To assess compensation for the absence of the exercise-induced fall in insulin, dogs underwent 150 min of treadmill exercise with insulin infused intraportally with (IC + Glc; n = 7) or without (IC; n = 6) glucose clamped. Glucose production (Ra), gluconeogenic conversion (Conv), and intrahepatic gluconeogenic efficiency (Eff) were assessed with tracers ([3H]glucose, [14C]alanine) and arteriovenous differences. Glucose fell by 6 +/- 4 and 11 +/- 2 mg/dl at 30 min of exercise and by 8 +/- 2 and 36 +/- 5 mg/dl at 150 min in IC + Glc and IC. Glucagon rose by 16 +/- 8 and 55 +/- 17 pg/ml by 30 min of exercise and by 18 +/- 6 and 93 +/- 22 pg/ml by 150 min in IC + Glc and IC. Norepinephrine was unaffected by the glycemic decrement in IC, whereas epinephrine was greater for the last 60 min of exercise. Ra rose by an average of 0.9 +/- 0.3 and 3.7 +/- 0.2 mg.kg-1.min-1 in IC + Glc and IC. Conv rose by 91 +/- 39 and 325 +/- 75% in IC + Glc and IC at 150 min of exercise, and Eff rose by 87 +/- 57 and 358 +/- 99%. The compensatory Ra exceeded the maximum possible gluconeogenic rate, indicating that glycogenolysis was also stimulated. In summary, in the absence of the exercise-induced fall in insulin 1) glycemia falls approximately fourfold faster; 2) minimal glycemic decrements elicit a large and rapid increase in Ra; 3) this compensation involves a glycogenolytic and gluconeogenic response; 4) the accelerated gluconeogenic rate is due, in large part, to stimulation of Eff; and 5) the compensatory Ra is likely mediated, in part, by glucagon. Hence, although the fall in insulin is essential for normal glucoregulation during exercise, a highly sensitive counterregulatory response prevents severe hypoglycemia. The remarkable sensitivity of the liver to small changes in glycemia implies that the normal coupling of the exercise-induced increase in Ra to glucose utilization may be signaled by small, nearly imperceptible changes in glucose.