High Plasma Resistin Levels Portend the Insulin Resistance-Associated Susceptibility to Early Cognitive Decline in Patients with Type 2 Diabetes Mellitus

INTRODUCTION

Type 2 diabetes mellitus (T2DM) is a worldwide epidemic with prevalence in China reaching 10.9% [1] and is an independent risk factor for Alzheimer’s disease (AD) [2] and conversion from mild cognitive impairment (MCI) to AD [3]. As a syndrome of cognitive impairment situated between normal aging and dementia, MCI is also the preclinical state of AD. Evaluation and early identification of MCI is beneficial for AD prevention, especially among patients with diabetes and high risk of AD.

Metabolic disorders, such as insulin resistance (IR) [4], obesity [5], and dyslipidemia [6] are involved in the progression of MCI in patients with diabetes, even before the disease onset. For example, IR usually occurs earlier than T2DM, thus promoting the chronic complications at early stages [7]. IR also impairs cognition and is an independent risk factor of MCI [8]. Dysfunction of insulin signaling may disrupt normal functions in regulating tau protein, amyloid-β, and amyloid- β protein precursor metabolism in neurons [9]. Moreover, some adipocytokines, e.g., adiponectin, leptin, and resistin, may play important roles in these situations [10].

Resistin is an adipocytokine produced by fat cells in mice and expressed mainly in macrophages in humans [11]. This cytokine regulates body weight, blood sugar, lipid levels, and systemic metabolism by modulating insulin sensitivity. The insulin action is improved when neutralizing antibodies consume the circulating resistin [11]. Resistin overexpression induces the development of IR and dyslipidemia [12]. Studies have associated elevated circulating resistin levels with increased risk for T2DM [13], obesity [14], and especially IR [15]. Clinical investigations have reported a positive correlation between resistin level and IR severity [16, 17], and resistin levels are remarkably high in people with prediabetes [18]. General consensus states that resistin affects insulin signaling by interfering with the activation of insulin receptor substrate (IRS)-1 and inducing the expression of the negative mediator of insulin signal cascade regulation [19]. Thus, resistin has an important relationship with IR.

In addition to its contribution to IR, resistin adversely influences brain functions through mechanisms, such as the promotion of inflammatory processes or oxidative stress [20–22]. Some observational studies have reported the negative effects of resistin on cognition [20, 23]. Altered levels of resistin in the central nervous system of obese mice may affect the carbohydrate metabolism of hippocampus, which is related to memory and learning [24], and these influences also represent a feature of MCI [25, 26]. Therefore, resistin is associated with cognitive impairment, especially MCI, and may be involved in the connection between IR and MCI.

Metabolic disorders, especially IR, increase the incidence of AD and MCI, and cognitive performance has a close correlation with resistin level. However, the links between resistin and metabolic imbalances and the early cognitive dysfunction in T2DM remain inconclusive. Comparison and observation of metabolic indicators in diabetic patients with or without MCI can reveal whether resistin is involved in the pathogenesis of MCI caused by metabolic abnormalities such as IR and whether this adipocytokine can be used as a clinical predictor or indicator of MCI in patients with diabetes.

MATERIALS AND METHODS

RESULTS

DISCUSSION

Our study suggests that patients with T2DM and MCI displayed remarkably high plasma levels of resistin and HOMA-IR scores, and similar results were obtained for both genders. In addition to old age and low educational attainment, high resistin level was also negatively correlated with most cognitive domains. This adipocytokine was related to IR but not with most obesity indices and blood lipid levels. Thus, resistin was an independent risk factor for MoCA and MMSE scores. High plasma levels of resistin were associated with IR-associated MCI in Chinese patients with T2DM.

Resistin is closely related to cognitive impairment. Patients with AD have elevated resistin levels compared with patients without AD [30, 31]. Altered levels of resistin in the central nervous system of obese mice affect the hippocampal metabolic glucose levels, which are connected with memory and learning capabilities [24] and also represent a feature of MCI [25, 26]. We reached a similar conclusion that high resistin level was negatively correlated with most cognitive domains. On the contrary, some studies have presented different conclusions. Liu found that resistin has a protective effect on AD in vitro studies [32]. Another work confirmed that resistin exerts neuroprotection on cell apoptosis induced by 6-OHDA [33]. Although the reasons for these differences remain to be further analyzed, we suggest that the studies showing the neuroprotection of resistin were limited to in vitro models, whereas population studies did not show similar results. The human internal environment is highly complex that resistin and other factors can simultaneously interact with and restrict each other. Therefore, further study must be conducted to determine whether resistin damages cognitive function or is associated with neuroprotection in cognitive impairment.

IR is one of the most distinctive characteristics of T2DM and emerges prior to dominant T2DM. HOMA-IR, an indicator of insulin sensitivity, is an important indicator for T2DM [34]. Another published research declared that IR is associated with increased AD risk [2] and plays a vital role in the early phase of AD [8]. Our research found that HOMA-IR score in the MCI group was higher than that in the patients without MCI. Although not statistically significant, patients with cognitive impairment were more likely to present abdominal obesity than patients without MCI, indicating a possible increase in visceral fat mass. In addition, MoCA and MMSE scores were negatively correlated with resistin levels, indicating the role of this cytokine in cognitive function impairment.

Consistent with previous studies [16, 17], we found that resistin and IR are closely related. Therefore, we only included resistin as the independent variable in the multivariate regression analysis and did not include HOMA-IR scores due to the strong interference. IR, resistin, and cognitive function have a complex relationship, and HOMA-IR changes may be related to resistin, leading to cognitive impairment. Although the mechanisms underlying this relationship remain a matter of debate, general consensus states that resistin affects insulin signaling by interfering with IRS-1 activation [19]. Emanuelli found that suppressor of cytokine signaling-3, a negative mediator of insulin signal cascade regulation, could be induced by resistin [35]. On the contrary, resistin and the insulin resistance it induces contribute to cognitive impairment [30, 36].

Although resistin can cross over blood-brain barrier, its concentration in cerebrospinal fluid is lower than that in plasma [37, 38]. Hence, resistin levels in peripheral blood may not play an important role in cognitive functions. On the contrary, the pro-inflammatory properties of resistin are remarkable because it can activate inflammatory processes by promoting TNF and IL-6 [39]. High TNF and IL-6 levels are associated with cognitive impairment [40]. In addition, resistin is expressed in the cortex, hypothalamus, and hippocampus to inactivate hypothalamic neurons [41–43]. Thus, we consider that resistin can also cause cognitive impairment through inflammation or inflammation-related insulin resistance. Additional research is needed to explore the underlying molecular mechanisms.

Certain limitations of this study should be noted. First, the study is at preliminary stage, and all participants were Chinese, thus limiting the generalizability of our results. The small sample size may also limit the reproducibility of the findings. Second, healthy volunteers or other patients without T2DM were not enrolled, and most patients are non-obese based on BMI but not on abdominal obesity. Third, data from neuroimaging examination, the pathological changes of MCI in T2DM caused by resistin, and resistin levels in the adipose tissues were not yet obtained. Finally, we did not collect information regarding body fat, C-reactive protein, and other parameters that may also play an important role in the relationship between resistin and MCI. Thus, further studies with large and heterogenous samples, additional related parameters, and different weight statuses are needed for the comprehensive understanding of resistin role in diabetes-related cognitive impairment.