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 I 2-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.

Lipoprotein-associated Phospholipase A2 Is Associated with Risk of Mild Cognitive Impairment in Chinese Patients with Type 2 Diabetes.

Type 2 diabetes mellitus (T2DM) is a low-grade chronic inflammatory diseases, which have been implicated in the pathogenesis of cognitive decline. We aim to evaluate associations between inflammatory markers and the risk of mild cognitive impairment (MCI) in T2DM. This study of 140 diabetic patients involved 71 with MCI and 69 controls. Clinical parameters, neuropsychological tests, high sensitivity C reactive protein (hsCRP), interleukin-6 (IL-6), lipoprotein-associated Phospholipase A2 (Lp-PLA2) mass and activity were measured. The results showed significantly higher plasma hsCRP, IL-6, Lp-PLA2 mass and activity in MCI group compared to controls. In T2DM with MCI, the Montreal Cognitive Assessment (MoCA) score was positively correlated with education level and high-density lipoprotein cholesterol (HDL-c), but inversely correlated with age, glycosylated hemoglobin, intima-media thickness (IMT), hsCRP, IL-6, and Lp-PLA2 mass and activity. Correlation analysis showed that both plasma Lp-PLA2 mass and activity were positively correlated with total cholesterol, low-density lipoprotein cholesterol, and IMT but negatively associated with MoCA score. Multivariable logistic regression analysis indicated higher hsCRP, Lp-PLA2 mass, Lp-PLA2 activity, and lower HDL-c to be independent risk factors increasing the possibility of MCI in T2DM. In conclusion, plasma Lp-PLA2 and hsCRP were found to be associated with the risk of MCI among T2DM patients.

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-ß 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.

Increased Plasma Homocysteine Level is Associated with Executive Dysfunction in Type 2 Diabetic Patients with Mild Cognitive Impairment.

BACKGROUND: Homocysteine (Hcy) is involved in the pathogenesis of type 2 diabetes mellitus (T2DM) and Alzheimer's disease. OBJECTIVE: We aimed to investigate the role of Hcy in T2DM patients with mild cognitive impairment (MCI), and to determine whether methylene tetrahydrofolate reductase (MTHFR) C677T or cystathionine beta-synthase (CBS) 844ins68 polymorphism is related to T2DM-associated MCI. METHODS: We recruited 285 T2DM patients and divided them into two groups, 140 patients with MCI, and 145 healthy-cognition controls, on the basis of Montreal Cognitive Assessment (MoCA) scores. Demographic characteristics, clinical parameters, and neuropsychological tests were assessed. MTHFR C677T and CBS 844ins68 polymorphisms were analyzed. RESULTS: The MCI group exhibited significantly higher plasma total Hcy (tHcy) levels than control group (p < 0.001). Plasma tHcy level was negatively correlated with MoCA scores (p = 0.002), but positively associated with Trail Making Test A and B scores (p = 0.044; p = 0.005, respectively). Multivariable logistic regression model showed that high tHcy level was an independent factor for MCI in T2DM patients. No significant difference was observed in the genotype or allele distributions of MTHFR and CBS between MCI and control groups. We did not find significant MCI risks in MTHFR T allele compared with C allele, and in CBS I allele compared with D allele (OR = 1.361, p = 0.067; OR = 1.048, p = 0.909, respectively). CONCLUSION: Increased plasma tHcy level was significantly related to T2DM-associated MCI, especially executive dysfunction. Further investigation with a large population size should be conducted to confirm these findings.

Association of plasma ghrelin levels and ghrelin rs4684677 polymorphism with mild cognitive impairment in type 2 diabetic patients.

BACKGROUND AND AIMS: People with insulin resistance and type 2 diabetes mellitus (T2DM) are at increased risks of cognitive impairment. We aimed to investigate the association of plasma ghrelin levels and ghrelin rs4684677 polymorphism with mild cognitive impairment (MCI) in T2DM patients. RESULTS: In addition to elevated glycosylated hemoglobin (HbA1c), fasting blood glucose (FBG) and homeostasis model assessment of insulin resistance (HOMA-IR), T2DM patients with MCI had decreased plasma ghrelin levels compared with their healthy-cognition subjects (all p < 0.05). Further logistic regression analysis showed that ghrelin level was one of independent factors for MCI in T2DM patients (p < 0.05). Moreover, partial correlation analysis demonstrated that ghrelin levels were positively associated with the scores of Montreal Cognitive Assessment (r = 0.196, p = 0.041) and Auditory Verbal Learning Test-delayed recall (r = 0.197, p = 0.040) after adjustment for HbA1c, FBG and HOMA-IR, wherein the latter represented episodic memory functions. No significant differences were found for the distributions of genotype and allele of ghrelin rs4684677 polymorphism between MCI and control group. MATERIALS AND METHODS: A total of 218 T2DM patients, with 112 patients who satisfied the MCI diagnostic criteria and 106 who exhibited healthy cognition, were enrolled in this study. Demographic characteristics, clinical variables and cognitive performances were extensively assessed. Plasma ghrelin levels and ghrelin rs4684677 polymorphism were also determined. CONCLUSIONS: Our results suggest that decreased ghrelin levels are associated with MCI, especially with episodic memory dysfunction in T2DM populations.

Saitohin Q7R polymorphism is associated with late-onset Alzheimer's disease susceptibility among caucasian populations: a meta-analysis.

Saitohin (STH) Q7R polymorphism has been reported to influence the individual's susceptibility to Alzheimer's disease (AD); however, conclusions remain controversial. Therefore, we performed this meta-analysis to explore the association between STH Q7R polymorphism and AD risk. Systematic literature searches were performed in the PubMed, Embase, Cochrane Library and Web of Science for studies published before 31 August 2016. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the strength of the association using a fixed- or random-effects model. Subgroup analyses, Galbraith plot and sensitivity analyses were also performed. All statistical analyses were performed with STATA Version 12.0. A total of 19 case-control studies from 17 publications with 4387 cases and 3972 controls were included in our meta-analysis. The results showed that the Q7R polymorphism was significantly associated with an increased risk of AD in a recessive model (RR versus QQ+QR, OR = 1.27, 95% CI = 1.01-1.60, P = 0.040). After excluding the four studies not carried out in caucasians, the overall association was unchanged in all comparison models. Further subgroup analyses stratified by the time of AD onset, and the quality of included studies provided statistical evidence of significant increased risk of AD in RR versus QQ+QR model only in late-onset subjects (OR = 1.56, 95% CI = 1.07-2.26, P = 0.021) and in studies with high quality (OR = 1.37, 95% CI = 1.01-1.86, P = 0.043). This meta-analysis suggests that the RR genotype in saitohin Q7R polymorphism may be a human-specific risk factor for AD, especially among late-onset AD subjects and caucasian populations.

Diabetes mellitus as a risk factor for incident chronic kidney disease and end-stage renal disease in women compared with men: a systematic review and meta-analysis.

Diabetes mellitus is a strong risk factor for chronic kidney disease and end-stage renal disease. Whether sex differences in chronic kidney disease and end-stage renal disease incidence exist among diabetic patients remains unclear. This systematic review and meta-analysis was conducted to evaluate the relative effect of diabetes on chronic kidney disease and end-stage renal disease risk in women compared with men. We systematically searched Embase, PubMed, and the Cochrane Library for both cohort and case-control studies until October 2015. Studies were selected if they reported a sex-specific relationship between diabetes mellitus and chronic kidney disease or end-stage renal disease. We generated pooled estimates across studies using random-effects meta-analysis after log transformation with inverse variance weighting. Ten studies with data from more than 5 million participants were included. The pooled adjusted risk ratio of chronic kidney disease associated with diabetes mellitus was 3.34 (95 % CI 2.27, 4.93) in women and 2.84 (95 % CI 1.73, 4.68) in men. The data showed no difference in diabetes-related chronic kidney disease risk between the sexes (pooled adjusted women-to-men relative risk ratio was 1.14 [95 % CI 0.97, 1.34]) except for end-stage renal disease-the pooled adjusted women-to men relative risk ratio was 1.38 (95 % CI 1.22, 1.55; p = 0.114, I² = 38.1 %). The study found no evidence of a sex difference in the association between diabetes mellitus and chronic kidney disease. However, the excess risk for end-stage renal disease was higher in women with diabetes than in men with the same condition, from which we assume that the female gender could accelerate the disease progression. Further studies are needed to support this notion and elucidate the underlying mechanisms.

Statins worsen glycemic control of T2DM in target LDL-c level and LDL-c reduction dependent manners: a meta-analysis.

OBJECTIVE: Recent studies demonstrated that a low target low-density lipoprotein cholesterol (LDL-c) level, high LDL-c reduction and high dose of statin therapy increased incident diabetes. This study aimed to explore how statin therapy influences glycemic control in type 2 diabetes mellitus (T2DM). METHODS: Medline, Embase, and Cochrane Central were searched for randomized control trials inT2DM. Trials with target LDL-c levels of ≤2.6 mmol/L or LDL-c reduction of ≥30% were analyzed. Then, we calculated mean differences in glycosylated hemoglobin (HbA1c) and fasting blood glucose via stratified LDL-c level, relative LDL-c reduction and statin dose. RESULTS: In total, trials involving 6,875 participants (3,619 statins, 3,256 controls) were included. Meta-analysis showed that detrimental effect of intensive LDL-c lowering statin therapy on HbA1c (SMD 0.10%; 95% CI 0.05, 0.15; p = 0.000) was more severe than all statin trials analyzed together (SMD 0.07%; 95% CI 0.02, 0.12; p = 0.005). Stratified analyses revealed that the effects on HbA1c became increasingly significant as target LDL-c level decreased and LDL-c reduction increased. Low baseline LDL-c and endpoint LDL-c levels were risk factors involved in increasing HbA1c level during statin therapy. CONCLUSIONS: Statin therapy worsens the glycemic control of T2DM in target LDL-c level and LDL-c reduction dependent manners.

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, χ(2) = 4.113, p = 0.043). Multivariable regression model showed that educational attainment, duration of diabetes, high-density lipoprotein cholesterol (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. 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.

Association of Increased Serum ACE Activity with Logical Memory Ability in Type 2 Diabetic Patients with Mild Cognitive Impairment.

Background: Angiotensin-converting enzyme (ACE) is involved in the chronic complications of type 2 diabetes mellitus (T2DM) and Alzheimer's disease. This study aimed to assess the pathogenetic roles of ACE and the genetic predisposition of its insertion/deletion (I/D) polymorphism in mild cognitive impairment (MCI) among T2DM patients. Methods: A total of 210 T2DM patients were enrolled. Among these patients, 116 satisfied the MCI diagnostic criteria and 94 exhibited healthy cognition. The cognitive functions of the patients were extensively assessed. The serum level and activity of ACE were measured via enzyme-linked immunosorbent assay and ultraviolet spectrophotography. The single-nucleotide polymorphisms of I/D gene of ACE were analyzed. Results: The serum level and activity of ACE in diabetic MCI patients (p = 0.022 and p = 0.008, respectively) were both significantly higher than those in the healthy controls. A significant negative correlation was found between their ACE activity and logical memory test score (LMT) (p = 0.002). Multiple stepwise regression iterated the negative correlation between ACE activity and LMT score (p = 0.035). Although no significant difference was found in the genotype or allele distribution of ACE I/D polymorphism between the groups, the serum levels and activity of ACE were higher in the DD group than in the ID and II groups (p < 0.05). Conclusions: Serum ACE activity could better predict logical memory in T2DM patients than ACE level. Further investigations on a large population size are necessary to test whether the D-allele of the ACE gene polymorphism is susceptible to memory deterioration.