PANCREATIC-ISLET RESPONSE TO DICARBOXYLIC-ACID ESTERS IN RATS WITH TYPE-2 DIABETES - ENZYMATIC, METABOLIC AND SECRETORY ASPECTS

This study aimed to compare the metabolic and secretory responses of p ancreatic islets from animals with non-insulin-dependent diabetes to D -glucose with the effects of the methyl esters of succinic acid (SME) and glutamic acid (GME). The insulin secretory response to D-glucose w as impaired in islets from rats with diabetes which was either inherit ed (Goto-Kakizaki (GK) rats) or acquired (streptozotocin-treated (STZ) rats). This coincided with a preferential alteration of oxidative rel ative to total glycolysis in intact islets and a selective defect of F AD-linked mitochondrial glycerophosphate dehydrogenase (m-GDH) in isle t homogenates. This enzymatic defect was also found in purified B cell s from STZ rats. It contrasted both with unaltered activities of gluta mate dehydrogenase and succinate dehydrogenase in the islets of diabet ic animals and with a normal or even increased activity of m-GDH in th e livers of GK and STZ rats. The oxidation of [1,4-C-14]SME and [U-C-1 4]GME appeared decreased in islets of GK or STZ animals when compared with control rats, but no significant difference between control and d iabetic rats was observed when the oxidative data were expressed relat ive to the rate of [U-C-14]GME hydrolysis. Nevertheless, the absolute values for insulin release evoked by a non-metabolized analogue of L-l eucine (BCH), by SME and by the association of BCH with either SME or GME were invariably lower in islets of GK and STZ rats than in those o f control animals. These findings indicate that the enzymatic and meta bolic situation in islets of GK and STZ rats could allow the expressio n of the insulinotropic potential of SME and GME, even if their immedi ate secretory effects are impaired in the islets of these diabetic ani mals.