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

Chiu, Jenny D.; Richey, Joyce M.; Harrison, L. Nicole; Zúñiga, Edward; Kolka, Cathryn M.; Kirkman, Erlinda L.; Ellmerer, Martin; Bergman, Richard N.

doi:10.2337/db07-1444

Cited by 79 publications

(94 citation statements)

References 56 publications

(46 reference statements)

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“…After local delivery of insulin to the skin, an increase in interstitial lactate and pyruvate was measured within the first 15 minutes, although the interstitial glucose concentration was not significantly changed. This is in contrast with previous studies, in which insulin was administered to muscle and a glucose decrease was observed (Chiu et al, 2008;Rosdahl et al, 2000). One explanation to why we did not observe a decrease in glucose in the skin, could be a rapid glucose supply from to the vasculature to the tissue, that may have been facilitated by insulin-mediated vasodilation.…”

Section: Microvascular and Metabolic Actions Of Insulin In The Skincontrasting

confidence: 55%

Assessment of microvascular and metabolic responses in the skin

Iredahl¹

2016

Linköping University Medical Dissertations

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The general aim of this project was to develop experimental in vivo models that allow for minimally invasive investigations of responses in the skin to microvascular and metabolic provocations. The cutaneous microvasculature has emerged as a valuable model and been proposed to mirror the microcirculation in other organs. Dysfunction in the cutaneous microcirculation has thus been linked to systemic diseases such as hypertension and diabetes mellitus. Models for investigating skin responses could facilitate the understanding of pathophysiological mechanisms as well as effects of drugs. In the first study, three optical measurement techniques (laser Doppler flowmetry (LDF), laser speckle contrast imaging (LSCI) and tissue viability imaging (TiVi)) were compared against each other and showed differences in their ability to detect microvascular responses to provocations in the skin. TiVi was found more sensitive for measurement of noradrenaline-induced vasoconstriction, while LSCI was more sensitive for measurement of vascular occlusion. In the second study, microvascular responses in the skin to iontophoresis of vasoactive drugs were found to depend on the drug delivery protocol. Perfusion half-life was defined and used to describe the decay in the microvascular response to a drug after iontophoresis. In the third study, the role of nitric oxide (NO) was assessed during iontophoresis of insulin. The results showed a NO-dependent vasodilation in the skin by insulin. In the fourth study the vasoactive and metabolic effects of insulin were studied after both local and endogenous administration. Local delivery of insulin increased skin blood flow, paralleled by increased skin concentrations of interstitial pyruvate and lactate, although no change in glucose concentration was observed. An oral glucose load resulted in an increased insulin concentration in the skin paralleled by an increase in blood flow, as measured using the microdialysis urea clearance technique, although no changes in perfusion was measured by LSCI. The thesis concludes that when studying skin microvascular responses, the choice of measurement technique and the drug delivery protocol has an impact on the measurement results, and should therefore be carefully considered. The thesis also concludes that insulin has metabolic and vasodilatory effects in the skin both when administered locally and as an endogenous response to an oral glucose load. The vasodilatory effect of insulin in the skin is mediated by nitric oxide

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Section: Microvascular and Metabolic Actions Of Insulin In The Skincontrasting

confidence: 55%

Assessment of microvascular and metabolic responses in the skin

Iredahl¹

2016

Linköping University Medical Dissertations

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“…However, this human study did not report actual levels of interstitial insulin but instead reported change from basal. Access to muscle is a major component of insulin sensitivity (1,11) likely due to the microvascular effects of insulin, which increase distribution of blood through muscle, thus increasing delivery to the insulin-sensitive tissues.…”

mentioning

confidence: 99%

Lipid-induced insulin resistance does not impair insulin access to skeletal muscle

Kolka

Richey

Castro

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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“…TET transport of insulin is the rate limiting step in time pharmacokinetic profile of insulin [9].This was observed in experiments utilizing glucose clamp technique. There was a time delay between achieving steady state insulin concentration in the plasma and thoracic duct lymph collections while the gradient between plasma and interstitial fluid insulin concentrations remained constant.…”

Section: Transendothelial Transport As the Rate Limiting Stepmentioning

confidence: 93%

Insulin Delivery: An Ever Changing Frontier

Janjua¹

2016

JED

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Insulin transport across vascular endothelial cells is the rate limiting step in its time action profile. Glucose uptake in response to insulin is estimated through different techniques and is influenced by insulin sensitivity of the tissue. Glucose clamp technique and minimal model imply an incremental increase in the levels of insulin in the ISF compartment evidenced by increase in glucose uptake. This can not merely be explanied by tissue capillary recruitment or increase in blood flow of already perfused areas. Although insulin is proven to affect the blood flow and capillary recruitment of already perfused areas, restoration of muscle blood flow in insulin resistant patients does not revert the insulin activity profile. By review of frequently cited articles, it can be interpreted that insulin causes a much greater increase in tissue recruitment by increasing the perfused capillary volume of previously unperfused areas, an increase in the permeability of the capillaries and recruitment of insulin transport receptors. This also results in an Increase in volume of distribution of glucose. Insulin, like other proteins, may be transported across by simple diffusion, paracellular pathway and transcellular pathway with the help of transport receptors. In conclusion, insulin is most likely transported across capillary endothelial cells by more than one mechanism and there may be recruitment of these pathways according to insulin levels. Thus further investigations of these possible pathways may help pave the way for more efficient insulin delivery methods in the future.

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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

Cited by 79 publications

References 56 publications

Assessment of microvascular and metabolic responses in the skin

Assessment of microvascular and metabolic responses in the skin

Lipid-induced insulin resistance does not impair insulin access to skeletal muscle

Insulin Delivery: An Ever Changing Frontier

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