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

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.

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 A_1c 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.

• Received March 21, 2017.
• Accepted May 20, 2017.

• © 2017 by the American Diabetes Association.