Mechanisms of the glucose lowering effect of a carnitine palmitoyl transferase inhibitor in normal and diabetic rats.

To determine the respective part of modifications of glucose appearance and disappearance rates in the hypoglycemic action of a compound (B 827-33) inhibiting carnitine palmitoyl transferase (CPT I), we measured glucose kinetics ([6,6(2)H2]glucose) in normal and diabetic (streptozocin) rats before and after injection of either saline or B 827-33. Studies were initiated 4 hours (postabsorptive groups) and 24 hours (fasted groups) after food withdrawal. In all groups, there was evidence of inhibition of fatty acids oxidation (sharp decrease of ketone bodies [KB] and increase of plasma nonesterified fatty acids [NEFA]) after B 827-33 injection. Glucose levels decreased also in all groups after B 827-33 administration, the decrease being more important in starved than in postabsorptive groups and, whatever the nutritional status, in diabetic than in normal rats. In all groups, the evolution of plasma insulin was comparable after saline or B 827-33 injection. The mechanisms responsible for the decrease in glucose levels appeared dependent on the nutritional status. In postabsorptive normal and diabetic rats, compared with saline-injected rats, we observed a moderate inhibitory action (P less than .05) of B 827-33 on glucose production without stimulation of glucose utilization rate. After 24 hours of starvation, the decrease in glucose levels of normal rats was entirely due to a stimulation of glucose utilization (P less than .05), whereas glucose production was unexpectedly increased (P less than .05) above values of saline-injected rats.(ABSTRACT TRUNCATED AT 250 WORDS)