INSULINOTROPIC ACTION OF GLUTAMIC-ACID DIMETHYL ESTER

Glutamic acid dimethyl ester (GME; 3.0-10.0 mM) enhanced insulin release evoked by 6.0-8.3 mM D-glucose, 1.0-10.0 mM L-leucine, or 5.0-10.0 mM 2-amino-bicyclo(2,2,1)heptane-2-carboxyl acid, causing a shift to the left of the sigmoidal relationship between insulin output and D-glucose concentration. In the absence of D-glucose, GME also unmasked the insulinotropic potential of glibenclamide. In islets exposed to L-leucine, the insulinotropic action of GME coincided with an early fall and later increase in Rb-86 outflow and augmentation of Ca-45 outflow from prelabeled islets. The measurement of O-2 uptake, NH4+ output production of (CO2)-C-14 from islets prelabeled with [U-C-14]palmitate, generation of C-14-labeled amino acids and (CO2)-C-14 from the dimethyl ester of either L-[1-C-14]glutamic acid or L-[U-C-14]glutamic acid, and D-[2-C-14]glucose as well as D-[6-C-14]glucose oxidation in the presence or absence of GME indicated that the latter ester was efficiently converted to L-glutamate and its further metabolites. The overall gain in O-2 uptake represented the balance between GME oxidation and its sparing action on the catabolism of endogenous fatty acids and exogenous D-glucose. It is proposed that GME might represent a new tool to bypass beta-cell, defects in D-glucose transport, phosphorylation, and further metabolism and, hence, to stimulate insulin release in experiments conducted in animal models of non-insulin-dependent diabetes mellitus.