Plasma Clusterin and the CLU Gene rs11136000 Variant Are Associated with Mild Cognitive Impairment in Type 2 Diabetic Patients

Objective: Type 2 diabetes mellitus (T2DM) is related to an elevated risk of mild cognitive impairment (MCI). Plasma clusterin is reported associated with the early pathology of Alzheimer's disease (AD) and longitudinal brain atrophy in subjects with MCI. The rs11136000 single nucleotide polymorphism within the clusterin (CLU) gene is also associated with the risk of AD. We aimed to investigate the associations among plasma clusterin, rs11136000 genotype and T2DM-associated MCI. Methods: A total of 231 T2DM patients, including 126 MCI and 105 cognitively healthy controls were enrolled in this study. Demographic parameters were collected and neuropsychological tests were conducted. Plasma clusterin and CLU rs11136000 genotype were examined.Results: Plasma clusterin was significantly higher in MCI patients than in control group (p=0.007). In subjects with MCI, plasma clusterin level was negatively correlated with Montreal cognitive assessment and auditory verbal learning test_delayed recall scores (p=0.027 and p=0.020, respectively). After adjustment for age, educational attainment, and gender, carriers of rs11136000 TT genotype demonstrated reduced risk for MCI compared with the CC genotype carriers (OR=0.158, χ2=4.113, p=0.043). Multivariable regression model showed that educational attainment, duration of diabetes, HDL-c, and plasma clusterin levels are associated with MCI in T2DM patients.Conclusions: Plasma clusterin was associated with MCI and may reflect a protective response in T2DM patients. TT genotype exhibited a reduced risk of MCI compared to CC genotype. Further investigations should be conducted to determine the role of clusterin in cognitive decline

Ethnicity-Specific Association Between Ghrelin Leu72Met Polymorphism and Type 2 Diabetes Mellitus Susceptibility: An Updated Meta-Analysis

Background: The Leu72Met polymorphism of ghrelin gene has been associated with genetic predisposition to type 2 diabetes mellitus (T2DM), while conclusions remain conflicting. Hence, we performed this updated meta-analysis to clarify the association between Leu72Met polymorphism and T2DM susceptibility.Methods: Six electronic databases were consulted for articles published before 1 January, 2018. Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated under five genetic models to assess this association. We used I2-test and Q statistics to measure heterogeneity across the included studies. Subgroup analyses and publication bias were also performed.Results: Thirteen case-control studies involving 4720 T2DM patients and 4206 controls were included in this meta-analysis. The overall results using fixed-effects models showed that Leu72Met polymorphism was significantly associated with an increased risk of T2DM under homozygous model (OR = 1.307, 95%CI 1.001–1.705, p = 0.049). Further subgroup analyses stratified by ethnicity revealed that the risk for T2DM was only increased in Asians (homozygous model: OR = 1.335, 95%CI 1.014–1.758, p = 0.040), while decreased in Caucasians (dominant model: OR = 0.788, 95%CI 0.635–0.978, p = 0.030; heterozygous model: OR = 0.779, 95%CI 0.626–0.969, p = 0.025; allelic model: OR = 0.811, 95%CI 0.661–0.995, p = 0.045). Funnel plots were basically symmetrical, and all p-values of Egger's test under five genetic models were >0.050, which indicated no evidence of publication bias.Conclusions: Our results demonstrate that the Leu72Met polymorphism of ghrelin gene may be protective against T2DM in Caucasians, while predisposing to T2DM in Asians

Effects of ABCA1 R219K Polymorphism and Serum Lipid Profiles on Mild Cognitive Impairment in Type 2 Diabetes Mellitus

Background: Accumulated evidence suggests that adverse lipid changes are risk factors for type 2 diabetes mellitus (T2DM) and neurodegenerative disorders. The ATP-binding cassette A1 transporter (ABCA1) gene contributes to both lipid processing and amyloid-β formation and thus shows promise as a biological target in the pathology of mild cognitive impairment (MCI) in T2DM.Objective: This study aimed to investigate the interactions among lipids, ABCA1 R219K polymorphism, and cognitive function in T2DM.Methods: Clinical parameters, including lipids, were measured. The testing scores of different cognitive domains were recorded, and the ABCA1 R219K polymorphisms were analyzed.Results: A total of 226 patients, including 124 MCI patients and 102 controls, were enrolled in this study. T2DM patients with MCI showed lower cognitive functions, serum high-density lipoprotein (HDL-c), and apolipoprotein A1 (apoA-I) levels; and higher total cholesterol level than the controls. Serum HDL-c (P = 0.001) and apoA-I (P = 0.016) were positively associated with the MoCA score in MCI patients. Further stratification analyses revealed that the subjects with higher HDL-c concentration showed better attention and memory for verbal, visual, and logical functions than the group with lower HDL-c concentration (P < 0.05). No significant differences were observed among the distributions of ABCA1 R219K variants between MCI patients and controls; however, the KK genotype carriers presented higher apoA-I levels than those with RR genotype in MCI individuals.Conclusion: This study does not support the association between R219K polymorphism and T2DM-related MCI. However, our data suggested that the serum HDL-c level might positively influence cognition, especially memory function, in T2DM patients. Further studies are needed to determine the interaction between lipids and ABCA1 genotype and its effect on cognition in T2DM patients.Trial registration: Advanced Glycation End Products Induced Cognitive Impairment in Diabetes: BDNF Signal Meditated Hippocampal Neurogenesis ChiCTR-OCC-15006060; http://www.chictr.org.cn/showproj.aspx?proj=10536