INSULIN-INDEPENDENT AND EXTREMELY RAPID SWITCH IN THE PARTITIONING OFHEPATIC FATTY-ACIDS FROM OXIDATION TO ESTERIFICATION IN STARVED-REFEDDIABETIC RATS - POSSIBLE ROLES FOR CHANGES IN CELL PH AND VOLUME

The requirement for a normal insulin response in mediating the starved -to-refed transition, with respect to the partitioning of hepatic fatt y acids between beta-oxidation and esterification to glycerol, was stu died. Diabetic rats were starved for 24 h and refed ad libitum for var ious periods of time. There was no increase in plasma insulin in respo nse to the meal. However, the fatty acid oxidation: esterification rat io was very rapidly decreased from the starved to the fed value, most of the transition being achieved within the first hour of refeeding. T here was a 2 h lag in the response of hepatic malonyl-CoA concentratio n, such that this rapid switch from oxidation to esterification could not be explained on the basis of changes in the absolute concentration of this inhibitor of carnitine palmitoyltransferase I (CPT I). Hepati c pyruvate and lactate concentrations both increased by several-fold u pon refeeding and peaked after 1 h and 3 h, respectively. The hepatic lactate:pyruvate ratio increased 3.2-fold during the first 3 h of refe eding, suggesting that the cytosolic NAD(+)-NADH couple became much mo re highly reduced during the lag-period between the onset of inhibitio n of flux of fatty acids towards oxidation and the rise in malonyl-CoA concentration. This may be indicative of a lowering of intracellular pH, which would amplify greatly the sensitivity of CPT I to the inhibi tor. In view of the very rapid and high food intake by these diabetic rats, the possibility is also considered that portal concentrations of amino acids and other metabolites could give rise to an increase in l iver cell-volume that would inhibit CPT I acutely by an as yet unknown mechanism [M. Guzman, G. Velasco, J. Castro and V. A. Zammit (1994) F EES Lett. 344, 239-241].