Type 2 diabetes mellitus (T2DM) is a common metabolic disorder characterized by the persistent hyperglycemia and insulin resistance. According to the report from the International Diabetes Federation (IDF), there are 537 million adult patients with diabetes mellitus, that is about 1 in 10 adults globally (1). In China, 140 million adults are diagnosed as T2DM in 2021 and the number is estimated to 170 million in 2045 (1). Due to T2DM patients are often accompanied by the chronic damage and dysfunction of blood vessels, nerves and brain (2, 3), most patients with diabetes have impaired cognitive function (4) or Alzheimer’s Disease (AD). Results of epidemiological perspectives indicated that the relative risk for dementia was 1.51 in people with T2DM compared with those without, and 25~36% of the patients have mild cognitive impairment (5). Unfortunately, there are no specific measures for preventing or treating the symptoms (6), and traditional hypoglycemic drugs are always low targeted. Thus, it is important to investigate the potential mechanism of T2DM-related cognitive dysfunction and explore the possible biomarkers for effective diagnosis and treatment.

The multifactorial process of cognitive dysfunction in T2DM is not yet completely understood, however, classical factors, such as oxidative stress and systemic inflammatory responses, may contribute to the pathogenesis of diabetes-related cognitive dysfunction (7, 8). It has been reported that cognitive impairment in T2DM rats can be improved by reducing inflammatory response (9). Among them, inflammatory cytokines IL-6 and CRP were significantly increased in T2DM patients with cognitive impairment (10). This may be due to the overproduction of pro-inflammatory factors in diabetes, which leads to changes in various neurotransmitters and damage to neurons (11). As a family of activating receptors, TREMs participate in the regulation of inflammatory response (12). The disruption of TREMs could exert an important influence on homeostatic activity (13), resulting in different outcomes in different diseases (14). Polymorphism and changed expression of TREM1 and TREM2 have been demonstrated to involve in the pathogenesis of neuropsychiatric diseases including AD (15). Apart from an imbalanced protein expression of TREM1 and TREM2 in the hippocampus of depression (16) or AD (17) rat model, results of our previous study have shown a turbulence of TREM1 and TREM2 abundance in T2DM patients (18).

Besides inflammation, depression and sleep disturbances have also been reported to play an important role in the pathogenesis of T2DM-related cognitive dysfunction. T2DM patients with depression had higher level of hyperglycemia and cognitive impairment than T2DM patients (19). Both depression and diabetes are accompanied by insulin resistance, which is the main reason for the high co-morbidity of the two diseases (20). And insulin resistance often exacerbates abnormalities in brain metabolism, showing cognitive impairment, which makes diabetes often accompanied by depression and cognitive impairment (21). In addition, it has been reported that T2DM mice with obstructive sleep apnea can damage neurons and lead to cognitive dysfunction (22). Other studies have shown that T2DM patients with cognitive impairment have poorer sleep quality, which is also associated with neuropathic pain, anxiety and depression, while patients taking sleep enhancing drugs have improved cognition (23, 24).

Vitamin D is a steroid hormone with versatile physiological activities (25). Recently, much attention has been paid to the effect of 25(OH)D in T2DM and its associated diseases (26, 27). Results from human studies have demonstrated that low 25(OH)D levels are associated with an increased risk of T2DM, including gestational diabetes mellitus (GDM) (28). Consistently, supplementation of 25(OH)D could not only prevent and treat GDM (29), but also contributed to blood glucose control and lipid balance in T2DM patients (30). Moreover, the “neuroprotective” effect of 25(OH)D has been demonstrated (31). It has been reported that lower 25(OH)D levels could accelerate the impaired hippocampal neurogenesis and cognitive decline in elder via promoting inflammatory response (32), and Vitamin D supplementation can improve the physical and cognitive performance (33). Similar conclusions were also obtained in animal models, in which the brain inflammation of T2DM rats supplemented with Vitamin D was reduced and the learning and cognitive abilities were significantly improved (34). These results indicated that 25(OH)D levels might be a diabetes risk modifier and linked to the cognitive impairment. However, its association with risk factors for the cognitive impairment remains to be further studied.

The aim of the present study is to investigate the role of VDI in the dysfunction of glucolipid metabolism and cognitive impairment in T2DM patients, especially the potential linking effect of cognitive function and its risk factors. Accordingly, T2DM patients were enrolled, the plasm concentration of activated 25(OH)D were measured, the parameters of inflammation and glucolipid metabolism were detected, and the cognitive ability, depression and sleep status were evaluated in the present study.

In this study, we investigated the plasma 25(OH)D level in T2DM patients and its correlation with the glucolipid metabolic dysfunction, inflammatory activation, depressive symptoms, sleep quality and cognitive impairment. The results revealed that plasma 25(OH)D levels were statistically significantly lower in T2DM patients with HbA1c ≥ 7% compared to the HbA1c< 7% group. Taken the clinical diagnosis criteria of VDI, our results showed that T2DM patients with VDI had a higher level of HbA1c, inflammatory cytokine, and BRIEF-A scores than patients with normal VD level. Results of the correlation analysis showed negative correlations between 25(OH)D and glycolipid metabolic parameters (HbA1c, FPG, PBG), depressive symptomatology (assessed by CES-D sum score), sleep disorders (assessed by PSQI sum sores), and three inflammatory markers (CRP, IL-6, sTREM1). And 25(OH)D level was positively associated with the biochemical indicator Scr. Moreover, results of the ROC curve showed a predictive role of 25(OH)D in discriminating T2DM patients with high scales of BRIEF-A (scores > 50th percentile) from low scores (scores< 50th percentile). These results indicated that VDI is likely be a risk and predicative factor for cognitive impairments in T2DM patients, and involved with the inflammatory response and glucolipid metabolism.

It has been reported that 25(OH)D status are involved with the process of T2DM and its complications (36), with a regulatory role on glucolipid metabolism and insulin resistance (37, 38). Moreover, in patients with a deficiency of 25(OH)D, there was a higher HbA1c as well as disorders of blood lipids (39). The results of our study showed that T2DM patients with VDI has a higher HbA1c, which has been a clinical indicator of predicting the risk of diabetic complications (40). Moreover, apart from the negative correlation between plasma 25(OH)D level and HbA1c, our results also showed that the plasma 25(OH)D level was also negatively related to FPG and PBG, but positively correlated with Scr. Together with the findings that T2DM were more susceptible to VDI (41). These above suggest that patients should be taken to the harmful effect of VDI in the pathogenesis or T2DM.

Excessive inflammation and immune activation have long been taken as etiological and concomitant conditions of T2DM (42). It has been reported that hyperglycemia and metabolic disorders could trigger the inflammatory response via incur an imbalance between the oxidizing species, oxidative stress and cellular death (43). 25(OH)D is essential in maintaining the normal immune system and modulating inflammation of the innate immune function (44). Besides, 25(OH)D may regulate inflammatory gene expression by suppressing endoplasmic reticulum stress, oxidative stress (45). Moreover, supplementation with 25(OH)D can improve metabolic disorders and alleviate inflammatory response of T2DM patients via reducing a number of inflammatory factors such as IL-6, CRP, and TNF-α levels (46, 47). Consistently, in the present study, our results showed that the plasma levels of IL-6 and sTREM1 were remarkable higher in T2DM patients with VDI than that the normal VD, with a negative correlation between plasma 25(OH)D concentrations and IL-6, sTEREM1, or CRP. These results suggested that VDI might play a detrimental role in the hyper-inflammatory response of T2DM patients.

Cognitive impairment is a common comorbidity or complication of T2DM (2). Besides poor glycemic control, the reported risk factors include hyperinsulinemia, increased oxidative stress (48) depression, and sleep disorders (49, 50). In line with these findings, in the present study, our results showed that the BRIEF-A scores were positively correlated with the FPG, PBG, IL-6, sTREM1, CES-D and PSQI sum scores, suggesting again a close relationship between the cognitive function and glycolipid metabolic parameters, inflammatory cytokines, depressive emotion, and sleep state. It has been reported that T2DM patients with cognitive impairment were at higher risk of low 25(OH)D level as compared to their healthy counterparts (51). Consistently, results of the present study demonstrated that compared with the normal VD group, the BRIEF-A scores of the VDI was higher, which indicated a worse cognitive competence of the VDI patients than that of the normal. In further, results of Pearson test showed that the plasma 25(OH)D level was negatively correlated with the BRIEF-A total scores, BRI, and MI scores. Also, 25(OH)D was negatively correlated with the risk factors for cognitive dysfunction, including inflammation, depressive emotion and sleep state. These results suggested that 25(OH)D played a crucial role in the cognitive dysfunction of T2DM patients. Although there has been demonstrated that low level of 25(OH)D was significantly associated with sleep disturbance and depression (52), and vitamin D supplements could improve the sleep score and quality of sleep disorders aging 20-50 (53), our results showed that there was no significant different between groups with regard to the depression and sleep status. Nevertheless, the indices of depression and sleep were slightly impaired in T2DM patients with VDI, with a significantly negative correlations between plasma 25(OH)D level and the CES-D or PSQI sum scores. It may suggest that 25(OH)D indeed has an effect on the depressive symptoms and sleep disturbances that accompany T2DM, but the extent of this is not known.

In this study, ROC curves were used to suggest the potential value of 25(OH)D in diagnosing cognitive function. The higher the sensitivity and the lower the 1-specificity in the ROC curve analysis, the more reliable an indicator is as a basis for diagnosis. We obtained a sensitivity and specificity of 62.12% and an area under the AUC curve of 0.62. These results suggest that 25(OH)D has a certain diagnostic basis for cognitive function in patients with T2DM. Nevertheless, 25(OH)D as a diagnostic criterion has a certain rate of misdiagnosis. Insufficient sample size is the main reason, which means lower power of test. Further higher accuracy might be obtained by expanding the sample size. In addition, other factors, such as age, may also have a potential impact. One study indicated that 25(OH)D deficiency was more closely associated with cognitive dysfunction in older patients (54). But the majority of our study participants were in middle age. These mean that we need to consider additional factors in the discussion of 25(OH)D as a basis for diagnosis, and further investigate its value while expanding the sample size.

There are several limitations in the present study. Firstly, the relatively small sample size limits the generalizability of the present results. Furthermore, although the changed 25(OH)D level and its correlation with some glucolipid, inflammation, or cognitive function was observed in T2DM patients, the detailed mechanism was not explored in the present study. Moreover, prospective studies with vitamin D supplements would have to warrant our findings in the future.

In conclusion, our study indicated that VDI should be a detrimental factor in the pathogenesis of T2DM, involved with not only the glucose metabolism and inflammatory response, but also the cognitive function. Moreover, plasma 25(OH)D level might play a predictive role in discriminating T2DM patients with higher cognitive impairments.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the Ethics Committee of Hefei Fourth People’s Hospital, Anhui Mental Health Center. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

J-FG designed this study. H-MS, YY, X-RG conducted most of the experiments, analyzed the data and wrote the manuscript. J-FG conceived the study and revised the manuscript, H-MS analyzed the results and write text. YY screened and selected the patients, collected material. X-RG processed the samples, analysis results. And Y-DW, C-ZQ, M-DM, D-DX and Y-YX assisted in the experiments. All authors contributed to the article and approved the submitted version.