| Diabetes mellitus (DM) is a complex metabolic disease characterized by abnormally high blood glucose levels based on insulin resistance and beta-cell dysfunction. Furthermore, DM has an evident genetic component and represents a polygenic disease. It currently affects 250 million people worldwide, with 6 million new cases reported each year. Approximately 90% of these cases are Type 2.There is an increasing body of research has reported a relationship between type 2 diabetes mellitus (T2DM) and an earlier cognitive impairment, including a two fold increase in the risk of dementia. T2DM increases the risk not only of vascular dementia but also of Alzheimer's disease. Though it is likely that hyperglycemia, vascular disease, hypoglycemia, and insulin resistance may play a role, the underlying neuropathologic changes and genetic association with cognitive impairment in T2DM patients remains un-clear.B rain-derived neurotrophic factor (BDNF) is a member of the nerve growth factor family and is the most abundant neurotrophin in the brain and peripheral nervous system, particularly high in the hippocampus and cortex. BDNF has well established effects on cell differentiation, synaptic connectivity and maintenance of its target neurons. Moreover, BDNF has also been implicated in regulating activity dependent synaptic plasticity processes and long-term potentiation (LTP) in the hippocampus region, thereby contributing to learning and memory. Inhibition of BDNF signaling leads to a reduction in LTP, resulting in impairments on several different memory tests such as Morris water maze and passive avoidance.In addition to its actions on learning and memory, numerous data from animal experiments indicate that BDNF performs an essential maintenance function in the regulation of blood glucose and energy metabolisms and has a hypoglycaemic action. For example, recent studies demonstrated that administration of BDNF to diabetic mice improved glucose and lipid metabolism and suppressed food consumption. In contrast, BDNF-deficient knockout mice develop hyperglycemia, and increase in blood glucose levels inhibits brain release of BDNF. Decreased levels of BDNF have been implicated in the pathogenesis of Alzheimer's disease which is characterized by cognitive impairment, and a negative correlation between the severity of insulin resistance and decreased circulating BDNF levels was also found in T2DM patients. This raises the possibility that BDNF may also have a pathogenic role in the development of T2DM as well as cognitive impairment in type 2 diabetic patients in humans.Therefore, the present study was designed to investigate the relationship between serum levels of BDNF and cognitive impairment in patients with T2DM, and then examined the relationships between BDNF gene polymorphisms and cognitive impairment in T2DM patients. Moreover, the associations between BDNF gene polymorphisms and T2DM itself and the relationship between BDNF val66met polymorphism and diabetes among schizophrenic patients receiving long-term clozapine treatment were also discussed in this paper.Part-1 Associations between serum BDNF levels and cognitive impairment in patients with type 2 diabetesObjective: To explore the associations between serum BDNF levels and cognitive dysfunction in patients with type 2 diabetes.Method: The 144 T2DM patients were compared with 120 age-sex and education matched, non-diabetic controls. Cognitive function was assessed using the Repeatable Battery for the Assessment of Neuropsychologieal Status(RBANS). Serum BDNF levels were measured by sandwich ELISA.Results: In the RBANS tests, patients differed significantly from healthy controls on the total index score and four subscales for attention, language, immediate and delayed memory (P <0.01). Also, a significant decline in serum levels of BDNF in T2DM group was observed compared with the controls(5.02±2.93ng/ml vs 12.10±7.33ng/ml, P <0.01). Performances on RBANS attention, visuospatial, immediate memory, delayded memory and total index scores of T2DM patients were positively correlated with the levels of serum brain-derived neurotrophic factor (P<0.05). Stepwise multiple regression analysis showed that the associations between serum BDNF levels and RBANS attention, delayed memory and total score remained significant even after controlling for age, gender, and education (adjust Ptotal =0.039; adjust Pdelayed memory =0.025; adjust Pattention =0.013).Conclusion: Persons with type 2 diabetes have poorer cognitive performance than healthy controls. Serum brain-derived neurotrophic factor level is decreased and associated with cognitive impairment in patients with type 2 diabetes , especially on the domains of attention and delayed memory.Part-2 Genetic associations between polymorphisms of BDNF gene and cognitive impairment in T2DM patientsObjective: To investigate the genetic associations between polymorphisms of BDNF gene and cognitive impairment in T2DM patients.Methods: All patients with T2DM were recruited from outpatient and inpatient clinics of Tangshan workers'hospital. According to their RBANS scores, participants were divied into two distinct groups: type 2 diabetes patients complicated with cognitive impairment (T2DM-CI) group (n=93) and type 2 diabetes patients without cognitive impairment (control) group (n=192). All subjects were Chinese Han origin.All the subjects gave written informed consent for the genetic analysis and peripheral blood samples were then taken from them. Genomic DNA used for PCR amplification was extracted from the whole blood sample. Four polymorphic SNPs including rs6265,rs12273539, rs10835210 and rs2030324 in the BDNF gene were genotyped using PCR-RFLP technology.The Hardy–Weinberg equilibrium for genotypic distributions was tested using the chi-square (χ2) goodness-of-fit test. The description of data, case-control analysis and association analysis between SNPs were performed with the SPSS15.0 program and online SHEsis program. The quantitative trait analysis was performed with the UNPHASED 3.1 program.Results:(1)Hardy-Weinberg equilibrium testThe chi-square (χ2) goodness-of-fit test showed that the genotype distributions of these 4 SNPs had no deviation from Hardy–Weinberg equilibrium both in the patient group (P>0.05) and the control group (P>0.05).(2)Single locus analysisIn the female samples, both rs6265 allele frequency and genotype distribution were significantly different between T2DM-CI patients and the control population (χ2=8.333, P =0.0042;χ2=7.589, P=0.0221, respectively). In the total samples and male samples, there was also a significant difference in BDNF rs12273539 genotype distribution between the patient and control groups (χ2=7.6394, P=0.0219;χ2=6.6430, P=0.0361, respectively). As for rs12273539 and rs10835210, no significant association with T2DM-CI was observed between two groups.(3)Haplotype analysisHaplotype analyses conducted by online SHEsis program showed that in the total samples, rs12273539(T)-rs2030324(C) (χ2=4.400, P=0.035),rs6265(A)-10835210(C)-rs2030324(T) (χ2=4.472, P=0.032) were significantly more common in cases than in controls. They may contain a susceptibility allele for T2DM-CI respectively.In the female samples, there were 5 haplotypes showing preferential transmission, including the rs6265(G)-rs10835210(A) (χ2=5.677, P=0.017),rs6265(A)-rs10835210(C) (χ2=4.910, P=0.026), rs6265(A)-rs2030324(T) (χ2=6.376, P=0.011), rs6265(A)-rs10835210(C)-rs2030324(T) (χ2=8.166, P=0.004), rs6265(A)-rs12273539(C)-rs10835210(C)-rs2030324(T) (χ2=5.038, P=0.025) haplotypes, showed disease susceptibility. Meanwhile, in the male samples, rs10835210(A)-rs2030324(T) (χ2=3.869, P=0.049) haploty pes showed disease resistance.(4)Quantitative trait analysisThe quantitative trait analysis was performed using the UNPHASED program (version 3.1). SNP rs6265 was associated with delayded memory score in T2DM-CI patients. No significant association of SNP rs12273539, rs10835210 and rs2030324 with RBANS scale scores was observed in the quantitative trait analysis in T2DM-CI patients.Conclusions: According to the present results, it can be concluded that (1) the genetic polymorphisms of BDNF gene are likely to confer susceptibility to T2DM-CI; (2) there are BDNF gene sex-specific genetic components involved in the pathology of T2DM-CI.Part-3 Genetic associations between polymorphisms of BDNF gene and type 2 diabetesObjective: To investigate the genetic associations between polymorphisms of BDNF gene and type 2 diabetes.Methods: Four hundred and eleven patients with T2DM and 375 sex-age matched unrelated healthy subjects were recruited in this study. All subjects were Chinese Han origin and came from the area of Tangshan city. T2DM related traits such as bodyweight, height, waistline, hip circumference, fasting blood glucose and serum lipids were assessed in a standardized fashion. Serum fasting insulin levels were tested by sandwich ELISA in T2DM patients. Then body mass index(BMI), waist hip ratio(WHR), homeostasis model assessment-insulin resistance(HOMA-IR) and homeostasis model assessment-βcell(HOMA-β) were calculated.All the subjects gave written informed consent for the genetic analysis and peripheral blood samples were then taken from them. Genomic DNA used for PCR amplification was extracted from the whole blood sample. Four polymorphic SNPs including rs6265,rs12273539, rs10835210 and rs2030324 in the BDNF gene were genotyped with case-control samples using PCR-RFLP technology.The Hardy–Weinberg equilibrium for genotypic distributions was tested using the chi-square (χ2) goodness-of-fit test. The description of data, case-control analysis and association analysis between SNPs were performed with the SPSS 15.0 program and online SHEsis program. The quantitative trait analysis was performed with the UNPHASED 3.1 program.Results:(1)Hardy-Weinberg equilibrium testThe chi-square (χ2) goodness-of-fit test showed that the genotype distributions of these 4 SNPs had no deviation from Hardy–Weinberg equilib-rium both in the patient group (P>0.05) and the control group (P>0.05).(2)Single locus analysisIn the total samples, there was a significant increase in frequency of AA genotype of BDNF rs6265 in T2DM patients as compared to healthy controls (χ2=7.196, P=0.027). Moreover, rs6265 allele frequency and genotype distribution showed a trend toward significantly different between T2DM pa-tients and the control population in the female samples (χ2=3.099, P=0.078;χ2=5.191, P=0.075, respectively) while not in the male samples(χ2=0.454, P=0.500;χ2=2.234, P=0.327, respectively). As for rs12273539, rs10835210 and rs2030324, no significant association with T2DM was observed between two groups in single locus analysis.(3)Haplotype analysisHaplotype analyses conducted by online SHEsis program showed that in the total samples, rs6265(G)-rs12273539(T) (χ2=4.423, P=0.037), rs6265(G)-rs12273539(T)-rs2030324(C) (χ2=4.668, P=0.031), rs6265(G)-rs10835210(C)-rs12273539(T)-rs2030324(C) (χ2=4.090, P=0.043) haplotypes were significantly more common in controls than in cases. They may contain a protective allele for T2DM respectively. On the other hand, rs6265(A)-rs2030324(T) (χ2=3.827, P =0.048),rs12273539(T)-rs2030324(C) (χ2=4.400, P=0.035), rs6265(A)-rs10835210(C)-rs2030324(T) (χ2=4.472, P=0.032) haplotypes were significantly more common in cases than in controls. They may contain a risk allele for T2DM respectively.In the male samples, rs6265(A)-rs10835210(C) (χ2=11.300, P=0.000 78) haplotype was only found in the case group , showed disease resistance. Meanwhile, in the female samples, rs6265(G)-rs12273539(T)-rs2030324(C) (χ2=3.858, P=0.049) haplotype was significantly more common in cases than in controls,showed disease susceptibility.(4)Quantitative trait analysisThe quantitative trait analysis was performed using the UNPHASED program (version 3.1). SNP rs6265 was associated with HOMA-IR and serum HDL-C lever in T2DM patients(χ2=5.129, P=0.024;χ2=6.982, P=0.008, respectively). SNP rs10835210 was also associated with HOMA-IR and serum HDL-C lever in T2DM patients(χ2=3.911, P=0.048;χ2=5.522, P=0.018, respectively). No significant association of SNP rs12273539 and rs2030324 with T2DM related traits was observed in the quantitative trait analysis.Conclusions: According to the present results, it can be concluded that (1) the polymorphisms of BDNF gene are likely to confer susceptibility to T2DM; (2) BDNF gene polymorphisms may play a role on insulin resistance other than insulin secretion and thus be involved in the pathology of T2DM.Part-4 Diabetes among schizophrenic patients receiving long-term clozapine treatment and its association with BDNF val66met polymorphismObjective: To examine the prevalence and correlates of diabetes in a sample of Chinese individuals with schizophrenia on long-term clozapine. Whether BDNF val66met polymorphism was assocatied with diabetes in schizophrenia patients receiving long-term clozapine treatment was also investigated.Methods: Two hundred and six Chinese Han inpatients meeting DSM-IV schizophrenia criteria were recruited in a cross-sectional naturalistic study. Diagnoses of diabetes were established with WHO diagnostic criteria for diabetes mellitus (1999). The SNP of val66met was detected by PCR—RFLP.Results: Diabetes mellitus was more common in patients than in the general population (22.3% vs 9.7%). The prevalence of diabetes increased with age as compared across five age-groups (χ2=18, df =4, P=0.001), with particularly greater increase in the age cohorts of over 65 years: 61.5%. The PANSS total score and sub-scores showed no differences between the diabetic and non-diabetic groups. Logistic regression in the patients revealed significant associations between diabetes and a family history of diabetes (P<0.001), age (P<0.01), BMI (P<0.05) and female gender(P<0.05). No significant association was observed between SNP val66met polymorphism and diabetes in schizophrenia patients receiving long-term clozapine treatment(P>0.05).Conclusions: The prevalence of diabetes was higher in Chinese chronic schizophrenic patients receiving long-term clozapine treatment than that in the general population. The possible risk factors for diabetes among patients taking clozapine include a family history of diabetes, increased age, higher body weight and female gender. There was no significant association between SNP val66met polymorphism and diabetes in schizophrenia patients receiving long-term clozapine treatment.
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