The relative impact of hepatic glucose production (HGP) and peripheral glucose uptake (GU) on plasma glucose concentration was assessed in 54 noninsulin-dependent diabetes mellitus (NIDDM) and 50 control subjects submitted to a variable period of fasting (14-108 h) with special focus on the normal and low hyperglycemic range. Within each population we found a highly significant (P < 0.001) positive correlation between plasma glucose concentration and HGP in the whole range of glycemia, but the slope of the regression line was steeper (P < 0.001) in the diabetic than in the control group. The two curves intersected at a glucose level of 4.0 mmol/L. Therefore, for a given HGP rate above the intersection point, diabetic patients had a higher plasma glucose concentration than nondiabetic individuals, owing to an approximately 15% reduction (P < 0.025) in the metabolic clearance rate, despite the fact that the plasma insulin level was 2-fold higher (P < 0.05) in the diabetic patients. When diabetic and nondiabetic subjects were compared at a similar low glucose level of 4.0 mmol/L brought about by short-term fasting, all parameters of glucose kinetics were identical in both groups. We thus conclude that 1) HGP is the major determinant of plasma glucose concentration in control as well as in diabetic subjects whatever the nutritional state; 2) the slight hyperglycemia prevailing in mild NIDDM results from the combination of an impaired insulin-induced inhibition of HGP and stimulation of GU because both parameters are inappropriately normal in the face of elevated plasma glucose and insulin levels; and 3) the normalization of GU and HGP after short-term fasting suggests that pathways of noninsulin-mediated GU operate in a normal way in NIDDM.