Although some previous studies suggested that diabetes-related inflammation may be one of the biological pathways linked fatty acids and cognitive decline, definite evidence also need to be verified. Thus, the mediation model was established to examine whether inflammation statistically mediated the relationship between plasma fatty acids and cognition function, which was evaluated by MMSE and MoCA scale.
Previous studies pointed that overweight and obesity were linked to insulin resistance, which was frequently associated with inflammation. On the contrary, those who were obesity might become insensitive to insulin. In the present study, we observed similar results. We found a higher HOMA-IR, hs-CRP and CRP levels were related to higher BMI and waist circumference, while QUICKI was negatively related to the markers of obesity. Early studies also revealed waist circumference was significantly related to high prevalence of cognitive dysfunction, which is independent of other related metabolic diseases and lifestyle risk factor, including smoking and drinking. Based on neuroimaging findings, those who were obesity showed damaged brain structure (brain volume loss and brain atrophy of the grey matter) [39, 40], which indeed lead to cognitive impairment . Similarly, in our study, BMI was negatively correlated with MoCA Language skills scores and the increasing of waist circumference may lead to a drop of the score of language skills in MoCA. These findings suggested that inflammation from obesity might cause cognitive decline in T2DM.
Most previous studies indicated high SFA may be a risk factor of learning and memory ability, while MUFA and PUFA had protective effects of age-related cognitive decline[42, 43]. Yu et al found high SFAs diet resulted in obesity in mice and subsequently damaged the function of spatial learning and memory in mice. In a follow-up study, a conclusion was drawn by using structured interviews, which indicated high intake of dietary SFAs could aggravate clinical symptoms in AD patients and increase the risk of AD. Our study gave similar conclusion that SFAs might destroy the orientation and language skills of patients with T2DM. In a prospective population-based study on elder participants with a typical Mediterranean diet, high PUFA and MUFA intakes seemed might be protective measure to against age-related cognitive decline. n-3 PUFA could improve cognitive function, while the effect on cognitive function of n-6 PUFA still remained controversial[48, 49]. Some previous studies showed n-6 PUFA enhanced the tissue inflammatory response, and increased the risk of cognitive impairment, whereas another study pointed that difference may result from the n-6/n-3 PUFA ratio in diet[52, 53]. Our result was consistent with previous studies. Higher SFAs levels in plasma were linked to cognitive decline (SFA, C16:0 and C18:0), and higher MUFAs intake might be a protective factor for cognitive function, except C16:1. In addition, although PUFA and C18:2n-6 had a positive association with MoCA Orientation, and most PUFAs levels stood out as having increasing trends that were positively correlated to cognitive function scores, the C18:3n-3, C18:3n-6 and C20:3n-6 gave opposite results. However, we didn’t find significant difference between cognition function and n-3 PUFA. This may due to the fact that plasma fatty acids reflect more short-term intake of dietary fatty acids. In addition, ratio of n-3: n-6 fatty acids might affect the PUFAs metabolism. As reported, the activity of SCD, D5D, D6D was associated with metabolic-related diseases. In this study, similarly, SCD-18 and D5D had positive relationships with cognitive function scores, instead, SCD-16 and D6D showed opposite results. SCD converted a portion of 16:0 into palmitoleic (16:1) and 18:0 into oleic acid (18:1), which might contribute to the moreabundant of MUFA species. Arachidonic acid (C20:4n-6) and g-linoleate (C18:3n-6) were derived from g-arachidonic acid (C20:3n-6) and linoleate (C18:2n-6) through desaturation (D6D and D5D) and elongation. So the activity of D5D and D6D could change the proportion of n-6 PUFAs. Previous studies showed that increasing SCD-1 activity was associated AD. Moreover, previous studies indicated higher D5D was associated with better insulin sensitive, while lower D6D activity led to lower risk of insulin resistance, which might result in different effect on cognitive function. And the genotype of related genes might affect the metabolic efficiency of PUFAs and desaturase activity, such as FADS1, which encoded D5D.
Several researches existed that inflammation is involved in the development and/or progression of T2DM[58, 59]. And the inflammatory response could be impacted by diet fatty acids. High fat diet may reduce synaptic plasticity and destroy insulin signaling/glucose homeostasis, which activate the innate immune system, including increased inflammatory cytokines, such as IL-6, IL-1β, TNFα. In our study, we found higher SFAs led to higher HOMA-IR and higher LPS levels, and positive correlation trends had been found between SFAs and NFκBp65, TNF-α. Another study also showed that high SFA diet led to activated protein kinase (AMPK), TLR4 and higher HOMA-IR values . SFA was reported that contributed to inflammatory response and higher levels of plasma inflammatory factors (e.g., IL-1β, IL-6) [21, 62]. While treating the high fat diet fed mice with palmitoleic acid or oleic acid daily by oral gavage decreased the expression of IL-1β and IL-12 in PPAR-α-knockout (KO) mice. There was another study showed that n-3 PUFA supplementation could reduce IL-6 and TNF-α production in T2DM . In this research, MUFAs, SCD-16 and SCD-18 were positively related to hs-CRP. That might due to the proportion of MUFA in the diet and diet pattern. In addition, IL-10 has been pointed out to be associated with the occurrence of AD as an anti-inflammatory mediator. IL-10 could reduce synthesis of pro-inflammatory and inflammatory responses in the brain as a suppressor so that it could negatively control the immunomodulatory action of IL-1, IL-2, IL-6, IL-8, IL-12 and TNF-α, and the effects may have been considerably influenced by single nucleotide polymorphisms. Interestingly, we found PUFAs were negatively related to IL-10,which might result from the ratio of n-3: n-6 fatty acids. In an animal experiment, researchers found that compared the subjects fed with Mediterranean diet (balanced n-6/n-3 PUFA ratio), the rats fed with Western diet (high n-6/n-3 PUFA ratio) showed lower IL-10 levels and accompanied by memory deficits. Furthermore, the Single Nucleotide Polymorphisms (SNP) of IL-10 should be note. In addition, higher PUFAs led to lower inflammatory cytokines levels, such as hs-CRP, CRP and LPS. This finding provided evidence that the intake of PUFAs could reduce inflammatory response. These increased inflammatory cytokines could induce activation microglia and result in neuroinflammation, accompanied by disrupt neurogenesis and brain structures. For example, in a case-control study, the serum levels of hs-CRP, IL-6 and TNF-α in T2DM subjects with MCI were significantly higher than type 2 diabetic patients. Consistently, we showed that higher IL-1β, IL-10 and NFκBp65 levels were related to lower cognitive function scores.
In order to verify the effects of fatty acids on inflammation and cognition function, the mediating effect analysis was conducted. There was a significant negative relationship between IL-10 and MoCA language skill in our study. This study found C18:0 could reduce MoCA language skills scores by regulating plasma IL-10 levels. More specifically, through decreasing IL-10 levels of patients with diabetes, higher C18:0 might damage their language skill, which was evaluated by MoCA. In the past few years, some researchers found fatty acids in diet could change IL-10 levels. Supplementation with n-3 PUFA can reduce the inflammatory response in rat, increase levels of IL-10, but decreasing levels of TNF-α, IL-6, IL-1β, and IL-17 and higher n-6: n-3 fatty acids ratio might reduce IL-10 levels and lead to cognitive impairment. Some evidence was given to prove IL-10 could improve spatial cognitive decline in transgenic AD mice. In a cross-sectional analysis, however, higher IL-10 levels were associated with greater odds of MCI diagnosis. Though we found the mediating effect of C18:0 on IL-10 and MoCA language skills, more researches were still needed to support this finding.
There were still some limitations in our study. We need expand the sample size and choose different sources of participants instead of limited to hospital patients. Apart from this, erythrocyte membrane fatty acid components of T2DM should be tested to evaluate the dietary fatty acid intake.
In conclusion, our study supports the hypothesis that plasma fatty acid can influence cognitive function by regulating inflammation, which suggested that plasma fatty acids can be evaluated as a potential indicator of cognitive function decline.