Prior exercise and the response to insulin-induced hypoglycemia in the dog. Am J Physiol Endocrinol Metab 282: E1128-E1138, 2002; 10.1152/ ajpendo.00370.2001.-To test whether hepatic insulin action and the response to an insulin-induced decrement in blood glucose are enhanced in the immediate postexercise state as they are during exercise, dogs had sampling (artery, portal vein, and hepatic vein) catheters and flow probes (portal vein and hepatic artery) implanted 16 days before a study. After 150 min of moderate treadmill exercise or rest, dogs were studied during a 150-min hyperinsulinemic (1 mU ⅐ kg Ϫ1 ⅐ min Ϫ1 ) euglycemic (n ϭ 5 exercised and n ϭ 9 sedentary) or hypoglycemic (65 mg/dl; n ϭ 8 exercised and n ϭ 9 sedentary) clamp. Net hepatic glucose output (NHGO) and endogenous glucose appearance (Ra) and utilization (Rd) were assessed with arteriovenous and isotopic ([3-3 H]glucose) methods. Results show that, immediately after prolonged, moderate exercise, in relation to sedentary controls: 1) the glucose infusion rate required to maintain euglycemia, but not hypoglycemia, was higher; 2) Rd was greater under euglycemic, but not hypoglycemic conditions; 3) NHGO, but not Ra, was suppressed more by a hyperinsulinemic euglycemic clamp, suggesting that hepatic glucose uptake was increased; 4) a decrement in glucose completely reversed the enhanced suppression of NHGO by insulin that followed exercise; and 5) arterial glucagon and cortisol were transiently higher in the presence of a decrement in glucose. In summary, an increase in insulin action that was readily evident under euglycemic conditions after exercise was abolished by moderate hypoglycemia. The means by which the glucoregulatory system is able to overcome the increase in insulin action during moderate hypoglycemia is related not to an increase in Ra but to a reduction in insulin-stimulated Rd. The primary site of this reduction is the liver. liver; metabolism; oxidation; glucose; lactate; nonesterified fatty acids IT IS WELL RECOGNIZED THAT the ability of insulin to stimulate glucose uptake is enhanced by a single bout of exercise (21). We have shown that the marked increase in insulin action during exercise is matched by an equally profound increase in insulin-induced hypoglycemic counterregulation in an exercising dog model (28). The effectiveness of this potent counterregulatory response may be important in decreasing the magnitude and frequency of hypoglycemia during a bout of exercise. Skeletal muscle remains more sensitive to insulin for a sustained period after exercise (21). In contrast, the counterregulatory response to insulininduced hypoglycemia is actually reduced a full day after prolonged exercise (9, 16). This is significant, because this likely contributes to the high risk of hypoglycemia in people with insulin-dependent diabetes (27). Whether hypoglycemic counterregulation during the interval immediately after exercise remains sensitized, as it is during exercise, or blunted, as it is after extended recovery from exercise, is unknow...