To quantitate the effects of weight loss on the mechanisms responsible for hyperglycemia in non-insulin-dependent diabetes mellitus (NIDDM), eight obese subjects with NIDDM were studied before and after weight reduction with posttreatment assessment after 3 wks of isocaloric (weight maintenance) refeeding. After weight loss of 16.8 +/- 2.7 kg (mean +/- SE), the fasting plasma glucose level decreased 55% from 277 +/- 21 to 123 +/- 8 mg/dl. The individual fasting glucose levels were highly correlated with the elevated basal rates of hepatic glucose output (HGO) (r = 0.91, P less than .001), which fell from 138 +/- 11 to 87 +/- 5 mg X m-2 X min-1 after weight loss. The change in fasting plasma glucose also correlated significantly with the change in the basal rates of HGO (r = 0.74, P less than .05). This was associated with reduced fasting serum levels of glucagon (from 229 +/- 15 to 141 +/- 12 pg/ml), reduced free fatty acids (from 791 +/- 87 to 379 +/- 35 mu eq/L), and unchanged basal insulin levels (17 +/- 4 to 15 +/- 2 microU/ml).(ABSTRACT TRUNCATED AT 250 WORDS)