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The Microvascular Response to Transdermal Iontophoresis of Insulin is Mediated by Nitric Oxide
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.ORCID iD: 0000-0002-4245-7565
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
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2013 (English)In: Microcirculation, ISSN 1073-9688, E-ISSN 1549-8719, Vol. 20, no 8, 717-723 p.Article in journal (Refereed) Published
Abstract [en]

ObjectiveInsulin has direct effects on blood flow in various tissues, most likely due to endothelial NO production. We investigated whether insulin delivered to the skin by iontophoresis increases microvascular perfusion and whether this effect is partly or completely mediated by the release of NO. MethodsIn healthy subjects, regular insulin and monomeric insulin were delivered to the skin by cathodal iontophoresis. The skin was pretreated either with L-NAME or control solution (PBS) using anodal iontophoresis. Microvascular responses were measured using laser Doppler flowmetry. ResultsA dose-dependent increase in perfusion was observed during iontophoresis of regular and monomeric insulin. The maximum perfusion was significantly elevated compared with control after PBS (regular insulin 53.6 (12.7-95.6) PU vs. 4.2 (3.4-4.8) PU, p = 0.002; monomeric insulin 32.6 (8.9-92.6) PU vs. 5.9 (3.4-56.0) PU, p = 0.03). The microvascular response to insulin was abolished after L-NAME (regular insulin: 25.6 (11.6-54.4) PU vs. control: 4.7 (2.9-11.5) PU, p = 0.15; monomeric insulin 10.9 (5.4-56.8) PU vs. control: 4.7 (2.9-11.5) PU, p = 0.22). ConclusionsThe main finding is that iontophoresis of insulin induces a dose-dependent vasodilation in the skin, which could be suppressed after pretreatment with a NO synthase inhibitor. This suggests that vasodilation in the skin after iontophoresis of insulin is mediated by the NO pathway.

Place, publisher, year, edition, pages
WILEY-BLACKWELL, 111 RIVER ST, HOBOKEN 07030-5774, NJ USA , 2013. Vol. 20, no 8, 717-723 p.
Keyword [en]
insulin, transdermal iontophoresis, endothelial function, vasodilation
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-102080DOI: 10.1111/micc.12071ISI: 000326607600008OAI: oai:DiVA.org:liu-102080DiVA: diva2:668999
Note

Funding Agencies|Linkoping University||County Council of Ostergotland||

Available from: 2013-12-02 Created: 2013-11-29 Last updated: 2017-12-06
In thesis
1. Assessment of microvascular and metabolic responses in the skin
Open this publication in new window or tab >>Assessment of microvascular and metabolic responses in the skin
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2016. 51 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1534
National Category
Pharmaceutical Sciences Clinical Medicine Medical Laboratory and Measurements Technologies Bioengineering Equipment Medical Biotechnology Biomedical Laboratory Science/Technology
Identifiers
urn:nbn:se:liu:diva-132167 (URN)10.3384/diss.diva-132167 (DOI)9789176857021 (ISBN)
Public defence
2016-11-18, Hugo Theorellsalen, Campus US, Linköping, 09:00 (Swedish)
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Available from: 2016-10-19 Created: 2016-10-19 Last updated: 2016-11-01Bibliographically approved

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Iredahl, FredrikTesselaar, ErikFarnebo, SimonSjöberg, Folke

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Iredahl, FredrikTesselaar, ErikFarnebo, SimonSjöberg, Folke
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Division of Clinical SciencesFaculty of Health SciencesDepartment of Clinical and Experimental MedicineDepartment of Hand and Plastic SurgeryDepartment of Anaesthesiology and Intensive Care in Linköping
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