The factors responsible for fasting hyperglycemia were investigated in 77 normal weight non-insulin-dependent diabetic (NIDD) and 72 age-, sex-, and weight-matched control individuals. In diabetic subjects with mild fasting hyperglycemia (less than 140 mg/dL) hepatic glucose production (1.85 +/- 0.03 mg/kg.min) was similar to controls (1.84 +/- 0.02); the major factor responsible for the elevated basal glucose level in the diabetic group was a decreased efficiency in the tissue uptake of glucose, as reflected by a 30% decline in the rate of glucose clearance (1.56 +/- 0.03 v 2.00 +/- 0.03 mL/kg.min, P less than .001). In contrast, in diabetic subjects with fasting plasma glucose concentrations above 140 mg/dL, basal hepatic glucose production was significantly elevated (2.42 +/- 0.08 mg/kg.min, P less than .001) and correlated closely with the increase in fasting plasma glucose concentration (r = .796, P less than .001). The basal rate of whole body glucose clearance reached a plateau value at fasting glucose levels of 160 to 180 mg/dL and did not contribute to the further rise in fasting plasma glucose concentrations above 160 to 180 mg/dL. Decreased efficiency of tissue glucose uptake is responsible the development of fasting hyperglycemia in patients with mild NIDDM (fasting plasma glucose less than 140 mg/dL). As the diabetic state worsens, an increase in basal hepatic glucose production is the major factor responsible for the progressive rise in fasting glucose levels.