indicate that increased flux through the TCA cycle is sufficient to activate the K_ATP channel-independent pathway.

ATP-sensitive K⁺ channel; 2-aminobicyclo[2,2,1]heptane-2-carboxylic acid

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