Insulin Access to Skeletal Muscle is Impaired During the Early Stages of Diet-Induced Obesity

Objective: Insulin must move from the blood to the interstitium to initiate signaling, yet access to the interstitium may be impaired in cases of insulin resistance, such as obesity. This study investigated whether consuming a short-and long-term high-fat diet (HFD) impairs insulin access to skeletal muscle, the major site of insulin-mediated glucose uptake. Methods: Male mongrel dogs were divided into three groups consisting of control diet (n = 16), short-term (n = 8), and long-term HFD (n = 8). Insulin sensitivity was measured with intravenous glucose tolerance tests. A hyperinsulinemic euglycemic clamp was performed in each animal at the conclusion of the study. During the clamp, lymph fluid was measured as a representation of the interstitial space to assess insulin access to muscle. Results: Short-and long-term HFD induced obesity and reduced insulin sensitivity. Lymph insulin concentrations were approximately 50% of plasma insulin concentrations under control conditions. Longterm HFD caused fasting plasma hyperinsulinemia; however, interstitial insulin concentrations were not increased, suggesting impaired insulin access to muscle. Conclusions: A HFD rapidly induces insulin resistance at the muscle and impairs insulin access under basal insulin concentrations. Hyperinsulinemia induced by a long-term HFD may be a compensatory mechanism necessary to maintain healthy insulin levels in muscle interstitium.