Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder defined by dysregulated glucose and lipid metabolism [1]. Peripheral artery disease (PAD) is a manifestation of systemic atherosclerosis, particularly prevalent in patients with T2DM. Studies have shown that PAD is an important influencing factor for the increased morbidity and mortality of cardiovascular disease in this patient population [2, 3]. Lower limb arterial calcification (LLAC) is common in patients with PAD, whereby it is associated with the severity of PAD symptoms and independently associated with increased amputation rates and mortality, which greatly affects the quality of life of this population [4, 5]. Therefore, it is imperative to identify and intervene in the associated risk factors of arterial calcification to enhance the prognosis of patients with T2DM [6].

Epidemiological studies have demonstrated a significant overlap in common risk factors between non-alcoholic fatty liver disease (NAFLD) and diabetes mellitus, with NAFLD being identified as a prevalent complication of T2DM [7, 8, 9]. Existing studies have shown that NAFLD is significantly associated with an increased risk of cardiovascular events in patients with T2DM. Specifically, it is an independent risk factor for other cardiovascular and metabolic indicators such as atherosclerosis and insulin resistance [10, 11]. Furthermore, the histological severity of NAFLD is widely recognized as a surrogate marker of subclinical atherosclerosis. Studies have shown a significant association between the severity of NAFLD and arterial stiffness and endothelial dysfunction [12, 13].

However, the existing literature does not definitively establish the association between NAFLD and LLAC in individuals with T2DM. Consequently, there is a gap in the current research addressing the potential correlation between NAFLD and LLAC in this patient population. To bridge this gap and improve clinical diagnosis and treatment, utilizing the fatty liver index (FLI) as a reliable marker for identifying NAFLD in patients with T2DM is critical. By calculating the patient’s FLI, healthcare providers can effectively and efficiently diagnose the presence of NAFLD, streamlining the diagnostic process for better patient care [14, 15]. In this study, we investigated the correlation between FLI and LLAC in T2DM patients to reveal the predictive value of NAFLD for the occurrence and development of LLAC in T2DM.

NAFLD is recognized as a well-established risk factor for cardiovascular events and can be easily and accurately diagnosed by calculating FLI. This study delved into the relationship between FLI and LLAC in T2DM patients, and the findings indicated a negative correlation between FLI levels and LLAC. Moreover, even after controlling for demographic characteristics, previous disease history, blood biochemical indicators, metformin, and insulin history, FLI remained an independent influence factor for the progression of LLAC. Nevertheless, the existing evidence does not yet support that NAFLD predicts the occurrence and progression of LLAC in T2DM patients.

Owing to the shifts in the dietary habits and lifestyles of individuals, NAFLD has emerged as a prevalent global chronic liver condition [22]. Previous studies have confirmed that NAFLD is strongly related to T2DM and metabolic syndrome and is associated with future cardiovascular disease in T2DM patients [7, 8, 9, 23, 24, 25]. A study by Ciardullo et al. [26] showed that all-cause mortality and cardiovascular mortality were significantly elevated among patients with PAD, irrespective of whether they were comorbid with T2DM. However, the relationship between NAFLD and PAD remains a topic of debate among experts in the field. Zou et al. [27] demonstrated that individuals with both T2DM and NAFLD exhibited a higher prevalence of PAD, characterized by an ankle–brachial index (ABI) 0.9 in either lower limb. This increased occurrence of PAD in NAFLD patients may be attributed to the presence of concurrent metabolic risk factors or an inflammatory response within the body [27]. However, the results of Liu et al. [28] did not demonstrate a statistically significant decrease in ABI levels among patients with NAFLD, which is consistent with the findings of our study. In this study, we utilized lower extremity vascular computed tomography angiography (CTA) to diagnose PAD with more precise and objective criteria. In addition, we measured the ABI of patients to assess their vascular health further. However, it was observed that not all patients with LLAC had an ABI less than 0.9. Thus, we propose that the increased prevalence of medial arterial calcification (MAC) in patients with T2DM is the underlying reason for the further reduced extremity blood pressure values and, consequently, elevated ABI value. Therefore, it is essential to note that using an ABI 0.9 as the sole metric for evaluating and diagnosing PAD in these patients may be inaccurate [29, 30]. This discrepancy partly accounts for the difference between our study and the study by Zou et al. [27]. In addition, MAC can occur without lipid deposition and inflammatory cell infiltration, which is different from the traditional mechanism of atherosclerotic calcification. Moreover, MAC is more common in lower extremity arteries than in coronary arteries [31, 32], while Salle et al. [33]demonstrated the significance of MAC in contributing to lower extremity vascular events in patients diagnosed with T2DM. Although the presence of MAC does not directly cause lumen obstruction, it can decrease the elasticity and compliance of the arterial wall, ultimately leading to atherosclerosis. This condition, in turn, can contribute to the development of CHD or PAD. It is worth mentioning that the factors contributing to the development of MAC and arterial intimal calcification may vary considerably due to the phenotypic switching of vascular smooth muscle cells [31]. Therefore, the presence of calcifications at various anatomical sites may partly explain why NAFLD patients are positively associated with the presence of CHD while being negatively related to the presence of LLAC. In addition, Ponziani et al. [34] conducted a recent prospective study and found no significant difference in the incidence of lower extremity atherosclerosis between the NAFLD and control groups. It is worth noting that 16.7% of NAFLD patients in their study suffer from T2DM, which partially confirmed our initial hypothesis [34].

Insulin resistance is a major characteristic of T2DM [35]. Recent research has highlighted the TyG index as a dependable indicator of insulin resistance, with its elevated levels being linked independently to coronary calcification [36]. Our study did not find any association between the TyG index and LLAC. However, we demonstrated that in T2DM patients with high FLI was significantly associated with an increased TyG index. It suggested that NAFLD was significantly associated with insulin resistance in T2DM, consistent with previous data [37, 38]. Moreover, oxidative stress [39] and inflammation [40] are possible mechanisms for LLAC. However, in our study, the levels of hs-CRP were not significantly different among the FLI groups. Regarding the SOD levels, we found high levels of SOD in the high-risk FLI group, although this is contradictory for the patients in this group that have less LLAC. It may attribute to the age factor, whereby the younger individuals in the high FLI group counteract the bad effect of SOD on the vessels. Additionally, we found that T2DM patients with potential NAFLD tended to be younger, which seems to be counterintuitive. However, Forlani et al. [41] presented the same conclusion in a cross-sectional study with a much larger sample size. A plausible explanation is that younger people tend to have more unhealthy living habits than older people, such as staying up all night and having a casual approach to diet [42].

This study has certain limitations. Firstly, it is important to note that this research is a single-center cross-sectional study, which may only partially capture the long-term changes and dynamic processes of the population under study. Secondly, since T2DM patients seldom completed the lower limb CT for renal dysfunction or economic reasons (most of them underwent ultrasonography measurement to evaluate lower limb artery), the number of patients we enrolled in this study was relatively small. Thirdly, we used the FLI score to define NAFLD, a diagnostic method lacking liver histological or imagological evidence. Lastly, the LLAC score, which specifically quantifies the calcified portion of atherosclerotic plaques, fails to capture the full extent of the plaque burden due to its exclusion of soft plaques.

Our study revealed an inverse relationship between FLI and the degree of LLAC. This implies that NAFLD may not be reliable as a predictor of LLAC in T2DM patients. The potential relationship demonstrated in this study warrants further corroboration through multi-center trials and prospective studies with larger sample sizes.

The data underlying this article will be shared upon reasonable request to the corresponding author.

PBM: Writing - original draft, Writing - review & editing, Conceptualization, Formal analysis, Investigation; QLL: Writing - original draft, Writing - review & editing, Data curation, Formal analysis, Methodology, Resources; SJL: Writing - review & editing, Investigation, Methodology, Validation, Visualization, Software; CHW: Writing - original draft, Formal analysis, Methodology, Resources; SWX: Writing - original draft, Data curation, Formal analysis, Investigation, Validation; KZ: Conceptualization, Funding acquisition, Project administration, Writing - review & editing; NSL: Conceptualization, Project administration, Resources, Supervision, Visualization, Writing - review & editing. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

This study was approved by the Ethics Committee of Sun Yat-sen Memorial Hospital (ethics approval number: SYSKY-2024-778-01). All patients or their families/legal guardians gave their written informed consent before they participated in the study.

This work was supported in part by National Natural Science Foundation of China (NSFC) [81600351] to Kun Zhang.

The authors declare no conflict of interest.