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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Available from: Cathryn M Kolka, Sep 24, 2015
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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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    ABSTRACT: The vascular endothelium is a dynamic structure responsible for the separation and regulated movement of biological material between circulation and interstitial fluid. Hormones and nutrients can move across the endothelium either via a transcellular or paracellular route. Transcellular endothelial transport is well understood and broadly acknowledged to play an important role in the normal and abnormal physiology of endothelial function. However, less is known about the role of the paracellular route. Although the concept of endothelial dysfunction in diabetes is now widely accepted, we suggest that alterations in paracellular transport should be studied in greater detail and incorporated into this model. In this review we provide an overview of endothelial paracellular permeability and discuss its potential importance in contributing to the development of diabetes and associated complications. Accordingly, we also contend that if better understood, altered endothelial paracellular permeability could be considered as a potential therapeutic target for diabetes.
    Diabetes & metabolism journal 04/2014; 38(2):92-99. DOI:10.4093/dmj.2014.38.2.92
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    • "Movement of insulin from the central circulation to the skeletal muscle microvasculature and subsequently to the interstitium is required to initiate capillary recruitment and GLUT4 translocation, therefore, anything that aids insulin transport to the capillaries and interstitium should accelerate muscle glucose uptake. This notion is supported by a recent study by Chiu and coworkers who found that intramuscular injection of insulin resulted in an immediate rise in hindlimb glucose uptake in dogs (Chiu et al. 2008). Postexercise skeletal muscle vasodilatation likely facilitates insulin-mediated vasodilatation and capillary recruitment by enhancing delivery of insulin to the microvasculature when the stimulus for glucose uptake is high, such as following exercise. "
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    07/2013; 1(2):e00033. DOI:10.1002/phy2.33
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    ABSTRACT: Modern close loop control for blood glucose level in a diabetic patient necessarily uses an explicit model of the process. A fixed parameter full order or reduced order model does not characterize the inter-patient and intra-patient parameter variability. This paper deals with a frequency domain nonparametric identification of the nonlinear glucose-insulin process in an insulin dependent diabetes mellitus patient that captures the process dynamics in presence of uncertainties and parameter variations. An online frequency domain kernel estimation method has been proposed that uses the input–output data from the 19th order first principle model of the patient in intravenous route. Volterra equations up to second order kernels with extended input vector for a Hammerstein model are solved online by adaptive recursive least square (ARLS) algorithm. The frequency domain kernels are estimated using the harmonic excitation input data sequence from the virtual patient model. A short filter memory length of M = 2 was found sufficient to yield acceptable accuracy with lesser computation time. The nonparametric models are useful for closed loop control, where the frequency domain kernels can be directly used as the transfer function. The validation results show good fit both in frequency and time domain responses with nominal patient as well as with parameter variations.
    12/2013; 93(4). DOI:10.1007/s40031-013-0037-0
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