Contrast-Enhanced Ultrasound Assessment of Impaired Adipose Tissue and Muscle Perfusion in Insulin-Resistant Mice

Abstract

Background— In diabetes mellitus, reduced perfusion and capillary surface area in skeletal muscle, which is a major glucose storage site, contribute to abnormal glucose homeostasis. Using contrast-enhanced ultrasound, we investigated whether abdominal adipose tissue perfusion is abnormal in insulin resistance and correlates with glycemic control. Methods and Results— Contrast-enhanced ultrasound perfusion imaging of abdominal adipose tissue and skeletal muscle was performed in obese insulin resistance (db/db) mice at 11 to 12 or 14 to 16 weeks of age and in control lean mice. Time–intensity data were analyzed to quantify microvascular blood flow (MBF) and capillary blood volume (CBV). Blood glucose response for 1 hour was measured after insulin challenge (1 U/kg, IP). Compared with control mice, db/db mice at 11 to 12 and 14 to 16 weeks had a higher glucose concentration area under the curve after insulin (11.8±2.8, 20.6±4.3, and 28.4±5.9 mg·min/dL [×1000], respectively; P =0.0002) and also had lower adipose MBF (0.094±0.038, 0.035±0.010, and 0.023±0.01 mL/min per gram; P =0.0002) and CBV (1.6±0.6, 1.0±0.3, and 0.5±0.1 mL/100 g; P =0.0017). The glucose area under the curve correlated in a nonlinear fashion with both adipose and skeletal muscle MBF and CBV. There were significant linear correlations between adipose and muscle MBF ( r =0.81) and CBV ( r =0.66). Adipocyte cell volume on histology was 25-fold higher in 14- to 16-week db/db versus control mice. Conclusions— Abnormal adipose MBF and CBV in insulin resistance can be detected by contrast-enhanced ultrasound and correlates with the degree of impairment in glucose storage. Abnormalities in adipose tissue and muscle seem to be coupled. Impaired adipose tissue perfusion is in part explained by an increase in adipocyte size without proportional vascular response.