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

ALAIN D. BARON, MARKKU LAAKSO, GINGER BRECHTEL and STEVEN V. EDELMAN

Department of Medicine, Veterans Administration Medical Center, Research Service San Diego, California 92161
Department of Medicine, Veterans Administration Medical Center, Research Service, and the Indiana University Medical Center Indianapolis, Indiana 46202
The University of California San Diego, California 92093

Address all correspondence and requests for reprints to: Alain D. Baron, M.D., Indiana University, Emerson Hall, Room 421, 545 Barnhill Drive, Indianapolis, Indiana 46202-5124.

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 (V_max) and affinity (K_m) 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 < 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 < 0.05), 3.1 ± 0.4 vs. 5.1 ± 0.7 (P < 0.05), 2.7 ± 0.2 vs. 6.3 ± 0.8 (P < 0.01), and 3.1 ± 0.7 vs. 6.5 ± 0.8 (P < 0.01) at each glucose level]. Kinetic analysis revealed that 1) the V_max for WBGU and LGU were reduced in IDDM vs. C (P < 0.05), and 2) the Vma, for skeletal muscle glucose extraction (FAVGD) was identical in C and IDDM (3.6 mmol/L). The K_m values for WBGU, LGU, and glucose extraction were not different in C and IDDM (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.

^* This work was supported in part by NIH Grants MOl-RR-00827 and DK-42469, the Juvenile Diabetes Foundation, the American Diabetes Association, and the Diabetes Education and Research Foundation.

Visiting scientist from the University of Kuopio, Finland, and recipient of International Research Fellowship Grant TW-03969-01 from the Fogarty International Center, NIH.

Received October 15, 1990.

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