Early Endothelial Dysfunction in Type 1 Diabetes Is Accompanied by an Impairment of Vascular Smooth Muscle Function: A Meta-Analysis

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Abstract

Background: A large yet heterogeneous body of literature exists suggesting that endothelial dysfunction appears early in type 1 diabetes, due to hyperglycemia-induced oxidative stress. The latter may also affect vascular smooth muscles (VSM) function, a layer albeit less frequently considered in that pathology. This meta-analysis aims at evaluating the extent, and the contributing risk factors, of early endothelial dysfunction, and of the possible concomitant VSM dysfunction, in type 1 diabetes.

Methods: PubMed, Web of Sciences, Cochrane Library databases were screened from their respective inceptions until October 2019. We included studies comparing vasodilatory capacity depending or not on endothelium (i.e., endothelial function or VSM function, respectively) in patients with uncomplicated type 1 diabetes and healthy controls.

Results: Fifty-eight articles studying endothelium-dependent function, among which 21 studies also assessed VSM, were included. Global analyses revealed an impairment of standardized mean difference (SMD) (Cohen's d) of endothelial function: −0.61 (95% CI: −0.79, −0.44) but also of VSM SMD: −0.32 (95% CI: −0.57, −0.07). The type of stimuli used (i.e., exercise, occlusion-reperfusion, pharmacological substances, heat) did not influence the impairment of the vasodilatory capacity. Endothelial dysfunction appeared more pronounced within macrovascular than microvascular beds. The latter was particularly altered in cases of poor glycemic control [HbA _1c > 67 mmol/mol (8.3%)].

Conclusions: This meta-analysis not only corroborates the presence of an early impairment of endothelial function, even in response to physiological stimuli like exercise, but also highlights a VSM dysfunction in children and adults with type 1 diabetes. Endothelial dysfunction seems to be more pronounced in large than small vessels, fostering the debate on their relative temporal appearance.

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Most cited references 95

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The effects of clinical and statistical heterogeneity on the predictive values of results from meta-analyses.

W Melsen, M Bonten, M Rovers … (2014)

Variance between studies in a meta-analysis will exist. This heterogeneity may be of clinical, methodological or statistical origin. The last of these is quantified by the I(2) -statistic. We investigated, using simulated studies, the accuracy of I(2) in the assessment of heterogeneity and the effects of heterogeneity on the predictive value of meta-analyses. The relevance of quantifying I(2) was determined according to the likely presence of heterogeneity between studies (low, high, or unknown) and the calculated I(2) (low or high). The findings were illustrated by published meta-analyses of selective digestive decontamination and weaning protocols. As expected, I(2) increases and the likelihood of drawing correct inferences from a meta-analysis decreases with increasing heterogeneity. With low levels of heterogeneity, I(2) does not appear to be predictive of the accuracy of the meta-analysis result. With high levels of heterogeneity, even meta-analyses with low I(2) -values have low predictive values. Most commonly, the level of heterogeneity in a meta-analysis will be unknown. In these scenarios, I(2) determination may help to identify estimates with low predictive values (high I(2) ). In this situation, the results of a meta-analysis will be unreliable. With low I(2) -values and unknown levels of heterogeneity, predictive values of pooled estimates may range extensively, and findings should be interpreted with caution. In conclusion, quantifying statistical heterogeneity through I(2) -statistics is only helpful when the amount of clinical heterogeneity is unknown and I(2) is high. Objective methods to quantify the levels of clinical and methodological heterogeneity are urgently needed to allow reliable determination of the accuracy of meta-analyses.

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Nitric oxide is responsible for flow-dependent dilatation of human peripheral conduit arteries in vivo.

R Joannides, W Haefeli, L. Linder … (1995)

Experimental evidence suggests that flow-dependent dilatation of conduit arteries is mediated by nitric oxide (NO) and/or prostacyclin. The present study was designed to assess whether NO or prostacyclin also contributes to flow-dependent dilatation of conduit arteries in humans. Radial artery internal diameter (ID) was measured continuously in 16 healthy volunteers (age, 24 +/- 1 years) with a transcutaneous A-mode echo-tracking system coupled to a Doppler device for the measurement of radial blood flow. In 8 subjects, a catheter was inserted into the brachial artery for measurement of arterial pressure and infusion of the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA; 8 mumol/min for 7 minutes; infusion rate, 0.8 mL/min). Flow-dependent dilatation was evaluated before and after L-NMMA or aspirin as the response of the radial artery to an acute increase in flow (reactive hyperemia after a 3-minute cuff wrist occlusion). Under control conditions, release of the occlusion induced a marked increase in radial blood flow (from 24 +/- 3 to 73 +/- 11 mL/min; P < .01) followed by a delayed increase in radial diameter (flow-mediated dilatation; from 2.67 +/- 0.10 to 2.77 +/- 0.12 mm; P < .01) without any change in heart rate or arterial pressure. L-NMMA decreased basal forearm blood flow (from 24 +/- 3 to 13 +/- 3 mL/min; P < .05) without affecting basal radial artery diameter, heart rate, or arterial pressure, whereas aspirin (1 g PO) was without any hemodynamic effect. In the presence of L-NMMA, the peak flow response during hyperemia was not affected (76 +/- 12 mL/min), but the duration of the hyperemic response was markedly reduced, and the flow-dependent dilatation of the radial artery was abolished and converted to a vasoconstriction (from 2.62 +/- 0.11 to 2.55 +/- 0.11 mm; P < .01). In contrast, aspirin did not affect the hyperemic response nor the flow-dependent dilatation of the radial artery. The present investigation demonstrates that NO, but not prostacyclin, is essential for flow-mediated dilatation of large human arteries. Hence, this response can be used as a test for the L-arginine/NO pathway in clinical studies.

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Endothelial dysfunction and increased arterial intima-media thickness in children with type 1 diabetes.

S Laine, Terho Lehtimäki, M Raitakari … (2004)

Endothelial dysfunction may play a pathophysiological role in the development of atherosclerosis in subjects with type 1 diabetes. We examined whether alterations in vascular endothelial function exist in children with type 1 diabetes and tested the hypothesis that endothelial dysfunction is associated with early structural atherosclerotic vascular changes in these children. Noninvasive ultrasound was used to measure brachial artery flow-mediated dilation (FMD) responses and carotid artery intima-media thickness (IMT) in 75 children (mean age 11+/-2 years), 45 with type 1 diabetes (diabetes duration 4.4+/-2.9 years) and 30 healthy control children. Children with diabetes had lower peak FMD response (4.4+/-3.4% versus 8.7+/-3.6%, P<0.001) and increased IMT (P<0.001) compared with controls. Sixteen children with diabetes (36%) had endothelial dysfunction defined as total FMD response in the lowest decile for normal children. These children had increased carotid IMT (0.58+/-0.05 versus 0.54+/-0.04 mm, P=0.01) and higher LDL cholesterol concentration (2.63+/-0.76 versus 2.16+/-0.60 mmol/L, P=0.03) compared with diabetic children without endothelial dysfunction. Multivariate correlates of increased IMT included diabetes group (P=0.03), low FMD (P=0.03), and high LDL cholesterol (P=0.08). Impaired FMD response is a common manifestation in children with type 1 diabetes and is associated with increased carotid artery IMT. These data suggest that endothelial dysfunction in children with type 1 diabetes may predispose them to the development of early atherosclerosis.

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Author and article information

Contributors

Mehdi Pawlak-Chaouch: URI : http://loop.frontiersin.org/people/936437/overview

Costantino Balestra: URI : http://loop.frontiersin.org/people/241376/overview

Serge Berthoin: URI : http://loop.frontiersin.org/people/556762/overview

Martin Feelisch: URI : http://loop.frontiersin.org/people/51030/overview

Matthieu Roustit: URI : http://loop.frontiersin.org/people/882613/overview

Elsa Heyman: URI : http://loop.frontiersin.org/people/882539/overview

Journal

Journal ID (nlm-ta): Front Endocrinol (Lausanne)

Journal ID (iso-abbrev): Front Endocrinol (Lausanne)

Journal ID (publisher-id): Front. Endocrinol.

Title: Frontiers in Endocrinology

Publisher: Frontiers Media S.A.

ISSN (Electronic): 1664-2392

Publication date (Electronic): 17 April 2020

Publication date Collection: 2020

Volume: 11

Electronic Location Identifier: 203

Affiliations

[1] ¹Univ. Lille, Univ. Artois, Univ. Littoral Côte d'Opale, ULR 7369 - URePSSS - Unité de Recherche Pluridisciplinaire Sport Santé Société , Lille, France

[2] ²Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement , Lille, France

[3] ³Environmental and Occupational (Integrative) Physiology Laboratory, Haute École Bruxelles-Brabant HE2B , Brussels, Belgium

[4] ⁴Clinical and Experimental Sciences, Faculty of Medicine, University Hospital Southampton NHS Foundation Trust, University of Southampton , Southampton, United Kingdom

[5] ⁵Univ. Grenoble Alpes, HP2, Inserm, CHU Grenoble Alpes , Grenoble, France

[6] ⁶Département d'endocrinologie, Diabète et maladies métaboliques, Hôpital Huriez, Université de Lille , Lille, France

Author notes

Edited by: Gaetano Santulli, Columbia University, United States

Reviewed by: Yoshifumi Saisho, Keio University School of Medicine, Japan; Philippz Obert, University of Avignon, France

*Correspondence: Elsa Heyman elsa.heyman@ 123456univ-lille.fr

This article was submitted to Clinical Diabetes, a section of the journal Frontiers in Endocrinology

†These authors have contributed equally to this work

Article

DOI: 10.3389/fendo.2020.00203

PMC ID: 7180178

PubMed ID: 32362871

SO-VID: 7dc99515-e872-428e-8c7c-41acd3e8346d

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This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 10 January 2020

Date accepted : 23 March 2020

Page count

Figures: 6, Tables: 1, Equations: 0, References: 112, Pages: 26, Words: 13636

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Early Endothelial Dysfunction in Type 1 Diabetes Is Accompanied by an Impairment of Vascular Smooth Muscle Function: A Meta-Analysis

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Journal of the ASEAN Federation of Endocrine Societies

Most cited references 95

The effects of clinical and statistical heterogeneity on the predictive values of results from meta-analyses.

Nitric oxide is responsible for flow-dependent dilatation of human peripheral conduit arteries in vivo.

Endothelial dysfunction and increased arterial intima-media thickness in children with type 1 diabetes.

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