Direct Administration of Insulin Into Skeletal Muscle Reveals That the Transport of Insulin Across the Capillary Endothelium Limits the Time Course of Insulin to Activate Glucose Disposal

Direct Administration of Insulin Into Skeletal Muscle Reveals That the Transport of Insulin Across the Capillary Endothelium Limits the Time Course of Insulin to Activate Glucose Disposal Jenny D. Chiu , Joyce M. Richey , L. Nicole Harrison , Edward Zuniga , Cathryn M. Kolka , Erlinda Kirkman , Martin Ellmerer and Richard N. Bergman Department of Physiology and Biophysics, University of Southern California, Keck School of Medicine, Los Angeles, California Address correspondence and reprint requests to Richard Bergman, PhD, Keck School of Medicine, 1333 San Pablo St., MMR 626, Los Angeles, CA 90033. E-mail: rbergman{at}usc.edu Abstract OBJECTIVE— Intravenous insulin infusion rapidly increases plasma insulin, yet glucose disposal occurs at a much slower rate. This delay in insulin's action may be related to the protracted time for insulin to traverse the capillary endothelium. An increased delay may be associated with the development of insulin resistance. The purpose of the present study was to investigate whether bypassing the transendothelial insulin transport step and injecting insulin directly into the interstitial space would moderate the delay in glucose uptake observed with intravenous administration of the hormone. RESEARCH DESIGN AND METHODS— Intramuscular injections of saline ( n = 3) or insulin ( n = 10) were administered directly into the vastus medialis of anesthetized dogs. Injections of 0.3, 0.5, 0.7, 1.0, and 3.0 units insulin were administered hourly during a basal insulin euglycemic glucose clamp (0.2mU · min −1 · kg −1 ). RESULTS— Unlike the saline group, each incremental insulin injection caused interstitial (lymph) insulin to rise within 10 min, indicating rapid diffusion of the hormone within the interstitial matrix. Delay in insulin action was virtually eliminated, indicated by immediate dose-dependent increments in hindlimb glucose uptake. Additionally, bypassing insulin transport by direct injection into muscle revealed a fourfold greater sensitivity to insulin of in vivo muscle tissue than previously reported from intravenous insulin administration. CONCLUSIONS— Our results indicate that the transport of insulin to skeletal muscle is a rate-limiting step for insulin to activate glucose disposal. Based on these results, we speculate that defects in insulin transport across the endothelial layer of skeletal muscle will contribute to insulin resistance. AUC, area under the curve LGU, local glucose uptake Footnotes Published ahead of p