Role of FFA-glucose cycle in glucoregulation during exercise in total absence of insulin

Muscle contraction in vitro increases glucose uptake (GU), independent of insulin, but in vivo, the exercise-induced increase in GU is impaired in insulin-deficient diabetic dogs. We wished to determine whether, in vivo, suppression of the free fatty acid (FFA)-glucose cycle with methylpalmoxirate (MP, inhibitor of FFA oxidation) alone or combined with propranolol (PRO, β- blocker) could improve GU during exercise in the absence of insulin. We performed four groups of exercise experiments (6 km/h, 10% slope) in depancreatized insulin-deprived dogs: 1) control (n = 6); 2) MP treated (5 oral doses of 10 mg/kg, twice daily, n = 6); 3) treated with MP + octanoate (OCT; oxidation unaffected by MP, 27 μmol · kg^-1 · min^-1 iv during exercise; n = 5); and 4) MP + PRO treated (5 μg · kg^-1 · min^-1 iv during exercise, n = 6). MP abolished ketosis (inhibition of hepatic FFA oxidation), decreased basal glucose production (GP), and increased metabolic clearance of glucose (MCR). During exercise, MP attenuated the increment in GP (P < 0.01), which was reversed by OCT. MP did not affect the exercise- induced increase in GU and MCR. With MP + PRO, FFAs decreased and lactate did not rise during exercise. GP was not further suppressed, but GU and MCR were increased (P < 0.01) to 89 and 31% of normal, respectively. In insulin- deprived depancreatized dogs, glucose cycling was increased to a greater extent than GP, as in type II diabetes. By the end of exercise, glucose cycling increased (P < 0.05), but to a similar extent as GP. In conclusion, in the absence of insulin, 1) at rest, inhibition of FFA oxidation with MP inhibits GP and increases MCR; 2) during exercise, inhibition of FFA oxidation blunts GP, but only combined inhibition of FFA oxidation, lipolysis, and perhaps also of muscle glycogenolysis with MP + PRO increases GU and MCR; and 3) because MP + PRO can improve GU and MCR in depancreatized dogs, an important action of insulin on the exercise-induced glucose uptake may be indirect through restraint of lipolysis and muscle glycogenolysis.