Temporal Changes in Skeletal Muscle Capillary Responses and Endothelial-Derived Vasodilators in Obesity Related Insulin Resistance

The inability of insulin to increase skeletal muscle capillary blood volume (CBV) reduces glucose uptake in insulin resistance (IR). We hypothesized that abnormalities in endothelial-derived vasodilator pathways are temporally associated with the development of IR and an impaired ability to increase skeletal muscle CBV. A comprehensive metabolic and vascular screening assessment was performed on ten adult rhesus macaques at baseline and every 4-6 months for 2 years after starting a high-fat diet supplemented with fructose. Diet changes resulted in an 80% increase in truncal fat by 4 months. Hyperinsulinemia and decreased glucose utilization were observed from 4 to 18 months. At 24 months, pancreatic secretory function and the glucose utilization rate both declined. CBV at rest and during an IVGTT demonstrated a sustained increase from 4 to 18 months then abruptly fell at 24 months. Nitric-oxide bioavailability progressively decreased over 2 years. Conversely, endothelial-derived vasodilators progressively increased over 18 months then abruptly decreased at 24 months in concert with the CBV. The increase in basal and glucose-mediated CBV early in IR may represent a compensatory response through endothelial-derived vasodilator pathways. The inability to sustain a vascular compensatory response limits glucose-mediated increases in CBV which correlates with the severity of IR.