Activation of the KATP channel-independent signaling pathway by the nonhydrolyzable analog of leucine, BCH.
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+ (KATP) 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 KATP 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 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.
Liu
Yi-Jia
YJ
Dept. of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853-6401, USA. sgs4@cornell.edu
Cheng
Haiying
H
Drought
Heather
H
MacDonald
Michael J
MJ
Sharp
Geoffrey W G
GW
Straub
Susanne G
SG
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000598:Amino Acids, Cyclic / Q000494:pharmacology*; D000818:Animals; D019343:Citric Acid / Q000378:metabolism; D002952:Citric Acid Cycle; D003981:Diazoxide / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004951:Esterification; D005947:Glucose / Q000494:pharmacology; D005969:Glutamate Dehydrogenase / Q000378:metabolism; D005973:Glutamine / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D050356:Lipid Metabolism; D008297:Male; D010084:Oxidation-Reduction; D019308:Palmitic Acid / Q000378:metabolism; D015221:Potassium Channels / Q000502:physiology*; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*
D000598:Amino Acids, Cyclic; D007328:Insulin; D015221:Potassium Channels; D005973:Glutamine; C006504:2-aminobicyclo(2,2,1)heptane-2-carboxylic acid; D019343:Citric Acid; D019308:Palmitic Acid; D011189:Potassium Chloride; D000255:Adenosine Triphosphate; D005969:Glutamate Dehydrogenase; D007930:Leucine; D005947:Glucose; D003981:Diazoxide