Previous studies demonstrated that administration of insulin and oral hypoglycemic agents tends to produce weight gain in type II diabetic patients. The goal of this study was to determine the potential contribution of changes in metabolic rate and urinary glucose excretion to changes in energy balance associated with treatment with glyburide and insulin. Six obese type II diabetic patients (52-61 yr old; 123-214% of ideal weight) were fed a weight-maintaining diet of fixed composition and caloric content in a Clinical Research Center. The mean fasting plasma glucose concentrations were 10.7 +/- 1.3 (+/- SE) mmol/L before treatment, 7.9 +/- 1.4 mmol/L at the end of 2 weeks of glyburide treatment, and 5.2 +/- 0.3 mmol/L at the end of 2 weeks of insulin treatment. Urinary glucose excretion decreased from 48 +/- 19 g/day before treatment to 20 +/- 9 g/day at the end of glyburide treatment and 2 +/- 1 g/day at the end of insulin treatment. Neither treatment affected mean postabsorptive resting metabolic rate (untreated 4.86 +/- 0.50 kJ/min; glyburide-treated, 4.63 +/- 0.45 kJ/min; insulin-treated, 4.70 +/- 0.46 kJ/min) or postprandial resting metabolic rate (untreated, 5.71 +/- 0.55 kJ/min; glyburide-treated, 5.60 +/- 0.39 kJ/min; insulin-treated, 5.70 +/- 0.51 kJ/min). However, the two patients with the largest decreases in urinary glucose excretion also had decreases in energy expenditure. These data indicate that many obese type II diabetic patients could have significant weight gain from reduced energy losses alone.