Inverted U-shaped correlation between serum low-density lipoprotein cholesterol levels and cognitive functions of patients with type 2 diabetes mellitus.

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) metabolic disorder is common in individuals with diabetes. The role of LDL-C in mild cognitive impairment (MCI) remains to be explored. We aim to investigate the associations between LDL-C at different levels and details of cognition decline in patients with type 2 diabetes mellitus (T2DM). METHODS: Patients with T2DM (n = 497) were recruited. Clinical parameters and neuropsychological tests were compared between patients with MCI and controls. Goodness of fit was assessed to determine the linear or U-shaped relationship between LDL-C and cognitive function. The cut-off point of LDL-C was calculated. Correlation and regression were carried out to explore the relationship between cognitive dysfunction and LDL-C levels above and below the cut-off point. RESULTS: Although no significant difference in LDL-C levels was detected in 235 patients with MCI, compared with 262 patients without MCI, inverted-U-shaped association was determined between LDL-C and Montreal Cognitive Assessment (MoCA). The cut-off point of LDL-C is 2.686 mmol/l. LDL-C (>2.686 mmol/l) is positively related to Trail Making Test B (TMTB) indicating executive function. LDL-C (<2.686 mmol/l) is positively associated with Clock Drawing Test (CDT) reflecting visual space function in patients with T2DM. CONCLUSION: Inverted U-shaped correlation was found between serum LDL-C and cognitive function in patients with T2DM. Despite that the mechanisms of different LDL-C levels involved in special cognitive dysfunctions remain incompletely clarified, excessive LDL-C damages executive function, while the deficient LDL-C impairs visual space function. TRIAL REGISTRATION: ChiCTR-OCC-15006060 .

Optimal duration of dual antiplatelet therapy followed by monotherapy in diabetic patients after percutaneous coronary intervention with drug­eluting stent implantation: a Bayesian network meta-analysis.

INTRODUCTION: The standard 12-month dual antiplatelet therapy (DAPT) following percutaneous coronary intervention (PCI) with drug-eluting stent (DES) implantation that is recommended for the general population may not be suitable for patients with diabetes. OBJECTIVES: The study aimed to evaluate the efficacy and safety of short-term (≤3 months), medium-term (6 months), standard-term (12 months), and extended-term (>12 months) DAPT in diabetic patients with DES implantation and to compare the outcomes of DAPT discontinuation followed by monotherapy with aspirin versus a P2Y12 receptor inhibitor. PATIENTS AND METHODS: Randomized controlled trials published up to October 10, 2020 were searched in the PubMed, Web of Science, Embase, Cochrane Library, and ClinicalTrials.gov databases. A Bayesian network meta-analysis with a random-effects model was performed. A total of 18 randomized trials involving 20 536 patients with diabetes were included. RESULTS: The network analysis showed that short-term DAPT was the most optimal in terms of reducing the primary endpoint and was superior to extended-term DAPT (odds ratio [OR], 0.48; 95% CI, 0.25­0.85). Standard-term DAPT was also associated with a reduced primary endpoint in comparison with extended-term DAPT (OR, 0.56; 95% CI, 0.32­0.90). There was no noticeable difference with respect to the primary endpoint between short-term DAPT followed by monotherapy with aspirin and a P2Y12 inhibitor. No significant differences were observed in secondary endpoints, including all-cause mortality, cardiac mortality, myocardial infarction, stroke, target vessel revascularization, definite or probable stent thrombosis, and major bleeding event. CONCLUSIONS: Short-term DAPT, as compared with extended-term therapy, was associated with a reduced primary endpoint in patients with diabetes after PCI with DES implantation.

Decreased Plasma Level of Lipoprotein Lipase Predicted Verbal Disfluency in Chinese Type 2 Diabetes Mellitus Patients with Early Cognitive Deficits.

BACKGROUND: Lipoprotein Lipase (LPL) is the rate-limiting enzyme catalyzing the hydrolysis of triglycerides and contributes to the amyloid-ß formation, which shows promise as a pathological factor of cognitive decline in Type 2 Diabetes Mellitus (T2DM). This study aimed to investigate the pathogenetic roles of LPL and rs328 polymorphism in Mild Cognitive Impairment (MCI) in patients with T2DM. METHODS: Chinese patients with T2DM were recruited and divided into two groups based on the Montreal Cognitive Assessment score. Demographic data were collected, LPL was measured and neuropsychological test results were examined. RESULTS: Seventy-nine patients with diabetes and MCI had significantly decreased plasma LPL levels (p = 0.007) when compared with health-cognition controls (n = 91). Correlation analysis revealed that LPL was positively correlated with clock drawing test (r = 0.158, p = 0.043) and logical memory test (r = 0.162, p = 0.037), while lipoprotein a (r = -0.214, p = 0.006) was inversely associated with LPL. Logistic regression analysis further demonstrated that LPL concentration was an independent factor for diabetic MCI (p = 0.036). No significant differences were observed in the distributions of rs328 variants between patients with MCI and the controls. Moreover, no remarkable association was found among plasma LPL levels, cognitive performances, and lipid levels between the genotypic subgroups. The trail making test A was increased in the GC group when compared with the CC genotype in the control group. CONCLUSION: Decreased plasma level of LPL could probably predict early cognitive deficits, especially verbal disfluency.

Increased Plasma Level of 24S-Hydroxycholesterol and Polymorphism of CYP46A1 SNP (rs754203) Are Associated With Mild Cognitive Impairment in Patients With Type 2 Diabetes.

BACKGROUND: Abnormal cholesterol metabolism is common in type 2 diabetes mellitus (T2DM) and causes dementia. Cholesterol 24S-hydroxylase (CYP46A1) converts cholesterol into 24S-hydroxycholesterol (24-OHC) and maintains cholesterol homeostasis in the brain. OBJECTIVE: This study aimed to investigate the roles of 24-OHC and the CYP46A1 (rs754203) polymorphism in patients with T2DM and mild cognitive impairment (MCI). METHODS: A total of 193 Chinese patients with T2DM were recruited into two groups according to the Montreal Cognitive Assessment (MoCA). Demographic and clinical data were collected, and neuropsychological tests were conducted. Enzyme-linked immunosorbent assay (ELISA) and Seqnome method were used to detect the concentration of plasma 24-OHC and the CYP46A1 rs754203 genotype, respectively. RESULTS: Compared with 118 healthy cognition participants, patients with MCI (n = 75) displayed a higher plasma level of 24-OHC and total cholesterol concentration (all p = 0.031), while no correlation was found between them. In the overall diabetes population, the plasma level of 24-OHC was negatively correlated with MoCA (r = -0.150, p = 0.039), and it was further proved to be an independent risk factor of diabetic MCI (OR = 1.848, p = 0.001). Additionally, patients with MCI and the CC genotype of CYP46A1 rs754203 showed the highest plasma level of 24-OHC even though the difference was not statistically significant, and they obtained low scores in both the verbal fluency test and Stroop color and word test A (p = 0.008 and p = 0.029, respectively). CONCLUSION: In patients with T2DM, high plasma level of 24-OHC and the CC genotype carrier of CYP46A1 rs754203 may portend a high risk of developing early cognitive impairment, including attention and executive deficits.

Elevated Plasma Free Fatty Acid Susceptible to Early Cognitive Impairment in Type 2 Diabetes Mellitus.

BACKGROUND: Elevated free fatty acid (FFA) induces lipotoxicity, attributed to diabetes and cognitive decline. Sterol regulatory element-binding protein-1c (SREBP-1c) regulates lipid metabolism. OBJECTIVE: We investigated the roles of FFA in mild cognitive impairment (MCI) of type 2 diabetes mellitus (T2DM) patients and determine its association with rs11868035 polymorphism. METHODS: We recruited 191 Chinese T2DM patients into two groups through Montreal Cognitive Assessment. Demographic and clinical data were collected, multiple domain cognitive functions were tested, plasma FFA levels were measured through ELISA, and SREBP-1c rs11868035 genotype was detected using the Seqnome method. RESULTS: In comparison with the healthy-cognition group (n = 128), the MCI group (n = 63) displayed lower glucose control (p = 0.012) and higher plasma FFA level (p = 0.021), which were independent risk factors of MCI in T2DM patients in multivariate regression analysis (OR = 1.270, p = 0.003; OR = 1.005, p = 0.036). Additionally, the plasma FFA levels of MCI patients were positively correlated with Stroop color word test-C time scores (r = 0.303, p = 0.021) and negatively related to apolipoprotein A1 levels (r = -0.311, p = 0.017), which are associated positively with verbal fluency test scores (r = 0.281, p = 0.033). Both scores reflected attention ability and executive function. Moreover, the G allele carriers of rs11868035 showed higher digit span test scores than non-carriers in T2DM patients (p = 0.019) but without correlation with plasma FFA levels. CONCLUSION: In T2DM, elevated plasma level of FFA, when combined with lower apolipoprotein A1 level portends abnormal cholesterol transport, were susceptible to early cognitive impairment, especially for attention and execution deficits. The G allele of SREBP-1c rs11868035 may be a protective factor for memory.

Glucagon-like peptide-1 attenuated carboxymethyl lysine induced neuronal apoptosis via peroxisome proliferation activated receptor-γ.

BACKGROUNDS AND AIMS: The role of peroxisome proliferator activated receptor-γ (PPAR-γ) in neuronal apoptosis remains unclear. We aim to investigate the role of PPAR-γ in glucagon-like peptide-1 (GLP-1) alleviated neuronal apoptosis induced by carboxymethyl-lysine (CML). MATERIALS AND METHODS: In vitro, PC12 cells were treated by CML/GLP-1. Moreover. the function of PPAR-γ was blocked by GW9662. In vivo, streptozotocin (STZ) was used to induce diabetic rats with neuronal apoptosis. The cognitive function of rats was observed by Morris water maze. Apoptosis was detected by TUNEL assay. Bcl2, Bax, PPAR-γ and receptor of GLP-1 (GLP-1R) were measured by western blotting or immunofluorescence. RESULTS: In vitro experiment, CML triggered apoptosis, down-regulated GLP-1R and PPAR-γ. Moreover, GLP-1 not only alleviated the apoptosis, but also increased levels of PPAR-γ. GW9662 abolished the neuroprotective effect of GLP-1 on PC12 cells from apoptosis. Furthermore, GLP-1R promoter sequences were detected in the PPAR-γ antibody pulled mixture. GPL-1 levels decreased, while CML levels increased in diabetic rats, compared with control rats. Additionally, we observed elevated bax, decreased bcl2, GLP-1R and PPAR-γ in diabetic rats. CONCLUSIONS: GLP-1 could attenuate neuronal apoptosis induced by CML. Additionally, PPAR-γ involves in this process.

Association of Low-Density Lipoprotein Receptor-Related Protein 1 and Its rs1799986 Polymorphism With Mild Cognitive Impairment in Chinese Patients With Type 2 Diabetes.

BACKGROUND: Low-density lipoprotein receptor-related protein 1 (LRP1) is involved in cerebral glucose metabolism and amyloid-ß clearance. This study aimed to investigate the pathogenetic roles of LRP1 and its rs1799986 polymorphism in mild cognitive impairment (MCI) among patients with type 2 diabetes mellitus (T2DM). METHODS: A total of 166 Chinese patients with T2DM were enrolled and divided into two groups according to Montreal Cognitive Assessment (MoCA) scores. Neuropsychological tests were performed. Soluble LRP1 (sLRP1) levels were assessed using enzyme-linked immunosorbent assay, and the genotype of LRP1 rs1799986 was detected using the Sequenom method. RESULTS: Diabetic patients with MCI (n = 60) exhibited significantly lower plasma sLRP1 levels (p = 0.033) and worse glucose control (p = 0.009) than the healthy cognition controls (n = 106). Multivariate regression analysis revealed plasma sLRP1 levels [odds ratio (OR) = 0.971, p = 0.005] and HbA1c (OR = 1.298, p = 0.003) as a risk factor for MCI in diabetic patients, in addition to insulin use and hypertension. However, there was no association between plasma sLRP1 levels and HbA1c. After adjusting for age, sex, and education level, plasma sLRP1 levels in the MCI group were negatively correlated with Stroop Color Word Test B number (r = -0.335, p = 0.011), which represents selective attention, cognitive flexibility, and processing speed. Additionally, patients with T2DM carrying the T allele of LRP1 rs1799986 showed higher Auditory Verbal Learning Test (AVLT) delayed recall scores (p = 0.025). CONCLUSION: Decreased plasma sLRP1 levels are associated with MCI, particularly with attention dysfunction, in patients with T2DM. Moreover, the T allele of LRP1 rs1799986 may decrease susceptibility to MCI. Further studies with large cohorts should be designed to elucidate the roles of LRP1 in hyperglycemia-induced cognitive decline.

The CC Genotype of Insulin-Induced Gene 2 rs7566605 Is a Protective Factor of Hypercholesteremia Susceptible to Mild Cognitive Impairment, Especially to the Executive Function of Patients with Type 2 Diabetes Mellitus.

METHODS: 233 T2DM patients with MCI or without MCI were recruited. Baseline data and genotype frequency were compared between MCI and non-MCI groups. Demographic parameters and neuropsychological tests results were analyzed among patients with different genotypes. Further correlation and regression analysis were conducted to find the association between cognition and cholesterol. RESULTS: Despite no significant statistical difference was detected, we observed higher levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL) in patients with MCI than those without MCI. In addition, we observed higher TC and LDL levels in patients with GG or GC genotypes than those with CC genotype (P < 0.001, P = 0.004, or P < 0.001, P = 0.002). Interestingly, increased MoCA and decreased TMTB scores were found in patients with CC genotype, compared to those with GG or CG genotype (P = 0.009, P = 0.024, or P = 0.005, P = 0.109). Moreover, partial correlation (P = 0.030 and P = 0.004, respectively) and multiple linear regression (P = 0.030 and P = 0.005, respectively) showed that TC and LDL levels are associated with the TMTB score, indicating the executive function. CONCLUSIONS: CC genotype of INSIG-2 rs7566605 may be a protective factor of hypercholesteremia susceptible to MCI, especially to the executive function of T2DM. This trial is registered with ChiCTROCC15006060.

Outcomes and prognostic factors of patients with stage IB and IIA pancreatic cancer according to the 8th edition American Joint Committee on Cancer criteria.

AIM: To evaluate the changes in the 8th edition American Joint Committee on Cancer (AJCC) for defining stage IB and IIA pancreatic cancer and identify their prognostic factors. METHODS: Pancreatic cancer patients were selected from the Surveillance Epidemiology and End Results database (1973-2013). The enrolled patients were divided into IB and IIA groups based on tumor size according to the 8th edition AJCC criteria. Clinical characteristics, including age, gender, race, tumor size, primary site, and grade were summarized. Univariate and multivariate analyses were performed to explore the prognostic factors of the IB and IIA stages of pancreatic cancer under new criteria. RESULTS: A total of 1349 pancreatic cancer patients were included. More patients had stage IB rather than stage IIA. Stage IB tumors (54.85%) were mainly located in the head of the pancreas, while stage IIA tumors were more often located in the tail and head of the pancreas (35.21% and 31.75%, respectively). The survival time of stage IB and IIA patients had no significant difference. Univariate and multivariate analyses indicated that the prognostic factors of survival for stage IB and IIA patients were different. For stage IB patients, age and primary site were the independent prognostic factors; for stage IIA patients, age and grade were the independent prognostic factors. The risk of death was lower among patients aged ≤ 65 years than those aged > 65 years. CONCLUSION: The prognostic factors for stage IB and IIA patients are different, but age is the independent prognostic factor for all patients. The survival time of stage IB and IIA patients has no significant difference.