A marked sexual dimorphism in neuroendocrine and metabolic responses to moderate, prolonged exercise occurs in healthy humans. It is unknown whether similar differences occur in type 1 diabetes mellitus (T1DM). Fifteen patients with T1DM (7 women and 8 men) were studied during 90 min of euglycemic exercise at 50% of the maximum rate of O(2) consumption. Men and women were matched for age, glycemic control, duration of diabetes, and exercise fitness, and had no history or evidence of autonomic neuropathy. Hypoglycemia was scrupulously avoided during the week preceding tests. Exercise was performed under constant infusion of regular insulin (1 U/h) and a variable 20% dextrose infusion, as needed to maintain euglycemia. At 15-min intervals, neuroendocrine, metabolic (glucose kinetics, intermediate metabolism, lipolysis), and cardiovascular responses were assessed. Indirect calorimetry was performed during the last 10 min of exercise. Plasma glucose and insulin did not differ between genders at baseline or during exercise. Key neuroendocrine responses were significantly reduced in women, compared with men, during exercise (epinephrine, 360 +/- 104 vs. 666 +/- 126 pM; norepinephrine, 2.3 +/- 0.8 vs. 4.1 +/- 1.0 nM; GH, 10 +/- 5 vs. 22 +/- 8 micro g/liter). Glucagon, cortisol, and pancreatic polypeptide responses were similar between genders. Despite reduced catecholamine responses in women, no gender differences were observed in endogenous glucose production (EGP) or exogenous glucose infusion rate during exercise. The lipolytic response to exercise (blood glycerol), on the other hand, was greater in women than in men. In conclusion, a marked sexual dimorphism exists in counterregulatory responses to exercise in T1DM, including key neuroendocrine (catecholamine, GH) and metabolic (lipolysis) responses. Other responses, including glucagon and EGP, were similar between genders, suggesting that the glucagon to insulin ratio may be the primary determinant of EGP during moderate intensity exercise in T1DM.