Abnormal regulation of growth hormone (GH) secretion has been reported in some patients with insulin-dependent diabetes (IDD). We compared the GH responses in 32 healthy subjects (age 25 +/- 2 SE years) and in 23 IDD patients (28 +/- 1.9 years old, diabetes duration 10.4 +/- 2 years, and glycohemoglobin levels 9.3 +/- 2.0%). During acute, severe hypoglycemia (glucose less than 40 mg/dl), the mean GH levels were similar. When prolonged mild hypoglycemia was induced (58.0 +/- 2.0 mg/dl in the controls and 54.0 +/- 2.0 mg/dl in the IDD patients), the mean GH levels were similar, although the increase in GH was delayed in the latter group. During brief (30 min) exercise at 40-50% of VO2max, GH rose comparably in both groups (IDD patients maintained euglycemia with basal insulin infusion). However, with more prolonged and intense exercise using a glucose clamp to maintain euglycemia, GH rose to 5.4 +/- 2.2 ng/ml in controls and 26.4 +/- 12.6 ng/ml in the diabetics (P less than 0.05). When the combination of intense exercise and hypoglycemia (approximately 55 mg/dl) was used, GH rose to a peak of 21.7 +/- 2.7 ng/ml in the controls and to 33 +/- 3.0 ng/ml in the diabetics (P = NS). Our data show that in insulin-infused IDD patients made euglycemic for these experiments: a) The GH response to acute, severe hypoglycemia was identical to that in the controls and the response to mild, prolonged hypoglycemia was delayed, but of similar magnitude compared with controls; b) Exercise-induced GH responses were observed in both groups, but exaggerated in the diabetics at a higher exercise intensity; c) Hypoglycemia during exercise produced an additive effect on GH secretion in the controls but not in the IDD patients. We conclude that the wide range of abnormal GH secretory responses in type I diabetes reflects a central, possibly hypothalamic, defect in GH regulation.