Discussion
To our knowledge, this is the first cross-sectional and prospective cohort study to investigate the associations of dietary macronutrients and energy intake with DKD and all-cause mortality in individuals with diabetes. In this cohort of adults aged 18 years and older individuals, our analyses revealed that higher levels of protein and dietary fiber intake were associated with lower odds of DKD. Specifically, daily protein intake above 74 g and fiber intake above 14 g were associated with lower DKD odds. Furthermore, we identified that BMI and HGB could partially elucidate these associations. Additionally, energy intake exhibited a U-shaped association with mortality risk, with the lowest mortality observed among those consuming between 1750 and 1810 kcal/day. These findings offer exploratory evidence for identifying dietary patterns that are most strongly associated with DKD and all-cause mortality among individuals with diabetes, thereby highlighting the potential importance of dietary interventions in managing these high-risk populations.
This study found that high protein intake was associated with lower DKD odds in patients with diabetes, but not with an increased mortality risk, which is consistent with previous studies.7 There have also been studies that have found a high protein intake is associated with a lower risk of death,35 36 while other studies have found a positive correlation between total protein intake and all-cause mortality.37 The different results may be that our study focused on patients with diabetes, while some studies included a broader range of patients with CKD and attributed more benefits to plant protein intake. Our study found that a daily protein intake of more than 74 g was associated with lower DKD odds, while previous studies have shown that protein intake should account for 15% to 20% of total energy intake for patients with normal kidney function.38 Based on an energy intake of 1800 kcal/day, this translates to roughly 68–90 g/day, aligning with our research findings. It is worth noting that our exploratory mediation analysis revealed that BMI accounted for small proportions of the associations of protein intake with DKD, suggesting that protein may be related to improved body composition, thereby maintaining muscle mass.39 Muscle tissue is a major site for GLU disposal and can improve insulin sensitivity. Second, moderate protein consumption may regulate appetite hormones, such as the anorexigenic hormones peptide YY (PYY) and glucagon-like peptide-1 (GLP-1), leading to increased satiety and aiding in weight management and metabolic control.40 Another possible explanation is that a high protein intake produces more bioactive peptides. These peptides are known to exhibit anti-inflammatory, anti-hypertensive, anti-oxidative, and anti-microbial effects,41 leading to lower DKD odds. However, because the DKD analysis is cross-sectional, we cannot establish temporal ordering between dietary intake, BMI, and DKD. Therefore, these mediation findings should be considered hypothesis-generating rather than evidence of causal pathways.
Our research findings on the protective association of dietary fiber with the kidneys align with existing studies.42–44 For example, in three large cohorts, those with the highest fiber intake had a 40%–50% lower prevalence of CKD.44–46 Additionally, the Tehran Lipid and Glucose Study (n=1630) found an 11% reduced risk of developing CKD for every 5 g/day increase in total fiber intake.43 While the relationship between fiber intake and risk of death varies among different populations.43 45 47 48 Following fiber-rich, plant-based diets is linked to lower all-cause mortality risk in the general population.47 48 Evidence suggests this link is stronger in individuals with non-dialysis CKD than those without CKD.16 43 49 However, some studies have not found a connection between fiber intake and mortality risk in patients with hemodialysis50 or peritoneal dialysis51. Our study found no relationship between fiber intake and mortality in patients with diabetes. This may be because we did not distinguish sources of fiber. The fiber threshold associated with lower DKD odds identified in our study (14 g/day) is lower than most current recommendations.52–54 Most countries now recommend adults consume 25–35 g of fiber daily, based on robust trials and large cohort studies on fiber supplements and fiber-rich diets.55 Although there are differences, it is worth noting that NHANES data shows that the average American adult consumes fiber of only 15–18 g/day,56 while the average Chinese resident consumes around 11 g/day. The vast majority of people do not reach the recommended standard.
The protective mechanisms of dietary fiber may be more varied. Chronic inflammation is a key driver of the progression of DKD and can lead to functional iron deficiency and anemia. Dietary fiber enhances excretion and regulates the intestinal microbiota, reducing the production and absorption of toxins such as indoxyl sulfate, and increasing the production of short-chain fatty acids (SCFAs). This, in turn, reduces systemic inflammation, improves intestinal barrier function, and regulates GLU and lipid metabolism, thereby promoting kidney health.57 Moreover, fiber slows down gastric emptying and GLU absorption, enhancing postprandial glycemic control and diminishing the harm caused by GLU toxicity to the kidneys.58 Fiber can also bind and promote the excretion of bile acids, thereby improving lipid metabolism and providing indirect protection to the kidneys. Most importantly, our exploratory mediation analysis highlighted that HGB statistically accounted for a portion of the association between fiber intake and DKD, suggesting a potential link between fiber intake, anemia status, and kidney function. Possible pathways include the role of dietary fiber in intestinal health and iron utilization, the effect of SCFAs on systemic inflammation and erythropoietin production, and the relationship between glycemic control and HbA1c levels. These potential mechanisms may help explain the observed association between fiber intake, anemia, and a lower odds of DKD.
The U-shaped relationship between energy intake and mortality is consistent with several previous studies.59–61 However, our study also differs from some others. A study targeting the elderly population indicated that higher total energy intake was associated with a lower risk of all-cause mortality.62 Another study involving elderly individuals from Spain indicated that higher energy intake was linked to an increased risk of mortality, especially from cardiovascular causes.63 Some studies have also shown that there is no significant association between total energy intake and all-cause mortality.64 65 These discrepancies in study outcomes may stem from differences in study populations and sample sizes. Our research underscores the significance of energy balance in the management of diabetes. Excessive energy intake leads to obesity, insulin resistance, chronic inflammation, and oxidative stress,66 which accelerate the progression of diabetes complications; conversely, insufficient energy intake may be associated with loss of lean body mass, malnutrition, and impaired immune function.67 Notably, the energy range (1750–1810 kcal) associated with the lowest mortality is close to the recommended intake for the Chinese diet (2000 kcal)68 and US diet (1000–3200 kcal).69 The recommended daily energy intake is not a fixed value because it needs to be adjusted dynamically based on factors such as age, gender, activity level, and disease status. In addition, lower energy intake may reflect underlying frailty or illness rather than a causal protective effect; residual reverse causation cannot be completely ruled out in the energy-mortality association. However, these threshold values are statistical inflection points derived from a spline model and should not be interpreted as precise clinical targets due to dietary measurement limitations.
Our study possesses several strengths. First, it uses high-quality dietary data from a representative population-based study (NHANES) to investigate the relationship of macronutrient and energy intake with DKD as well as all-cause mortality in patients with diabetes. Second, it uses various statistical methods to comprehensively evaluate the correlation between macronutrients and health outcomes in patients with diabetes. It establishes a dose-response relationship between nutrients and DKD and reveals the mediating effects of BMI and HGB, thereby providing insights into potential mechanisms. Third, the associations reported in this study have been adjusted for various important confounding factors, ensuring the stability and reliability of the observed relationships.
However, it is important to acknowledge certain limitations. First, the study is based on an observational, retrospective analysis of existing databases, which restricts causal inference. Second, although total macronutrient intake should be taken into account, we analyzed absolute intakes without energy adjustment in the primary analysis. We will apply energy-adjusted models in our further exploratory studies. Third, multiple comparisons increase type I error risk. While trend and dose-response analyses support our main findings, chance findings cannot be ruled out. Replication in studies with pre-specified hypotheses and correction for multiple testing is needed. Fourth, dietary intake was assessed using only two 24-hour recalls, which are subject to within-person variability and recall bias. This may cause non-differential misclassification and regression dilution bias.
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