September 1, 1991The Journal of Clinical Endocrinology & Metabolism215 citations
View Full PaperMechanism of Insulin Resistance in Insulin-Dependent Diabetes Mellitus: A Major Role for Reduced Skeletal Muscle Blood Flow*
Structured PICO
Does reduced skeletal muscle blood flow contribute to insulin resistance in men with insulin-dependent diabetes mellitus compared to healthy controls?
P
Population
12 men (5 with insulin-dependent diabetes mellitus [IDDM] and 7 healthy controls), matched for age, lean body mass, and leg volume.
I
Intervention
120 mU/m2.min insulin infusion with blood glucose clamped at approximately 4, 7, 12, and 21 mmol/L
C
Comparator
Healthy control men undergoing the same insulin infusion and glucose clamp protocol
O
Outcome
Maximal capacity (Vmax) and affinity (Km) for glucose uptake in whole body (WBGU) and leg skeletal muscle (LGU), and leg blood flow (LBF)surrogate
In patients with insulin-dependent diabetes mellitus, insulin resistance is driven by reduced glucose and insulin delivery (blood flow) to skeletal muscle rather than impaired muscle glucose extraction.
Abstract
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.