Role Of Nesfatin-1 Associated Immune Imbalance In The Cognitive Impairment Of Type 2 Diabetes Patients

Type 2 diabetes mellitus?T2DM?is a systemic metabolic disease characterized by a decrease in insulin secretion or a decrease in insulin sensitivity by target cells,resulting in a elevated blood glucose and dysfuction of multiple organs.In addition to common complications including the impairments of heart,eye and kidney,T2DM can induce neuropsychiatric symptoms,among which cognitive impairment is highly concerned by scholars.Nesfatin-1 is an anorexia factor derived from nucleobindin 2?NUCB2?and discovered in 2006.It is widely expressed in both the central nervous system and peripheric tissues.Apart from the role in feeding behavior and glycolipid metabolism,research about the biological activities of Nesfatin-1 are mainly focused on the regulation of brain function including mood and congition.Results of our previous studies have demonstrated that intraperitoneal injection of Nesfatin-1 could induce anxiety-and depression-like behaviors in rats,the mechanism of which might be partly involved in the hyperactivity of inflammatory and immune response,together with the alternated synaptic plasticity in the hippocampus and prefrontal cortex.Moreover,high-fat diet-induced obese rats showed not only obesity,glycolipid metabolism,liver morphological and functional impairment,but also the decreased learning and memory abilities,which was related to the elevated plasma Nesfatin-1 concentration,and the imbalanced TREM1/2 expression and synaptic plasticity in the hippocampus and prefrontal cortex.Therefore,Nesfatin-1 might be an important factor in bridging glycolipid metabolism disorders and neuropsychiatric injuries.Objective:By collecting T2DM patient demographic and medical history data,physical examination and biochemical test results and performing cognitive function assessment,the aim of the present study is to explore the possible causes of cognitive impairment in T2DM patients,especially focusing on the potential role of Nesfatin-1 so as to provide reliable evidence for the clinical observation and intervention of the cognitive dysfunction in T2DM patients.Methods:Taking the T2DM patients diagnosed in the Department of Endocrinology,the Fourth Affiliated Hospital of Anhui Medical University from April 2017 to April2018 as the research object,a total of 132 cases were eligible for inclusion,including 71males and 61 females,with an average age of?57.85±12.33?years.The demographic and medical history information were collected using questionnaires,the physical examination results including height,weight,waist circumference,and hip circumference were collected,based on which the body mass ratio?BMI?and waist-to-hip ratio?WHR?were calculated.The plasma concentrations of total cholesterol?TC?,triglyceride?TG?,high-density lipoprotein cholesterol?HDL-C?,low-density lipoprotein cholesterol?LDL-C?,alanine aminotransferase?ALT?,aspartate transaminase?AST?,total bilirubin?TBIL?,direct bilirubin?DBIL?,indirect bilirubin?IBIL?,serum creatinine?SCR?,blood uria nitrogen?BUN?,fasting plasma glucose?FPG?,post-prandial glucose?PPG?,and glycated hemoglobin?HbA1C?level were measured via electrochemiluminescence methods.The plasma levels of Nesfatin-1,sTREM1/2,C-reactive protein?CRP?,interleukin-6?IL-6?,leptin,insulin,and25?OH?D₃ concentration were detected by enzyme-linked immunosorbent assay?ELISA?method.The executive function of the T2DM patient was evaluated using the Behavior Rating Inventory of Executive Function.The EPI version 3.1 was used to perform the function performance rating scale data entry and the SPSS version 19.0 was used for data statistical analysis.The measurement data is expressed in the form of mean±standard deviration,and the count data is expressed in the form of the number of cases.The student's t-test and chi-square test were used to compare the relevant demographic data,physical examination data,biochemical indicators,and the BRIEF scale scores between groups;The correlation analysis was performed by Pearson test.P<0.05 was considered statistically significant.Result:1.According to the reports of 2010 American Diabetes Association Diabetes Treatment Guidelines that HbA1C>7%could increase the risk of microvascular and neurological complications in DM patients,the subjects in the present study were divided into two groups including the HbA1C?7%group?33 cases?and the HbA1C>7%group?99cases?.The results showed that compared with that in the HbA1C?7%group,the number of peripheral neuropathy and fatty liver in HbA1C>7%group was relatively increased,and the plasma concentrations of TG,FPG,PPG,and HOMA-IR were significantly increased,and ISI were significantly decreaseed.Results of Pearson correlation test showed that the plasma HbA1C level was positively correlated with the HOMA-IR and plasma concentrations of TG,FPG,and PPG,but negatively correlated with ISI.These results suggested that the high HbA1C level might be a core risk factor in the pathogenesis of T2DM and the consequent complications,with more severe disorders of glucose and lipid metabolism,insulin resistance,and insulin secretion in T2DM patients with higher HbA1C levels2.Compared with that in HbA1C?7%group,T2DM patients in the HbA1C>7%group showed higher scores in the items of inhibition,shift,emotional control,self-monitor,initiation,working memory,plan,organization of materials,task monitor factor score,behavioral regulation and metacognitive index scores,and the total score of BRIEF-A.It suggested an important role of HbA1C in the cognitive impairment of T2DM patients,with moreserious cognitive impairment in T2DM patients with higher HbA1C levels.3.Compared with that in the HbA1C?7%group,the plasma concentrations of Nesfatin-1,CRP,and IL-6 were significantly increased in HbA1C>7%group.Results of Pearson correlation test showed that the plasma HbA1C concentration was positively correlated with that of Nesfatin-1,CRP,and IL-6.These results suggested that inflammatory response is over-activated in T2DM patients with higher HbA1C levels.Hyperglycemia might be an inducing factor that causes the increase of plasma Nesfatin-1 concentration,which might be involved in the elevation of HbA1C.4.Based on the standard using in our previors study,the T2DM patients were divided into low Nesfatin-1 group?<264.17pg/ml?and high Nesfatin-1 group??264.17pg/ml?in the present study,to observe the role of Nesfatin-1 in the cognitive dysfunction of T2DM.The results showed that compared with those in the low Nesfatin-1 group,the scores of various executive functions were arising,with a significant difference between groups as regards to the total scores of executive ability,behavioral management index scores,inhibition,shift,and initiation factor scores.The results of multiple linear regression model showed that with the increase of plasma Nesfatin-1 level,the initiation and working memory factor scores increased significantly,together with the elevation of the shift and plan factor scores,the metacognitive index scores,and executive ability scores,and the association was close to a statistical significance.These results suggested that the change of the plasma Nesfatin-1 abundance might well be associated with the cognitive impairment in T2DM patients,with more cognitive impairments in T2DM patients with higher plasma Nesfatin-1 levelst.5.Compared with that in the low Nesfatin-1 group,the plasma concentrations of HbA1C,FPG,and HOMA-IR were significantly increased,and ISI were significantly decreased,with an increasing trendency of TG in high Nesfatin-1 group.Results of Pearson correlation test showed that plasma Nesfatin-1 concentration was positively correlated with FPG concentration and negatively correlated with ISI.These results suggested a regulative role of Nesfatin-1 in glucolipid metabolism.6.Compared with that in the low Nesfatin-1 group,the plasma concentrations of IL-6,sTREM1 and sTREM2 were significantly increased in high Nesfatin-1 group,together with an increased mRNA expression of TREM1 and TREM2 in the peripheral lymphocytes and a decreased plasma concentration of 25?OH?D₃.Results of Pearson correlation test showed that the plasma Nesfatin-1 concentration was positively correlated with that of sTREM1 and sTREM2 concentrations,but negatively related with that of 25?OH?D₃.These results suggested that the increased abundance of Nesfatin-1 might play a core role in inducing the hyperactivity of inflammation and immune function and the imbalance of TREM1/2.Nesfatin-1 and its induced immune function over-activation and 25?OH?D₃ deficiency might mediate the cognitive dysfunction in T2DM patients.Conclusion:Disregulation of the glucolipid metabolism,especially the level of plasma HbA1C,is an important risk factor for cognitive dysfunction in T2DM patients.The alternation of the plasma Nesfatin-1 abundance is closely related to the increase of HbA1C level,and plays an important role in the cognitive dysfunction of T2DM patients,the mechanism of which might be involved with its induced hyperactivity of imflammatory and immune response,together with the imbalanced function of TREM1and TREM2.