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

Department of Physiology and Biophysics, University of Southern California, Keck School of Medicine, 1333 San Pablo St., MMR 626, Los Angeles, CA 90033, USA.
Diabetes (Impact Factor: 8.1). 05/2008; 57(4):828-35. DOI: 10.2337/db07-1444
Source: PubMed


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.
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 x min(-1) x kg(-1)).
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.
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.

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    • "This endothelium acts as a barrier which regulates the exchange of hormones, proteins and small molecules between the vascular compartment and the interstitial space [1,2]. The actions of a hormone or nutrient on a target tissue is implicitly dependent upon the ability of these factors to gain access to the target and numerous studies have indicated that hormone and nutrient concentrations in blood differ from those surrounding cells on the tissue side of the blood vessel endothelium [3,4,5,6,7,8,9,10,11]. In this regard, it is our contention that the significance of the endothelium as a regulator of hormone and substrate access to target tissues is often underappreciated. "
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