Leptin is the protein product of the ob gene, an adipocyte-specific gene, recently discovered in mice. Plasma leptin levels were determined in six normals, twenty-one subjects with impaired glucose tolerance, and forty-nine untreated NIDDM subjects. They increased with the augmentation of obesity (body mass index, BMI kg/m2) and were higher in females than in males: in BMI less than 25 kg/m2 the values of plasma leptin were 2.24 +/- 0.25 ng/ml (n=29) in males and 3.01 +/- 0.39 ng/ml (n=13) in females (P<0.054), respectively, in BMI between 25 kg/m2 and 30 kg/m2 they were 3.14 +/- 0.31 ng/ml (n=10) in males and 10.66 +/- 2.86 ng/ml (n=7) in females (P<0.0018) and in BMI higher than 30 kg/m2 their levels were 8.98 +/- 1.5 ng/ml (n=11) and 11.74 +/- 2.2 ng/ml (n=6) (P<0.23), respectively. The severity of diabetes mellitus judged from the fasting plasma glucose level had no influence on the plasma leptin levels during OGTT, but the leptin levels decreased significantly during a tolerance test (P<0.001), and similar results were also seen during a breakfast test. The fasting plasma leptin in the male with FBS less than 140 mg/dl had a significant correlation with the fasting plasma IRI level, but this correlation disappeared after taking obesity into consideration. Thus the plasma leptin was chiefly dependent on the body weight and gender and had no special relation to diabetic severity.