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

Abstract

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 2H 2]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 < .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 < .05), whereas glucose production was unexpectedly increased ( P < .05) above values of saline-injected rats. Glucose utilization was also increased by B 827-33 in fasted diabetic rats ( P < .05); the modifications of glucose production were more complicated: when glucose remained greater than 4 to 5 mmol/L, a decreased glucose production participated in the decrease in glucose level, but when glucose decreased to 4 mmol/L or less, as in starved normal rats, there was instead an increase ( P < .05) in glucose production. These different evolutions of glucose production rates suggest that in starved normal and in some starved diabetic rats, the decrease in glucose level was sufficient to trigger counterregulatory mechanisms. In conclusion, (1) the mechanisms of the hypoglycemic action of CPT I inhibitors appear dependent on the nutritional status, and (2) the present results confirm that such compounds could be useful in the treatment of some diabetic patients if their hypoglycemic action persists on a long-term basis.