Endothelial Function Assessed by Digital Volume Plethysmography Predicts the Development and Progression of Type 2 Diabetes Mellitus

Background Endothelial dysfunction is a consequence of type 2 diabetes mellitus, but it is unclear whether endothelial dysfunction of conductance versus resistance vessels may also precede type 2 diabetes mellitus development. Methods and Results In a population-based cohort of 15 010 individuals from the GHS (Gutenberg Health Study) (aged 35-74 years at enrollment in 2007-2012), we identified 1610 cases of incident pre-diabetes mellitus and 386 cases of incident type 2 diabetes mellitus by hemoglobin A_1c (HbA_1c) and/or medical history between 2012 and 2017. Endothelial function of conductance and resistance vessels was measured by flow-mediated dilation and digital volume plethysmography-derived reactive hyperemia index, respectively. Multivariable regression modeling was used to estimate β coefficients of HbA_1c levels at follow-up and relative risks of incident (pre-)diabetes mellitus. Reactive hyperemia index was independently associated with HbA_1c after multivariable adjustment for baseline HbA_1c, sex, age, socioeconomic status, arterial hypertension, waist/height ratio, pack-years of smoking, non-high-density lipoprotein/high-density lipoprotein ratio, physical activity, family history of myocardial infarction/stroke, prevalent cardiovascular disease, medication use, and C-reactive protein (β=-0.020; P=0.0029). The adjusted relative risk per SD decline in reactive hyperemia index was 1.08 (95% CI, 1.02-1.15; P=0.012) for incident pre-diabetes mellitus and 1.16 (95% CI, 1.01-1.34; P=0.041) for incident type 2 diabetes mellitus. Flow-mediated dilation independently increased the relative risk for developing pre-diabetes mellitus by 8% (95% CI, 1.02-1.14; P=0.012), but it was not independently associated with incident type 2 diabetes mellitus (relative risk, 1.01; 95% CI, 0.86-1.19; P=0.92) and with HbA_1c (β=-0.003; P=0.59). Conclusions Endothelial dysfunction of resistance rather than conductance vessels may precede the development of (pre-)diabetes mellitus. Assessment of endothelial function by digital volume plethysmography may help to identify subjects at risk for development of type 2 diabetes mellitus.