L-valine is a powerful stimulator of GLP-1 secretion in rodents and stimulates secretion through ATP-sensitive potassium channels and voltage-gated calcium channels

BACKGROUND: We previously reported that, among naturally occurring amino acids, L-valine is the most powerful luminal stimulator of GLP-1 release from the upper rat small intestine, but the molecular mechanism was unknown. METHODS: We examined orally administered L-valine in mice, and defined mechanisms of L-valine–stimulated GLP-1 secretion using the isolated perfused rat small intestine and GLUTag cells; effects on distal gut hormones were tested in perfused rat colon. RESULTS: Oral L-valine (1 g/kg) increased plasma active GLP-1 in male mice to levels comparable with oral glucose (2 g/kg) (tAUC, P>0.05). In perfused rat small intestine, luminal L-valine (50 mM) robustly stimulated GLP-1 (P<0.0001); the response was inhibited by the voltage-gated Ca2+ channel blocker nifedipine (10 µM; P<0.01). Luminal Na+ depletion did not affect L-valine–induced GLP-1 (P>0.05), indicating Na+-coupled co-transport is not required for depolarization. The KATP opener diazoxide (250 µM) abolished the L-valine–induced GLP-1 response (P<0.05), suggesting metabolism-dependent closure of KATP channels underlies depolarization and activation of Ca2+ channels. L-valine tended to stimulate GLP-1 and PYY in perfused colon. CONCLUSIONS: L-valine potently stimulates GLP-1 secretion in rodents. Data support a mechanism in which intracellular metabolism of L-valine closes KATP channels, leading to depolarization and opening of voltage-gated Ca2+ channels to drive GLP-1 secretion.

Ida Marie Modvig, Mark M. Smits, Katrine Douglas Galsgaard, Anna Pii Hjørne, Anna Katarzyna Drzazga, Mette Marie Rosenkilde, Jens Juul Holst