PROTECTIVE ACTION OF SUCCINIC ACID MONOMETHYL ESTER AGAINST THE IMPAIRMENT OF GLUCOSE-STIMULATED INSULIN RELEASE CAUSED BY GLUCOPENIA OR STARVATION - METABOLIC DETERMINANTS

The monomethyl ester of succinic acid (SME) was recently found to prot ect pancreatic islet B-cells against the impairment of glucose-stimula ted insulin release caused by either glucopenia or starvation. The pos sible metabolic determinants of such a protective action are now scrut inized. After 180 min preincubation at 2.8 mM D-glucose in the presenc e of SME (10 mM), the oxidation of D-[U-C-14]glucose, relative to eith er the utilization of D-[5-H-3]glucose or the generation of C-14-label ed acidic metabolites, was higher than that after preincubation in the absence of SME, and became close to that otherwise found after preinc ubation at 16.7 mM D-glucose. Likewise, after 3 days of culture at a l ow concentration of D-glucose (2.8 nM), the presence of SME in the cul ture medium tended to increase the subsequent oxidation of D-[6-C-14]g lucose and utilization of D-[5-H-3]glucose. These two variables increa sed as a function of the concentration of D-glucose in the culture med ium, this coinciding with a modest increase in hexokinase activity and a more pronounced increase in glucokinase activity. The presence of S ME in the culture medium failed, however, to exert any obvious effect upon the respiration of the islets, suggesting that the protective act ion of the ester against glucopenia may also involve variables distinc t from the metabolism of either endogenous or exogenous nutrients. Lik ewise, the fact that SME infusion tb starved rats prevents the impairm ent of glucose-induced insulin release otherwise attributable to starv ation may involve enzymatic determinants, such as a less severe decrea se in glucokinase activity, metabolic variables, such as a greater rel ative increase in D-[U-C-14]glucose oxidation relative to D-[5-H-3]glu cose utilization in response to a rise in extracellular D-glucose conc entration, and other factors yet to be identified that-participate in the secretory sequence at a site distal to those metabolic events trig gered by D-glucose in the islet cells. (C) 1994 Academic Press, Inc.