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In non-insulin-dependent diabetes mellitus (NIDDM), both liver and peripheral tissues are resistant to insulin, but the relative severity and contribution of these abnormalities to fasting hyperglycemia are poorly understood. We, therefore, determined the dose-response characteristics for insulin-mediated suppression of hepatic glucose production (GP) and stimulation of peripheral glucose uptake (GU) in 14 NIDDM subjects and 14 age- and weight-matched nondiabetic volunteers (NV) using the glucose clamp sequential insulin infusion technique along with isotopic estimation of glucose flux. Postabsorptive rates of both GP (94 ± 7 v 72 ± 2 mg/M²/min in NV, P < .01) and GU (88 ± 5 v 72 ± 2 in NV, P < .01) were significantly increased in NIDDM subjects. The ED₅₀ (half-maximally effective plasma insulin concentration) in NIDDM subjects for suppression of GP (64 ± 14 μU/mL) and stimulation of GU (118 ± 20 μU/mL …