Association Between Blood Glucose Control Levels And Cognitive Function In Patients With Type 2 Diabetes

Diabetes is a metabolic disease characterized by chronic hyperglycemia.Diabetes can lead to complications such as cardiovascular disease,blindness,renal failure,and nerve damage.Diabetes can cause central nervous system lesions which will finally result in cognitive impairment.In severe cases,patients can develop dementia.As the world’s most populous country with the largest aging population,China faces a severe challenge with respect to the prevention,diagnosis,and treatment of dementia.Dementia places substantial burdens on patients,families,and health care systems.It is very important to identify and prevent the occurrence and development of cognitive impairment.Chronic hyperglycemia,recurrent hypoglycemic episodes and glycemic excursions have been implicated as potential causative factors of cognitive impairment.There have been three main methods for assessing diabetes control,i.e.glycosylated hemoglobin A1c(Hb A1c),glycated albumin and self-monitoring of blood glucose(SMBG).Hb A1 c remains the gold standard for monitoring glycaemic control,albeit with the limitations that it only measures average glucose concentration and cannot report glycaemic excursions or frequency of hypoglycaemia.Previous studies have shown that higher levels of Hb A1 c and higher average fasting plasma glucose levels are correlated with poorer cognitive performance.However,some studies have shown that higher levels of Hb A1 c and higher average fasting plasma glucose levels are not correlated with poorer cognitive performance.We conducted a cross-sectional analysis of the relationships between Hb A1c/fasting plasma glucos and specific cognitive domains in patients with T2 DM.For this reason,continuous glucose monitoring(CGM)has evolved as an essential part of diabetes management for diabetic patients with cognitive impairment.With the development of CGM technology,flash glucose monitoring(FGM)systems have increased in popularity in recent years because of the highly detailed information and enhanced accuracy that they provide.The key FGM-derived metrics enable quantitative evaluation of the quality of short-term glycemic control,including time in range(TIR),time below range(TBR)and time above range(TAR).However,as a single metric,TIR does not indicate whether the out-of-range readings are too low or too high;therefore,several researchers have proposed a new evaluation index of the blood glucose-glycemia risk index(GRI).The GRI is based on weighted combinations of TBR(the hypoglycemia component)and TAR(the hyperglycemia component).Key FGM-derived metrics and GRI provide more direct,comprehensive and complete information on blood glucose.Previous studies have shown that TIR,TBR and severe hypoglycemia are associated with cognitive impairment.However,no studies have expounded upon the relationships between TBR/TAR/TIR/GRI and different cognitive domains in patients with T2 DM.In this study,we conducted a cross-sectional analysis of the relationships between TBR/TAR/TIR/GRI and specific cognitive domains in patients with T2 DM to prevent the occurrence and development of cognitive impairment.Increasing numbers of studies have shown that dysfunction of the microbiota-gut-brain axis has been implicated in the pathogenesis of cognitive impairment.Dysbiosis of intestinal microbiota can directly perturb host immune regulatory networks.The Bacteroidetes/Firmicutes ratio is associated with increased plasma glucose concentrations and a decrease in butyrate-producing bacteria in T2 DM patients.Dysbiosis might cause intestinal inflammation,disruption of the gut barrier,and bacterial translocation.Disruption of the gut barrier may allow increased intestinal permeability to bacterial endotoxins,such as LPS,and in turn may increase mucosal inflammation and lead to systemic inflammation.Some studies have shown that Hb A1 C levels are related to intestinal barrier function.However,no one has reported the relationship between TBR and intestinal barrier,blood-brain barrier and cognitive function.In this study,we investigated the relationship between TBR and indicators related to the intestinal barrier and blood-brain barrier,and further elaborated the relationship between impaired intestinal barrier and blood-brain barrier and cognitive impairment.This study used FGM system to more comprehensively reflect the relationship between blood glucose control levels and cognitive function in patients with type 2 diabetes.We have identified the main risk factors for intestinal barrier damage in patients with type 2 diabetes.Our study investigated the relationship between TBR and indicators related to the intestinal barrier and blood-brain barrier,and further elaborated the relationship between impaired intestinal barrier and blood-brain barrier and cognitive impairment,providing clinical evidence for early screening and prevention of cognitive impairment in patients with type 2 diabetes.Part One Relationship between fasting plasma glucose / glycosylated hemoglobin levels and cognitive function in patients with type2 diabetesObjective: To investigate the correlation between fasting plasma glucose/glycosylated hemoglobin(Hb A1c)levels and cognitive function in patients with type 2 diabetes mellitus,and to explore the correlation between fasting plasma glucose / Hb A1 c levels and different cognitive domains.Method:1.A total of 96 patients with type 2 diabetes were enrolled in the endocrinology Department of the First Hospital of Hebei Medical University.2.Neuropsychological tests were performed for all patients,and basic clinical data and biochemical indicators were collected.Spearman correlation test was used for correlation analysis.Multiple linear regression was used to analyse risk factors in each cognitive domain.Results:1.Spearman correlation analysis showed that fasting plasma glucose was negatively correlated with digital span test forward,Boston Naming Test,long delayed recall,and cue recall scores(P < 0.05).2.Multiple linear regression analysis showed that fasting plasma glucose was an independent risk factor for Boston naming test(β =-0.233,P = 0.012),delayed recall(β =-0.225,P = 0.030),cue recall(β =-0.316,P = 0.003)and verbal fluency test 30 s scores(β =-0.240,P = 0.027).3.There is no correlation between Hb A1 c and cognitive function.Conclusions:Fasting plasma glucose is strongly associated with cognitive function in patients with type 2 diabetes.Fasting hyperglycemia is an independent risk factor for cognitive impairment in patients with type 2diabetes.The higher fasting plasma glucose,the worse language ability,memory,attention and executive ability in patients with type 2 diabetes.Part Two Relationship between continuous glucose monitoring-derived metrics and cognitive function in patients with type 2 diabetes mellitusObjective: To investigate the relationship between TBR/TAR/TIR/GRI/CV/MAGE and specific cognitive domains in patients with type 2 diabetes mellitus.Method:1.A total of 96 patients with type 2 diabetes were enrolled in the endocrinology Department of the First Hospital of Hebei Medical University.2.All patients were divided into glucose ≥ 3.9 mmol/L group and glucose < 3.9 mmol/L(TBR < 3.9)group according to the presence or absence of hypoglycemia,and TAR was divided into level 1 hyperglycemia(TAR 10.1-13.9 mmol/L,TAR 10.1-13.9)and level 2 hyperglycemia(TAR >13.9 mmol/L,TAR > 13.9).All patients underwent neuropsychological scale assessment including Trail Making Test A(TMTA),Clock Drawing Test(CDT),Auditory Vocabulary Learning Test(AVLT)and Boston Naming Test(BNT),and subjects wore flash continuous glucose monitoring systems.Basic clinical data and biochemical indexes were collected.Spearman correlation test was used for correlation analysis.Multiple linear regression and logistics regression were used to analyze the risk factors in each cognitive domain.Results:1.Compared with the glucose ≥ 3.9 mmol/L group and the glucose <3.9 mmol/L group,the TMTA scores of type 2 diabetic patients in the glucose< 3.9 mmol/L group were significantly higher than those in the glucose ≥3.9 mmol/L group,and the CDT scores of type 2 diabetic patients in the glucose < 3.9 mmol/L group were significantly lower than those in the glucose ≥ 3.9 mmol/L group(P < 0.05).2.Spearman correlation analysis,TBR < 3.9 was positively correlated with TMTA scores(P < 0.01)and negatively correlated with cue recall and CDT scores(P < 0.05).3.Logistic regression showed that TMTA scores(OR = 1.010,P =0.036),CDT scores(OR = 0.429,P = 0.016)and education(OR = 0.195,P =0.019)were influencing factors for the occurrence of hypoglycemia.4.Multiple linear regression analysis,fasting plasma glucose(β =-0.307,P = 0.003),TBR < 3.9(β =-0.214,P = 0.033),and TAR > 13.9(β =-0.216,P= 0.030)were independent risk factors for cue recall scores.TAR 10.1-13.9(β= 0.206,P = 0.042)was a protective factor for cue recall scores.5.All of the participants were stratified according to tertiles of TIR(TIR< 57%;57% ≤ TIR < 79%;TIR ≥ 79%).In patients with the same incidence of TBR < 3.9,compared with T2 DM patients with 57% ≤ TIR < 79%,T2 DM patients with TIR ≥ 79% exhibited significantly better performance on the BNT(P = 0.020).Conclusion:1.TBR < 3.9 and TAR > 13.9 were strongly associated with memory in patients with type 2 diabetes,and the higher the proportion of TBR < 3.9 and TAR > 13.9,the faster the decline in memory in patients with type 2 diabetes.2.TBR < 3.9 was also strongly associated with visuospatial ability and executive function in patients with type 2 diabetes.3.The incidence of TBR < 3.9 was higher in type 2 diabetic patients with poor visuospatial ability and executive ability.4.At the same incidence of TBR< 3.9,the patients with a higher TIR exhibited better performance on language ability.Therefore,our study suggests that there is a bidirectional association between TBR < 3.9 and cognitive impairment.TBR < 3.9 can increase the risk of cognitive impairment,and cognitive impairment can also increase the risk of hypoglycemia.As such,when adjusting the glucose-lowering regimen for patients with T2 DM,the first priority in this regimen should be to reduce TBR to target levels,followed by addressing TIR.Moreover,implementing individualized glucose-lowering treatment regimens may prevent the occurrence and progression of cognitive impairment.Part Three Association between TBR,zonulin,LPS and HMGB1 and cognitive function in patients with type 2 diabetesObjective: The study was conducted to investigate the relationship between TBR,zonulin,Lipopolysaccharide(LPS)and High mobility group box 1(HMGB1)and cognitive function.Method:1.A total of 96 patients with type 2 diabetes were enrolled in the endocrinology Department of the First Hospital of Hebei Medical University.2.According to the presence or absence of hypoglycemia,all patients were divided into glucose ≥ 3.9 mmol/L group and glucose < 3.9 mmol/L.All patients underwent neuropsychological scale assessment,and wore a flash continuous glucose monitoring system.The levels of zonulin,LPS and HMGB1 were detected by ELISA,and the basic clinical data and biochemical indexes were collected.Spearman correlation test was used for correlation analysis.Multiple linear regression was used to analyse risk factors in specific cognitive domains.Results:1.The levels of zonulin,LPS and HMGB1 in glucose < 3.9 mmol/L group were higher than those in glucose ≥ 3.9 mmol/L group(P < 0.05).2.TBR < 3.9 was positively correlated with zonulin and LPS(P < 0.05).3.LPS was positively correlated with zonulin and HMGB1(P < 0.05).4.LPS was negatively correlated with delayed recall,cued recall and AVLT scores,and positively correlated with TMTA scores.5.Zonulin was positively correlated with self-assessment of depression scores and negatively correlated with verbal fluency(15s)scores(P < 0.05).6.Multiple linear regression analysis showed that TBR < 3.9(β = 0.325,P = 0.002)was an independent influence for zonulin.TBR < 3.9(β = 0.207,P= 0.043)was an independent influence for LPS.HMGB1(β =-0.290,P =0.006)was an independent influence for immediate memory scores.HMGB1(β =-0.210,P = 0.046)was an independent risk factor for AVLT scores.Zonulin(β =-0.208,P = 0.035)was an independent risk factor for clock drawing test scores.Zonulin(β =-0.247,P = 0.013)was an independent risk factor for verbal fluency test 15 s scores.LPS(β = 0.202,P = 0.040)was an independent influencing factor for TMTA scores.Conclusion:1.TBR < 3.9 is closely associated with impaired intestinal barrier in patients with type 2 diabetes mellitus.2.HMGB1 is an independent risk factor for memory in patients with type 2 diabetes mellitus.3.Zonulin is an independent risk factor for visuospatial and executive function in patients with type 2 diabetes4.LPS is an independent risk factor for executive function in patients with type 2 diabetes mellitus.Therefore,TBR < 3.9 is closely related to the intestinal barrier in patients with type 2 diabetes mellitus,and impaired intestinal barrier and blood-brain barrier are independent risk factors for cognitive impairment.Impaired intestinal barrier and blood-brain barrier play an important role in the development of cognitive impairment.