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1 Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
2 Childrens Diabetes Center, University of Wisconsin, Madison, WI, USA
* To whom correspondence should be addressed. E-mail: sgs4{at}cornell.edu.
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 KATP channel-independent pathway was studied in the presence of diazoxide and KCl, leucine and its non-metabolizable analog BCH both stimulated insulin secretion to a greater extent than glucose. Glutamine and dimethyl-glutamate had no effect. As the only known action of BCH is stimulation of glutamate dehydrogenase, this is sufficient to develop the full effect of the KATP channel-independent pathway. Glucose, leucine and BCH had no effect on intracellular citrate levels. Leucine and BCH both decreased glutamate levels. 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 KATP 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 KATP channel-independent pathway.
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