221-OR: Skeletal Muscle Insulin Resistance—The Rate-Limiting Step in Humans Is at the Level of the Vasculature

Type 2 diabetes (T2D) is characterized by impaired insulin-stimulated glucose disposal in skeletal muscle tissue (SKM), called insulin resistance. Insulin facilitates glucose uptake through GLUT4 recruitment following insulin receptor-mediated signal transduction pathways. Insulin also regulates glucose uptake through 1) regulation of arterial blood flow, 2) capillary recruitment and 3) rate of its own transendothelial transport. The rate-limiting step of insulin on SKM glucose uptake in humans is currently unknown.

In a cross-sectional study, 20 people with T2D [age 67±6 years, BMI 30±4 kg/m², HbA1c 7.6±1.1%] and 20 matched controls (HC) [age 68±7, years, BMI 29±2 kg/m², HbA1c 5.7±0.7%] underwent a frequently-sampled 75-g oral glucose tolerance test (OGTT) with paired forearm arterial and venous glucose and insulin concentrations to calculate glucose (FE_gluc) and insulin (FE_ins) fractional extraction. Forearm blood flow was measured by Doppler ultrasound.

Area under the glucose curve was increased in T2D vs HC (p<0.01). FE_gluc increased from 4±3% to 16±3% in both groups from the fasted state to T=30 min, but was higher in T2D vs HC from min T=60 to T=120 of the OGTT (p<0.001). Fasting FE_ins was 13±9% for T2D and 14±12% for HC and peaked at T=15 (27±13% for HC and 22±12% for T2D; p=0.16). FE_ins was similar between groups during the OGTT. FE_gluc/FE_ins, as measure for insulin metabolic effects, was not different between groups. Brachial arterial blood flow was not changed during OGTT.

We show that FE_gluc is reduced in T2D vs HC under physiological conditions. As reduced SKM glucose uptake was not driven by changes in insulin uptake into SKM interstitium, the glucose uptake defect is likely secondary to impaired vascular actions of insulin. With arterial blood flow unchanged, we propose that reduced insulin-induced capillary recruitment may be the key defect. Microvascular recruitment measured by contrast-enhanced ultrasound (CEUS) are being analyzed and are available at the ADA.