Prediabetes and Type 2 Diabetes are Associated with Generalized Microvascular Dysfunction: The Maastricht Study

Sörensen BM, Houben AJHM, Berendschot TTJM, et al.
Circulation 2016; published online ahead of print

Background

Type 2 diabetes mellitus (T2DM) causes not only macrovascular, but also microvascular complications, including retinopathy, nephropathy, neuropathy, heart failure, stroke, depression, and cognitive dysfunction [1,2]. While it has been established that macrovascular dysfunction occurs already in prediabetes [3,4], there is no systemic evaluation of microvascular dysfunction in prediabetes and if so, whether this is more severe in T2DM compared to prediabetes.

In this study, it was assessed whether prediabetes, T2DM and hyperglycaemia are associated with microvascular function in the retina and skin, independently of potential CV risk factors, in the observational, prospective, population-based MAASTRICHT study. This study consisted of 2213 individuals and microvascular function was measured by flicker light-induced arteriolar dilation and heat-induced skin hyperemia (increased blood flow). Fully adjusted statistical models included age, sex, BMI, triglyceride levels, total/HDL-c ratio, smoking, SBP, use of antihypertensive and/or lipid-modifying drugs, history of CV disease, retinopathy, eGFR and urinary albumin secretion.

Main results

• Whereas the baseline arteriolar diameter did not differ among the 3 groups, the average percent arteriolar dilation was lower in individuals with prediabetes and T2DM as compared to individuals with normal glucose metabolism (P trend <0.001).
• The decline (regression) in microvascular function in prediabetes was around 1/2 to 1/4 of that in T2DM.  
• In the fully adjusted model, possible confounders associated with the retinal dilator response were: age (B: -0.04; 95% CI: -0.06 to -0.02), SBP (B: 0.01; 95% CI: 0.00 to 0.02), triglycerides (B: -0.18; 95% CI: -0.37 to 0.01) and retinopathy (B: -1.34; -2.41 to -0.26).
  Betas indicate the change in percent dilation per 1 unit higher age, SBP and triglycerides, or when having retinopathy.
• Whereas baseline skin blood flow did not significantly differ among the three groups in crude or adjusted analyses, the hyperaemic response was lower in individuals with prediabetes and T2DM as compared to individuals with normal glucose metabolism (P trend <0.001).
• In the fully adjusted model, possible confounders significantly associated with the skin hyperaemic response were: age (B: -12; 95% CI: -19 to -6), female sex (B: 311; 95% CI: 224 to 397), BMI (B: 11; 95% CI: 1 to 21), smoking (B: -265; 95% CI: -398 to -132), SBP (B: 3; 95% CI: 0 to 5), triglycerides (B: -89; 95% CI: -144 to -33).  
  Betas indicate the change in percent hyperaemia per unit higher age, BMI, SBP and triglycerides, or being female or a current (versus never) smoker.
• HbA1c, fasting plasma glucose (FPG), and 2h post-load glucose levels were not associated with baseline retinal arteriolar diameter or baseline skin blood flow, neither in crude, nor in adjusted models.
• HbA1c and FPG were associated with the average percentage dilation and hyperaemic response, both in crude and adjusted models. The association of 2h post-load glucose levels with retinal arteriolar percentage dilation lost significance after adjustment for CV risk factors but its association with skin hyperaemic response was significant in both crude and adjusted models.

Conclusion

In a population-based study, prediabetes, T2DM, and continuous measures of hyperglycaemia, were linearly associated with impaired microvascular function in retina and skin, independently of a broad array of potential confounders including major CV risk factors and clinically defined diabetic retinopathy and nephropathy. These data support the concept that generalised microvascular dysfunction precedes the clinical diagnosis of T2DM and that both early hyperglycaemia and microvascular dysfunction should be considered as potential targets of intervention.

Find this article online at Circulation

References

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