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-carboxylic 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 86Rb outflow and augmentation of 45Ca outflow from prelabeled islets. The measurement of O2 uptake, NH4+ output, production of 14CO2 from islets prelabeled with [U-14C]palmitate, generation of 14C-labeled amino acids and 14CO2 from the dimethyl ester of either L-[1-14C]glutamic acid or L-[U-14C]glutamic acid, and D-[2-14C]glucose as well as D-[6-14C]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 O2 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.
Sener
A
A
Laboratory of Experimental Medicine, Brussels Free University, Belgium.
Conget
I
I
Rasschaert
J
J
Leclercq-Meyer
V
V
Villanueva-Peñacarrillo
M L
ML
Valverde
I
I
Malaisse
W J
WJ
D000818:Animals; D002118:Calcium / Q000493:pharmacokinetics; D002245:Carbon Dioxide / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D005947:Glucose / Q000494:pharmacology; D005971:Glutamates / Q000378:metabolism / Q000494:pharmacology*; D005905:Glyburide / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D007930:Leucine / Q000494:pharmacology; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D012413:Rubidium / Q000493:pharmacokinetics
D005971:Glutamates; D007328:Insulin; D002245:Carbon Dioxide; C035873:glutamic acid dimethyl ester; D007930:Leucine; D005947:Glucose; D012413:Rubidium; D005905:Glyburide; D002118:Calcium