PHOSPHATE-DEPLETION IMPAIRS LEUCINE-INDUCED INSULIN-SECRETION

Phosphate depletion (PD) in vivo causes a sundry of abnormalities in p ancreatic islets including a rise in cytosolic calcium, low ATP conten t, reduced Ca2+ ATPase and Na+-K+ ATPase activity, and impaired insuli n secretion in response to glucose or potassium. L-Leucine is a strong secretagogue that triggers insulin secretion by deamination to alpha- ketoisocaproic acid (KIC) and the subsequent metabolism of the latter to ATP and by the activation of glutamate dehydrogenase (GLDH), which acts on glutamate to generate alpha-ketoglutarate, the metabolism of w hich results in ATP production. The generation of ATP triggers events that lead to insulin secretion. It is not known whether PD impairs leu cine-induced insulin secretion, and the cellular derangements that are involved in such an abnormality are not defined. These issues were st udied in PD rats and in pair-weighed normal animals as controls. D-leu cine uptake by islets from PD rats is normal, but both leucine- and KI C-induced insulin secretions are impaired and the activity of branched -chain keto acid dehydrogenase, which facilitates the metabolism of KI C, is reduced. Both leucine and 2-aminobicyclo (2-2-1) haptene failed to stimulate GLDH and to augment the generation of alpha-ketoglutarate in the islets of PD rats. Also, the concentration of basal alpha-keto glutarate was significantly higher in the islets of PD rats, suggestin g that its metabolism is impaired. In addition, the activity of glutam inase is significantly reduced, an abnormality that would result in de creased production of glutamate, the substrate for GLDH. The data show that PD impairs leucine-induced insulin secretion. This derangement i s due to impairment in the leucine-alpha-ketoisocaproic acid pathway a s well as in the leucine-GLDH-alpha-ketoglutarate-glutaminase pathway. The results support the notion that PD is associated with a generaliz ed failure of the pancreatic islets to respond to the three main secre tagogues of insulin, i.e., glucose, potassium, and amino acids.