Impaired mitochondrial function and gluconeogenesis in late shock

Abstract

This study sought to elucidate mechanisms of hypoglycemia in late hemorrhagic shock by investigating the relationship between shock-induced alterations in hepatic mitochondrial energy-linked functions and mitochondrial ability to synthesize the glucose precursor phosphoenolypyruvate (PEP). Paired, nonfasted, anesthetized guinea pigs were subject to hemorrhagic shock for 180 min. Blood glucose and hepatic glycogen were then determined. Hepatic mitochondria were isolated for both polarographic determination of energy-linked functions and ability to synthesize PEP. Shocked animals with impaired mitochondrial energy-linked functions had a significant ( P < 0.01) decrease in ability to synthesize PEP. Shocked animals that maintained mitochondrial energy-linked functions also maintained PEP synthesis similar to that of nonshocked controls. When ADP was substituted for ATP the amounts of PEP synthesized in each group were similar to that observed with ATP. The decreased PEP synthesis in animals with impaired mitochondrial function was again significant ( P < 0.001) but the percentage decrease was greater with ADP than ATP. When ATP or ADP was eliminated there was a marked decrease in PEP synthesis in all groups but particularly in shocked animals with impaired mitochondrial function. Animals with impaired mitochondrial function maintained their blood glucose concentration at the expense of depleting their hepatic glycogen reserves. This study supports the hypothesis that decreased gluconeogenesis in late hemorrhagic shock is secondary to defective high-energy phosphate production. Furthermore, ATP appears to improve impaired gluconeogenesis by enhancing the synthesis of PEP. This improvement may account for the reported beneficial effects of ATP administration in shock.