This study provides a comprehensive epidemiologic insight into the potential associations between CVH and DN based on the CVH metrics identified by the American Heart Association. In this study, we demonstrated that higher LE8 scores were significantly associated with a lower prevalence of DN. In all, maintaining good CVH by refining LE8 metrics may help reduce the adverse effects.
Currently, there is limited research evidence on the association between cardiovascular fitness levels and DN. Gao et al. explored the association between LE8 score and the prevalence risk of DN in a Chinese community-based study17, and similarly, their study also found a negative association between LE8 score and DN. However, their studies focused primarily on correlations between single outcomes and did not delve into alterations in clinical indicators specific to DN (including eGFR and UACR), furthermore, their analyses did not specifically consider the impact of the various components of the LE8 score. Most importantly, their study overlooked the effects of many important confounders, such as inflammatory and immune indicators, antioxidants, etc. In fact, the development of DN is closely related to microvascular endothelial damage, and inflammatory cells (factors) and antioxidants have been shown to play a pivotal role in the maintenance of endothelial function14,18–20. A recent prospective study delved into the relationship between cardiovascular health and vascular complications21. This study included UK participants aged 40 to 69 years from the UK Biobank. However, in their analyses, the study only considered the impact of the overall risk of vascular complications and did not address specific vascular complications (e.g. DN) and the specific clinical indicators. To our knowledge, our study is the first to systematically report the association of CVH with the prevalence risk of DN and its corresponding clinical indicators in US adults.
The detailed mechanisms linking CVH to DN in diabetes have not yet been elucidated, but results from selected studies may provide strong evidence. Endothelial cell damage is an important mechanism of diabetic microvascular complications22. Hyperglycaemia and its by-products can lead to endothelial cell over-transport, which leads to the production of toxic intermediates, especially reactive oxygen species (ROS), which in turn leads to increased endothelial cell permeability, dysfunction, fibrosis, and even apoptosis, thus exacerbating microvascular endothelial damage2. The diabetic environment also induces pathological adaptive changes in podocytes, including cytoskeletal rearrangement, dedifferentiation, apoptosis, and autophagy, which are manifested by morphological broadening, contraction, and flattening, decreased motility, and increased formation of intercellular tight junctions, which are manifested by a decrease in eGFR and the development of proteinuria, ultimately leading to renal failure23.
The pathogenesis of DN is well-documented to be multifactorial and cannot be explained by the interaction of hemodynamic and metabolic factors or molecular alterations in a hyperglycaemic state alone6. Previous studies have found that damaged endothelial cells may be more susceptible to further damage, such as elevated blood pressure24, and the results of a prospective study suggest that the risk of microvascular complications increases with elevated blood pressure in patients with diabetes7. In a large-scale meta-analysis25, a 10 mmHg reduction in systolic blood pressure was associated with a 17 percent reduction in the prevalence risk of proteinuria. A clinical trial showed that glycemic control alone did not completely prevent retinopathy, renal and peripheral neuropathy, possibly due to the involvement of dyslipidemia in the progress of microangiopathy8. There is ample evidence that hyperlipidemia enhances lipid-mediated oxidative stress and inflammation, adipogenesis, ectopic lipid deposition, alterations in lipid partitioning, metabolism, and β-oxidation to cause renal injury26,27. Huang et al.28 used the UK Biobank data and a Mendelian Randomization analysis to discuss the possibility that an elevated BMI may be a potential risk factor for the development of diabetes concerning the microvascular complications of diabetes. Daniel et al.29 used anthropometric data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) to examine the association of waist circumference and BMI variability with the risk of microangiopathy and found that BMI variability was associated with a higher risk of renal microangiopathy. Due to the high metabolic and endocrine activity of adipose tissue, the rapid remodeling of adipose tissue associated with high obesity variability may cause abnormal secretion of pro-inflammatory adipokines, which may lead to adverse health outcomes that may influence the development of diabetes-related complications5,30.
In addition, there are several hypotheses regarding the potential mechanisms by which health behaviors and lifestyles influence the physiological characteristics of microangiopathy. The rapid decline in eGFR is a consequence of short sleep duration, which may be attributable in part to circadian rhythms and systemic inflammation31. There is also evidence that exposure to environmental tobacco smoke reduces serum antioxidant defenses without directly impairing endothelial function32,33. A sample of patients with diabetes found that glomerular hyperfiltration was associated with smoking34. Although these associations were not found in the current analysis, possibly due to the heterogeneity of the sample or multi-factoriality, in all, nicotine exposure is associated with poorer renal function indices. The effect of moderate physical activity on microvascular complications in diabetes may be multifaceted, physical activity improves endothelial function through a variety of mechanisms, including the synthesis of molecular mediators, changes in neurohormone release, and oxidant/antioxidant balance35. On the other hand, physical activity can also elicit systemic molecular pathways associated with angiogenesis and chronic anti-inflammatory effects, thereby altering endothelial function and thus preventing the onset and progression of microvascular complications. Some studies have demonstrated that adherence to a dietary healthy lifestyle is associated with a significant reduction in the risk of DN in patients with diabetes and that this favorable association is mediated in part by improved biomarkers of glycemic control, systemic inflammation, liver function, and lipid profile36,37.
Our study has several strengths. First, to the best of our knowledge, this is the first study to systematically report the association of CVH with the prevalence risk of DN and its corresponding clinical indicators in US adults. In addition, we integrated the linear or nonlinear relationships in detail to avoid losing important statistical information. Of interest, we also conducted subgroup analyses to assess differences in these specific effects across populations, to provide targeted guidance for the prevention and management of DN in populations with different baseline characteristics.
We also note some limitations of this study. Firstly, we agree that the observational nature of this study means that causality cannot be established and therefore careful attention needs to be paid when interpreting the results. Additionally, due to limitations of the NHANES database, we were unable to collect data on the duration of diabetes as well as determine the specific type of diabetes, which may have cut down on the true statistical effect. Meanwhile, while this study deepened the academic understanding of DN, it does not provide direct guidance for clinical practice or patient management at this time, and future research could focus on how to apply these findings to real-world settings. As kidney biopsy is considered the gold standard for the diagnosis of diabetic nephropathy, we acknowledged the limitations of the lack of pathological biopsies. In the future, more research evidence, as well as large-sample, multi-center cohorts involving a larger scale of participants, are needed to examine these potential associations to provide more detailed and reliable clinical guidance.