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e-Letters: Observations

Hyperglycemia Is the Main Mediator of Prediabetes- and Type 2 Diabetes–Associated Impairment of Microvascular Function: The Maastricht Study

  1. Ben M. Sörensen1,2,
  2. Alfons J.H.M. Houben1,2,
  3. Tos T.J.M. Berendschot3,
  4. Jan S.A.G. Schouten3,
  5. Abraham A. Kroon1,2,
  6. Carla J.H. van der Kallen1,2,
  7. Ronald M.A. Henry1,2,4,
  8. Annemarie Koster5,6,
  9. Koen D. Reesink1,7,
  10. Pieter C. Dagnelie1,5,8,
  11. Nicolaas C. Schaper1,2,5,
  12. Casper G. Schalkwijk1,2,
  13. Miranda T. Schram1,2,4 and
  14. Coen D.A. Stehouwer1,2⇑
  1. 1School for Cardiovascular Diseases (CARIM), Maastricht University, Maastricht, the Netherlands
  2. 2Department of Internal Medicine, Maastricht University Medical Center+, Maastricht, the Netherlands
  3. 3University Clinic for Ophthalmology, Maastricht University Medical Center+, Maastricht, the Netherlands
  4. 4Heart and Vascular Center, Maastricht University Medical Center+, Maastricht, the Netherlands
  5. 5Care and Public Health Research Institute (CAPHRI), Maastricht University, Maastricht, the Netherlands
  6. 6Department of Social Medicine, Maastricht University, Maastricht, the Netherlands
  7. 7Department of Biomedical Engineering, Maastricht University, Maastricht, the Netherlands
  8. 8Department of Epidemiology, Maastricht University, Maastricht, the Netherlands
  1. Corresponding author: Coen D.A. Stehouwer, cda.stehouwer{at}mumc.nl.
Diabetes Care 2017 Aug; 40(8): e103-e105. https://doi.org/10.2337/dc17-0574
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Prediabetes and type 2 diabetes (T2D) are associated with microvascular dysfunction (1), which may explain their increased risk of microvascular complications. However, mechanisms remain poorly understood. We investigated to what extent prediabetes- and T2D-associated microvascular dysfunction is potentially attributable to (composite indices of) hyperglycemia, insulin resistance, blood pressure, arterial stiffness, lipid profile, and/or low-grade inflammation.

In the Maastricht Study (2), a T2D-enriched population-based cohort study (n = 1,791, 49% women, aged 60 ± 8 years), we determined flicker light–induced retinal arteriolar %-dilation (1) using the Dynamic Vessel Analyzer, heat-induced skin %-hyperemia (1) using laser Doppler flowmetry, and diabetes status using the oral glucose tolerance test (normal glucose metabolism [NGM] [n = 1,040], prediabetes [n = 276], or T2D [n = 475]) (Table 1). Mediating effects of composite indices on prediabetes- and T2D-associated microvascular dysfunction were estimated by linear regression.

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Table 1

General characteristics and retinal and skin measures for the retinal study population according to glucose metabolism status

Age- and sex-adjusted analyses showed lower retinal arteriolar %-dilation in prediabetes (B = −0.16 [95% CI –0.53; 0.21]), with further deterioration in T2D (B = −0.83 [–1.15; –0.51]) versus NGM; P for trend <0.001. Skin %-hyperemia was lower in prediabetes (B = −80 [–198; 38]), with further deterioration in T2D (B = −210 [–309; –112]) versus NGM; P for trend <0.001. T2D-associated differences in retinal and skin microvascular function were explained mainly by hyperglycemia (mediating effect [bootstrapped 95% CI] 55.3% [20.4%; 91.3%] and 64.8% [6.2%; 122.4%], respectively). In contrast, insulin resistance, blood pressure, lipid profile, and low-grade inflammation did not significantly contribute. Patterns of mediation were qualitatively similar for prediabetes-associated microvascular dysfunction, with mediation effects of hyperglycemia of 69.2% [25.3%; 119.5%] and 47.5% [5.0%; 91.2%], respectively. Qualitatively similar patterns of mediation were found in additional analyses (available on request) in which we additionally adjusted for smoking, BMI, and (micro)vascular complications, used absolute retinal arteriolar diameter and skin blood flow as outcomes, investigated arterial stiffness as a potential mediator, or used a composite index of long-term hyperglycemic measures (glycated hemoglobin A1c and skin autofluorescence).

These findings suggest that hyperglycemia itself, rather than the cardiovascular risk context associated with prediabetes and T2D, is the main contributor to both prediabetes- and T2D-associated retinal and skin microvascular dysfunction. This supports an early detrimental effect of hyperglycemia on the retinal and skin microvascular responses. Impairments in both these responses reflect decreased availability of nitric oxide and are likely a reflection of microvascular endothelial dysfunction, possibly in conjunction with neuronal dysfunction (3,4).

Our study had some limitations. First, data were cross-sectional; therefore, we cannot exclude reverse causality. Second, inflammatory markers drawn from venous plasma, compared with local measurement, may have underestimated the mediation effect of the inflammation index (5). Last, generalizability of the results should be interpreted with caution, as in our cohort individuals with T2D were generally well controlled for their diabetes and cardiovascular risk factors. Hence, our population may be representative for a population with access to quality diabetes care. As a consequence, we cannot exclude the possibility that mediation effects of the other composite indices exist in populations with greater differences in cardiovascular risk profile between individuals without and with diabetes.

We conclude that hyperglycemia is the main contributor to prediabetes- and T2D-associated retinal and skin microvascular dysfunction. Longitudinal studies should assess whether hyperglycemia, via retinal and skin microvascular (endothelial) dysfunction, contributes to the development of microvascular complications in prediabetes and T2D.

Article Information

Acknowledgments. The authors would like to acknowledge the ZIO Foundation (Vereniging Regionale HuisartsenZorg Heuvelland) for its contribution to the Maastricht Study. The researchers are indebted to the participants for their willingness to participate in the study.

Funding. This study was supported by the European Regional Development Fund via OP-Zuid, the Province of Limburg, the Dutch Ministry of Economic Affairs (grant 31O.041), Stichting De Weijerhorst (Maastricht, the Netherlands), the Pearl String Initiative Diabetes (Amsterdam, the Netherlands), the Cardiovascular Center (Maastricht, the Netherlands), School for Cardiovascular Diseases (CARIM, Maastricht, the Netherlands), Care and Public Health Research Institute (CAPHRI, Maastricht, the Netherlands), School for Nutrition and Translational Research in Metabolism (NUTRIM, Maastricht, the Netherlands), Stichting Annadal (Maastricht, the Netherlands), Health Foundation Limburg (Maastricht, the Netherlands), Perimed (Järfälla, Sweden), and by unrestricted grants from Janssen-Cilag B.V. (Tilburg, the Netherlands), Novo Nordisk Farma B.V. (Alphen aan den Rijn, the Netherlands), and Sanofi-Aventis Netherlands B.V. (Gouda, the Netherlands).

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

Author Contributions. B.M.S. contributed to conception and design, participated in acquisition of data, analyzed and interpreted data, drafted the manuscript (with C.D.A.S.), revised the manuscript critically for important intellectual content, and provided final approval of the version to be published. T.T.J.M.B., J.S.A.G.S., A.A.K., C.J.H.v.d.K., R.M.A.H., A.K., K.D.R., P.C.D., N.C.S., and C.G.S. contributed to conception and design, revised the manuscript critically for important intellectual content, and provided final approval of the version to be published. A.J.H.M.H., M.T.S., and C.D.A.S. contributed to conception and design, contributed to analysis and interpretation of data, revised the manuscript critically for important intellectual content, and provided final approval of the version to be published. B.M.S. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

  • Received March 21, 2017.
  • Accepted May 20, 2017.
  • © 2017 by the American Diabetes Association.
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Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.

References

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    1. Sörensen BM,
    2. Houben AJ,
    3. Berendschot TT, et al
    . Prediabetes and type 2 diabetes are associated with generalized microvascular dysfunction: the Maastricht Study. Circulation 2016;134:1339–1352
    OpenUrlAbstract/FREE Full Text
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    1. Schram MT,
    2. Sep SJ,
    3. van der Kallen CJ, et al
    . The Maastricht Study: an extensive phenotyping study on determinants of type 2 diabetes, its complications and its comorbidities. Eur J Epidemiol 2014;29:439–451
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    1. Falsini B,
    2. Riva CE,
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    . Flicker-evoked changes in human optic nerve blood flow: relationship with retinal neural activity. Invest Ophthalmol Vis Sci 2002;43:2309–2316
    OpenUrlAbstract/FREE Full Text
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    1. Minson CT,
    2. Berry LT,
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    . Nitric oxide and neurally mediated regulation of skin blood flow during local heating. J Appl Physiol (1985) 2001;91:1619–1626
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    . High vitreous concentration of IL-6 and IL-8, but not of adhesion molecules in relation to plasma concentrations in proliferative diabetic retinopathy. Ophthalmic Res 2013;49:108–114
    OpenUrlCrossRefPubMedWeb of Science
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Hyperglycemia Is the Main Mediator of Prediabetes- and Type 2 Diabetes–Associated Impairment of Microvascular Function: The Maastricht Study
Ben M. Sörensen, Alfons J.H.M. Houben, Tos T.J.M. Berendschot, Jan S.A.G. Schouten, Abraham A. Kroon, Carla J.H. van der Kallen, Ronald M.A. Henry, Annemarie Koster, Koen D. Reesink, Pieter C. Dagnelie, Nicolaas C. Schaper, Casper G. Schalkwijk, Miranda T. Schram, Coen D.A. Stehouwer
Diabetes Care Aug 2017, 40 (8) e103-e105; DOI: 10.2337/dc17-0574

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Hyperglycemia Is the Main Mediator of Prediabetes- and Type 2 Diabetes–Associated Impairment of Microvascular Function: The Maastricht Study
Ben M. Sörensen, Alfons J.H.M. Houben, Tos T.J.M. Berendschot, Jan S.A.G. Schouten, Abraham A. Kroon, Carla J.H. van der Kallen, Ronald M.A. Henry, Annemarie Koster, Koen D. Reesink, Pieter C. Dagnelie, Nicolaas C. Schaper, Casper G. Schalkwijk, Miranda T. Schram, Coen D.A. Stehouwer
Diabetes Care Aug 2017, 40 (8) e103-e105; DOI: 10.2337/dc17-0574
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