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Assessment of microvascular and metabolic responses in the skin
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.ORCID iD: 0000-0002-4245-7565
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: urn:nbn:se:liu:diva-132167DOI: 10.3384/diss.diva-132167ISBN: 9789176857021 (Print)OAI: oai:DiVA.org:liu-132167DiVA: diva2:1038702
Public defence
2016-11-18, Hugo Theorellsalen, Campus US, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2016-10-19 Created: 2016-10-19 Last updated: 2016-11-01Bibliographically approved
List of papers
1. Non-Invasive Measurement of Skin Microvascular Response during Pharmacological and Physiological Provocations
Open this publication in new window or tab >>Non-Invasive Measurement of Skin Microvascular Response during Pharmacological and Physiological Provocations
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2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 8, 1-15 p., e0133760Article in journal (Refereed) Published
Abstract [en]

Introduction Microvascular changes in the skin due to pharmacological and physiological provocations can be used as a marker for vascular function. While laser Doppler flowmetry (LDF) has been used extensively for measurement of skin microvascular responses, Laser Speckle Contrast Imaging (LSCI) and Tissue Viability Imaging (TiVi) are novel imaging techniques. TiVi measures red blood cell concentration, while LDF and LSCI measure perfusion. Therefore, the aim of this study was to compare responses to provocations in the skin using these different techniques. Method Changes in skin microcirculation were measured in healthy subjects during (1) iontophoresis of sodium nitroprusside (SNP) and noradrenaline (NA), (2) local heating and (3) post-occlusive reactive hyperemia (PORH) using LDF, LSCI and TiVi. Results Iontophoresis of SNP increased perfusion (LSCI: baseline 40.9 +/- 6.2 PU; 10-min 100 +/- 25 PU; pless than0.001) and RBC concentration (TiVi: baseline 119 +/- 18; 10-min 150 +/- 41 AU; p = 0.011). No change in perfusion (LSCI) was observed after iontophoresis of NA (baseline 38.0 +/- 4.4 PU; 10-min 38.9 +/- 5.0 PU; p = 0.64), while RBC concentration decreased (TiVi: baseline 59.6 +/- 11.8 AU; 10-min 54.4 +/- 13.3 AU; p = 0.021). Local heating increased perfusion (LDF: baseline 8.8 +/- 3.6 PU; max 112 +/- 55 PU; pless than0.001, LSCI: baseline 50.8 +/- 8.0 PU; max 151 +/- 22 PU; pless than0.001) and RBC concentration (TiVi: baseline 49.2 +/- 32.9 AU; max 99.3 +/- 28.3 AU; pless than0.001). After 5 minutes of forearm occlusion with prior exsanguination, a decrease was seen in perfusion (LDF: p = 0.027; LSCI: pless than0.001) and in RBC concentration (p = 0.045). Only LSCI showed a significant decrease in perfusion after 5 minutes of occlusion without prior exsanguination (pless than0.001). Coefficients of variation were lower for LSCI and TiVi compared to LDF for most responses. Conclusion LSCI is more sensitive than TiVi for measuring microvascular changes during SNP-induced vasodilatation and forearm occlusion. TiVi is more sensitive to noradrenaline-induced vasoconstriction. LSCI and TiVi show lower inter-subject variability than LDF. These findings are important to consider when choosing measurement techniques for studying skin microvascular responses.

Place, publisher, year, edition, pages
Public Library of Science, 2015
National Category
Physiology
Identifiers
urn:nbn:se:liu:diva-121109 (URN)10.1371/journal.pone.0133760 (DOI)000359492800006 ()26270037 (PubMedID)
Available from: 2015-09-07 Created: 2015-09-07 Last updated: 2016-10-19
2. Modeling Perfusion Dynamics in the Skin During Iontophoresis of Vasoactive Drugs Using Single-Pulse and Multiple-Pulse Protocols
Open this publication in new window or tab >>Modeling Perfusion Dynamics in the Skin During Iontophoresis of Vasoactive Drugs Using Single-Pulse and Multiple-Pulse Protocols
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2015 (English)In: Microcirculation, ISSN 1073-9688, E-ISSN 1549-8719, Vol. 22, no 6, 446-453 p.Article in journal (Refereed) Published
Abstract [en]

Objective: After iontophoresis of vasoactive drugs into the skin, a decrease in perfusion is commonly observed. We delivered vasoactive drugs by iontophoresis using different delivery protocols to study how these affect this decrease in perfusion as measured using LDF. Methods: We measured skin perfusion during iontophoresis of (ACh), MCh, andNAusing a single pulse or separate pulses at different skin sites, and during repeated delivery of ACh at the same site. Results: Perfusion half-life was 6.1 (5.6-6.6) minutes for ACh and 41 (29-69) minutes for MCh (p less than 0.001). The maximum response with multiple pulses of ACh iontophoresis was lower than with a single pulse, 30 (22-37) PU vs. 43 (36-50) PU, p less than 0.001. Vasoconstriction to NA was more rapid with a single pulse than with multiple pulses. The perfusion half-life of ACh decreased with repeated delivery of ACh at the same site-first 16 (14-18), second 5.9 (5.1-6-9) and third 3.2 (2.9-3.5) minutes, p less than 0.001. Conclusions: The drug delivery protocol affects microvascular responses to iontophoresis, possibly as a result of differences in the dynamics of local drug concentrations. Perfusion half-life may be used as a measure to quantify the rate of perfusion recovery after iontophoresis of vasoactive drugs.

Place, publisher, year, edition, pages
Informa Healthcare / Wiley: 12 months, 2015
Keyword
microcirculation; iontophoresis; acetylcholine; metha choline; noradrenaline; skin
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-121138 (URN)10.1111/micc.12211 (DOI)000359676500002 ()26016387 (PubMedID)
Available from: 2015-09-08 Created: 2015-09-08 Last updated: 2016-10-19
3. The Microvascular Response to Transdermal Iontophoresis of Insulin is Mediated by Nitric Oxide
Open this publication in new window or tab >>The Microvascular Response to Transdermal Iontophoresis of Insulin is Mediated by Nitric Oxide
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2013 (English)In: Microcirculation, ISSN 1073-9688, 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
Keyword
insulin, transdermal iontophoresis, endothelial function, vasodilation
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-102080 (URN)10.1111/micc.12071 (DOI)000326607600008 ()
Note

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

Available from: 2013-12-02 Created: 2013-11-29 Last updated: 2016-10-19
4. Skin glucose metabolism and microvascular blood flow during local insulin delivery and after an oral glucose load
Open this publication in new window or tab >>Skin glucose metabolism and microvascular blood flow during local insulin delivery and after an oral glucose load
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2016 (English)In: Microcirculation, ISSN 1073-9688, E-ISSN 1549-8719, Vol. 23, no 7, 597-605 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: Insulin causes capillary recruitment in muscle and adipose tissue, but the metabolic and microvascular effects of insulin in the skin have not been studied in detail. The aim of this study was to measure glucose metabolism and microvascular blood flow in the skin during local insulin delivery and after an oral glucose load.

METHODS: Microdialysis catheters were inserted intracutanously in human subjects. In eight subjects two microdialysis catheters were inserted, one perfused with insulin and one with control solution. First the local effects of insulin was studied, followed by a systemic provocation by an oral glucose load. Additionally, as control experiment, six subjects did not recieve local delivery of insulin or the oral glucose load. During microdialysis the local blood flow was measured by urea clearance and by laser speckle contrast imaging (LSCI).

RESULTS: Within 15 minutes of local insulin delivery, microvascular blood flow in the skin increased (urea clearance: P=.047, LSCI: P=.002) paralleled by increases in pyruvate (P=.01) and lactate (P=.04), indicating an increase in glucose uptake. An oral glucose load increased urea clearance from the catheters, indicating an increase in skin perfusion, although no perfusion changes were detected with LSCI. The concentration of glucose, pyruvate and lactate increased in the skin after the oral glucose load.

CONCLUSION: Insulin has metabolic and vasodilatory effects in the skin both when given locally and after systemic delivery through an oral glucose load.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2016
National Category
Endocrinology and Diabetes Physiology Clinical Medicine Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:liu:diva-132368 (URN)10.1111/micc.12325 (DOI)27681957 (PubMedID)
Available from: 2016-11-01 Created: 2016-11-01 Last updated: 2016-11-30Bibliographically approved

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