Mechanism of Insulin Resistance in Insulin-Dependent Diabetes Mellitus: A Major Role for Reduced Skeletal Muscle Blood Flow*

To define the kinetic mechanisms of insulin resistance (IR) in insulin-dependent diabetes (IDDM), we studied seven control (C) and five IDDM (glycohemoglobin, 14 +/- 2+) men matched for age (36 +/- 2 vs. 37 +/- 3 yr), lean body mass (59 +/- 2 vs. 58 +/- 3 kg), and leg volume (mean +/- SEM, 10.4 +/- 0.3 vs. 9.8 +/- 0.5 L). Maximal capacity (Vmax) and affinity (Km) for glucose uptake in whole body (WBGU) and leg skeletal muscle (LGU) were measured during a 120 mU/m2.min insulin infusion, and blood glucose was clamped at about 4, 7, 12, and 21 mmol/L. LGU = femoral arterio-venous glucose difference (FAVGD) X leg blood flow (LBF). Compared to C, IDDMs had about 35% lower rates of WBGU at all glucose levels (P less than 0.01). The FAVGD (millimoles per L) in C vs. IDDM was 1.23 +/- 0.05 vs. 1.06 +/- 0.09, 2.44 +/- 0.11 vs. 2.24 +/- 0.16, 2.91 +/- 0.18 vs. 2.91 +/- 0.30, and 3.27 +/- 0.12 vs. 3.35 +/- 0.4 (P = NS at each glucose). LBF (decaliters per min) was reduced in IDDM vs. C 2.8 +/- 0.5 vs. 4.3 +/- 0.4 (P less than 0.05), 3.1 +/- 0.4 vs. 5.1 +/- 0.7 (P less than 0.05), 2.7 +/- 0.2 vs. 6.3 +/- 0.8 (P less than 0.01), and 3.1 +/- 0.7 vs. 6.5 +/- 0.8 (P less than 0.01) at each glucose level. Kinetic analysis revealed that 1) the Vmax for WBGU and LGU were reduced in IDDM vs. C (P less than 0.05), and 2) the Vmax for skeletal muscle glucose extraction (FAVGD) was identical in C and IDDM (3.6 mmol/L). The Km values for WBGU, LGU, and glucose extraction were not different in C and IDDM (approximately 6 mmol/L). Thus, in IDDM 1) decreased glucose uptake is due to reduced skeletal muscle glucose uptake; 2) muscle glucose extraction is normal, but blood flow is reduced; and thus, 3) in IDDM, IR is due to reduced glucose and insulin delivery (blood flow) to skeletal muscle. This represents a novel mechanism for in vivo IR.