EFFECTS OF BLOCKADE OF FATTY-ACID OXIDATION ON WHOLE-BODY AND TISSUE-SPECIFIC GLUCOSE-METABOLISM IN RATS

We examined the effect of the long-chain fatty acid oxidation blocker methyl palmoxirate (methyl 2-tetradecyloxiranecarboxylate, McN-3716) o n glucose metabolism in conscious rats. Fasted animals [5 h with or wi thout hyperinsulinemia (100 mU/1) and 24 h] received methyl palmoxirat e (30 or 100 mg/kg body wt po) or vehicle 30 min before a euglycemic g lucose clamp. Whole body and tissue-specific glucose metabolism were c alculated from 2-deoxy-[H-3]-glucose kinetics and accumulation. Oxidat ive metabolism was assessed by respiratory gas exchange in 24-h fasted animals. Pyruvate dehydrogenase complex activation was determined in selected tissues. Methyl palmoxirate suppressed whole body lipid oxida tion by 40-50% in 24-h fasted animals, whereas carbohydrate oxidation was stimulated 8- to 10-fold. Whole body glucose utilization was not s ignificantly affected by methyl palmoxirate under any conditions; hepa tic glucose output was suppressed only in the predominantly gluconeoge nic 24-h fasted animals. Methyl palmoxirate stimulated glucose uptake in heart in 24-h fasted animals [ 15 +/- 5 vs. 220 +/- 28 (SE) mumol . 100 g1-1 . min-1], with smaller effects in 5-h fasted animals with or without hyperinsulinemia. Methyl palmoxirate induced significant acti vation of pyruvate dehydrogenase in heart in the basal state, but not during hyperinsulinemia. In skeletal muscles, methyl palmoxirate suppr essed glucose utilization in the basal state but had no effect during hyperinsulinemia; pyruvate dehydrogenase activation in skeletal muscle was not affected by methyl palmoxirate under any conditions. The resp onses in skeletal muscle are consistent with the operation of a mechan ism similar to the Pasteur effect. The lack of effect of methyl palmox irate on whole body glucose utilization was consistent with a sum of o pposing effects in tissues behaving like heart and like skeletal muscl es.