Cumulative impact of microvascular complications in individuals with type 2 diabetes mellitus on cardiorespiratory function
E Uchiyama, S Yamada, N KinoshitaAbstract
Background
Impaired microcirculation plays a key role in reduced exercise capacity in individuals with type 2 diabetes (T2DM). Clinically, this impairment manifests as microvascular complications such as neuropathy, retinopathy, and nephropathy. While the impact of individual complications on physical function has been studied, the cumulative effect on peak oxygen uptake (peak VO₂) and ventilatory threshold (VT) remains unclear, although both are essential markers for prognosis and exercise prescription.
Purpose
To assess the cumulative burden of microvascular complications in individuals with T2DM on cardiorespiratory function measured by cardiopulmonary exercise testing (CPX).
Methods
This retrospective study included 377 individuals with T2DM who underwent CPX on a cycle ergometer. Microvascular complications were defined as follows: retinopathy, classified as mild to moderate non-proliferative, severe non-proliferative, or proliferative based on fundus photography; nephropathy, defined as an estimated glomerular filtration rate <60 mL/min/1.73 m² or 24-hour urinary albumin excretion ≥30 mg/day; and neuropathy, defined as absence of the Achilles tendon reflex or decreased heart rate (HR) variability (coefficient of variation of RR intervals <1.5%). Participants were categorised by the number of complications as 0, 1, or ≥2. Peak VO₂ and VT (mL/kg/min) were defined as co-primary outcomes. Secondary outcomes included peak HR, peak minute ventilation, peak systolic blood pressure, oxygen uptake efficiency slope, VE/VCO₂ slope, and peak O₂ pulse. Outcomes were analysed using age- and sex-adjusted analysis of covariance. Bonferroni correction was applied to the co-primary outcomes, and dose–response relationships were evaluated using linear contrast analysis.
Results
Both co-primary outcomes showed significant overall group effects (peak VO₂: p=0.021; VT: p=0.042), with significant linear dose–response trends across increasing complication burden (linear contrast estimates: peak VO₂ -1.92, p=0.006; VT -0.75, p=0.044; Figure 1). Higher complication burden was also associated with lower age- and sex-adjusted peak HR (142, 139, and 136 bpm for 0, 1, and ≥2 complications, respectively; p=0.043). Other secondary cardiopulmonary variables did not differ significantly.
Conclusion
The observed linear declines in peak VO₂ and VT indicate that accumulation of microvascular complications progressively impairs cardiorespiratory reserve in individuals with T2DM. This impairment was accompanied by a reduction in peak HR, which may further limit exercise capacity. These findings highlight the importance of early preventive strategies, including exercise interventions, to preserve exercise tolerance during the early stages of complication development.