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 protect pancreatic islet B-cells against the impairment of glucose-stimulated insulin release caused by either glucopenia or starvation. The possible metabolic determinants of such a protective action are now scrutinized. After 180 min preincubation at 2.8 mM D-glucose in the presence of SME (10 mM), the oxidation of D-[U-¹⁴C]glucose, relative to either the utilization of D-[5-³H]glucose or the generation of ¹⁴C-labeled acidic metabolites, was higher than that after preincubation in the absence of SME, and became close to that otherwise found after preincubation at 16.7 mM D-glucose. Likewise, after 3 days of culture at a low concentration of D-glucose (2.8 nM), the presence of SME in the culture medium tended to increase the subsequent oxidation of D-[6-¹⁴C]glucose and utilization of D-[5-³H]glucose. These two variables increased as a function of the concentration of D-glucose in the culture medium, this coinciding with a modest increase in hexokinase activity and a more pronounced increase in glucokinase activity. The presence of SME in the culture medium failed, however, to exert any obvious effect upon the respiration of the islets, suggesting that the protective action of the ester against glucopenia may also involve variables distinct from the metabolism of either endogenous or exogenous nutrients. Likewise, the fact that SME infusion to starved rats prevents the impairment of glucose-induced insulin release otherwise attributable to starvation may involve enzymatic determinants, such as a less severe decrease in glucokinase activity, metabolic variables, such as a greater relative increase in D-[U-¹⁴C]glucose oxidation relative to D-[5-³H]glucose utilization in response to a rise in extracellular D-glucose concentration, and other factors yet to be identified that-participate in the secretory sequence at a site distal to those metabolic events triggered by D-glucose in the islet cells.