We aimed to determine the effect of insulin replacement on serum leptin concentration in lean and obese patients with diabetic ketoacidosis (DKA). We compared serial leptin levels in 52 patients with DKA, 14 obese subjects with hyperglycemia, and 52 nondiabetic control subjects. Leptin levels on admission were significantly decreased in lean and obese patients with DKA and/or hyperglycemia compared with weight- and gender-matched controls. Insulin therapy resulted in a significant increase in leptin levels within 4 h, with peak stimulation at 12 h. Leptin levels on admission and at resolution of hyperglycemia were higher in obese DKA (9.7 +/- 2 ng/ml and 26.5 +/- 5 ng/ml, respectively; P < 0.001) and obese hyperglycemia subjects (11.9 +/- 4 ng/ml vs. 24.4 +/- 2 ng/ml; P < 0.001) than in lean DKA subjects (5.3 +/- 0.3 ng/ml and 10.1 +/- 2 ng/ml; P < 0.001). We conclude that insulin treatment in patients with acute hyperglycemic crises is followed by rapid and significant increase in leptin concentration, and this increase is more discernible in obese subjects. The low serum leptin level on admission in subjects with hyperglycemic crises may be the result of impaired adipocyte glucose utilization due to insulin deficiency and/or to increased catecholamine levels.