UNASSIGNED: Gallbladder cancer (GBC) is a rare malignancy of the digestive tract, characterized by a remarkably poor prognosis. Currently, there is a controversy on the relationship between type 2 diabetes (T2D) and GBC. Additionally, no definitive conclusions were established regarding the causal relationships between alcohol intake frequency (AIF), age at menarche (AAM) and GBC. The objective of this study was to elucidate the causal association between T2D, AIF, AAM, and GBC.
UNASSIGNED: Single-nucleotide polymorphisms (SNPs) associated with exposures and outcomes were sourced from the Integrative Epidemiology Unit (IEU) Open Genome-Wide Association Study (GWAS) database. Specifically, the data of GBC comprised 907 East Asians (pathological results of all cases were registered into Biobank Japan) and 425,707 SNPs; T2D comprised 655,666 Europeans with 5,030,727 SNPs; AIF comprised 462,346 Europeans and 9,851,867 SNPs; AAM comprised 243,944 Europeans and 9,851,867 SNPs. The measurement of exposure traits is collected uniformly from the UK Biobank (UKB) database and presented in the form of standard deviation (SD) or the logarithmic form of the odds ratio (logOR). We employed a two-sample Mendelian randomization (MR) analysis to discern the causalities between T2D, AIF, AAM, and GBC. Sensitivity analyses were conducted to identify and address potential heterogeneity, horizontal pleiotropy, and outliers.
UNASSIGNED: Our findings indicated that T2D reduced GBC risk [odds ratio (OR) =0.044; 95% confidence interval (CI): 0.004-0.55; P=0.015, inverse variance-weighted (IVW)]. However, no causal relationship was observed between AIF (OR =0.158; 95% CI: 5.33E-05 to 466.84; P=0.65, IVW), AAM (OR =0.19; 95% CI: 0.0003-140.34; P=0.62, IVW), and GBC. Sensitivity analysis revealed no evidence of horizontal pleiotropy, heterogeneity, or outliers, suggesting the robustness and reliability of our conclusions.
UNASSIGNED: T2D emerged as a potentially protective factor against GBC, whereas neither AIF nor AAM demonstrated a causal relationship with GBC risk. Regulation of glucose metabolism may be one of the methods for preventing GBC.

BACKGROUND: The impacts of long-term exposure to air pollution on the risk of subsequent non-alcoholic fatty liver disease (NAFLD) among participants with type 2 diabetes (T2D) is ambiguous. The modifying role of Life\'s Essential 8 (LE8) remains unknown.
METHODS: This study included 23,129 participants with T2D at baseline from the UK Biobank. Annual means of nitrogen dioxide (NO2), nitrogen oxides (NOX), and particulate matter (PM2.5, PM2.5-10, PM10) were estimated using the land-use regression model for each participant. The associations between exposure to air pollution and the risk of severe NAFLD were evaluated using Cox proportional hazard models. The effect modification of LE8 was assessed through stratified analyses.
RESULTS: During a median 13.6 years of follow-up, a total of 1,123 severe NAFLD cases occurred. After fully adjusting for potential covariates, higher levels of PM2.5 (hazard ratio [HR] = 1.12, 95%CI:1.02, 1.23 per interquartile range [IQR] increment), NO2 (HR = 1.15, 95%CI:1.04, 1.27), and NOX (HR = 1.08, 95%CI:1.01, 1.17) were associated with an elevated risk of severe NAFLD. In addition, LE8 score was negatively associated with the risk of NAFLD (HR = 0.97, 95% CI: 0.97, 0.98 per point increment). Compared with those who had low air pollution and high LE8, participants with a high air pollution exposure and low LE8 had a significantly higher risk of severe NAFLD.
CONCLUSIONS: Our findings suggest that long-term exposure to air pollution was associated with an elevated risk of severe NAFLD among participants with T2D. A lower LE8 may increase the adverse impacts of air pollution on NAFLD.

Though type 2 diabetes (T2D) has been known as a metabolic disease caused by multiple factors, the etiology remains insufficiently understood. Here, we aimed to figure out whether circulating immune cell profiles causally impact T2D liability.
We applied one genome-wide association study (GWAS) summary statistics of blood traits in 563,085 participants from the Blood Cell Consortium and another GWAS of flow cytometric profile of lymphocyte subsets comprising 3,757 Sardinians to identify genetically predicted blood immune cells. We also obtained GWAS summary statistics in 898,130 individuals from the DIAGRAM Consortium to evaluate genetically predicted T2D. We primarily used inverse variance weighted (IVW) and weighted median methods to perform Mendelian randomization analyses and sensitivity analyses to evaluate heterogeneity and pleiotropy.
For circulating blood leukocyte and its subpopulations, the increase of genetically predicted circulating monocyte count was causally correlated with a higher risk of T2D [odds ratio (OR) = 1.06, 95% confidence interval (CI) = 1.02-1.10, p = 0.0048]. For lymphocyte subsets, CD8+ T cell and CD4+ CD8dim T cell count were identified with causal effect on T2D susceptibility (CD8+ T cell: OR = 1.09, 95% CI = 1.03-1.17, p = 0.0053; CD4+ CD8dim T cell: OR = 1.04, 95% CI = 1.01-1.08, p = 0.0070). No pleiotropy was determined.
These findings demonstrated that higher circulating monocyte and T-lymphocyte subpopulation predicted increased T2D susceptibility, which confirmed the immunity predisposition for T2D. Our results may have the potential to provide new therapeutic targets for the diagnosis and treatment of T2D.

UNASSIGNED: Patients with obesity and poorly controlled type 2 diabetes (T2D) are at high risk of diabetic complications. This study aimed to determine the associations of visceral adipose tissue (VAT), hepatic proton-density fat fraction (PDFF), and pancreatic PDFF with poor glycemic control in patients with obesity and T2D and to evaluate the metabolic effect of bariatric surgery in patients with obesity and poorly controlled diabetes.
UNASSIGNED: In this retrospective cross-sectional study, from July 2019 to March 2021, 151 consecutive obese patients with new-onset T2D (n=28), well-controlled T2D (n=17), poorly controlled T2D (n=32), prediabetes (n=20), or normal glucose tolerance (NGT; n=54) were included. A total of 18 patients with poorly controlled T2D were evaluated before and 12 months after bariatric surgery, and 18 non-obese healthy individuals served as controls. VAT, hepatic PDFF, and pancreatic PDFF were quantified by magnetic resonance imaging (MRI) using a chemical shift-encoded sequence [iterative decomposition of water and fat with echo asymmetry and least-squares estimation quantitation (IDEAL-IQ)]. Univariate analysis and multivariate regression analysis were performed.
UNASSIGNED: There were significant differences in VAT, hepatic PDFF, and all pancreatic PDFF between the new-onset T2D, prediabetes, and NGT groups (all P<0.05). Pancreatic tail PDFF was significantly higher in the poorly controlled T2D group than in the well-controlled T2D group (P=0.001). In the multivariate analysis, only pancreatic tail PDFF was significantly associated with increased odds of poor glycemic control [odds ratio (OR) =2.09; 95% confidence interval (CI): 1.11-3.94; P=0.022]. The glycated hemoglobin (HbA1c), hepatic PDFF, and pancreatic PDFF significantly decreased (all P<0.01) after bariatric surgery, and the values were statistically similar to those observed in the non-obese healthy controls.
UNASSIGNED: Increased fat in the pancreatic tail is strongly associated with poor glycemic control in patients with obesity and T2D. Bariatric surgery is an effective therapy for poorly controlled diabetes and obesity, which improves glycemic control and decreases ectopic fat deposits.

UNASSIGNED: Previous research has reported that variability in glucose levels is associated with a variety of patient characteristics in colon cancer. However, relevant research is still lacking in relation to hepatocellular carcinoma (HCC).
UNASSIGNED: A total of 95 HCC patients with Barcelona Clinic Liver Cancer (BCLC) stage B-C who underwent liver resection at the Eastern Hepatobiliary Surgery Hospital and Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine were included in this study. The patients were divided into 2 groups with type 2 diabetes (T2D) and without T2D. The primary outcome variable was blood glucose variability at 1 month and within 1 year of HCC surgery.
UNASSIGNED: In this study, the age of patients with T2D was greater than that of patients without T2D (mean age: 70.3±8.45 vs. 60.4±11.27 years, P=0.031). Compared to the patients without T2D, those with T2D had higher blood glucose measurements within 1 month (33 vs. 7) and 1 year (46.5 vs. 22.5, P<0.001) of surgery. The T2D patients and non-T2D patients did not differ in terms of chemotherapy medication or other characteristics. Among the 95 patients with BCLC stage B-C HCC, those with T2D had higher variability in glucose levels (P<0.001) than those without T2D within 1 month of surgery [standard deviation (SD) =46.43 mg/dL, coefficient of variation (CV) =23.5% vs. SD =21.56 mg/dL, CV =13.21%], and within 1 year of surgery (SD =42.49 mg/dL, CV =26.14% vs. SD =20.45 mg/dL, CV =17.36%). A correlation was found between a lower body mass index and higher variability in glucose levels within 1 month of surgery among patients with T2D [SD (r=-0.431, P<0.05) and CV (r=-0.464, P<0.01)]. A higher preoperative blood glucose level in T2D patients was correlated with a higher blood glucose variability within 1 year of surgery (r=0.435, P<0.01). Variability in glucose levels was weakly correlated with the demographic and clinical characteristics of patients who do not have T2D.
UNASSIGNED: HCC patients with T2D in BCLC stage B-C showed greater variability in glucose levels within 1 month and 1 year of surgery. Preoperative hyperglycemia, insulin use, and a lower cumulative dose of steroids were clinical features correlated with a higher variability in glucose levels in T2D patients.

Epidemiological evidence regarding the possible link between multiple essential metals levels and all-cause mortality and cardiovascular disease (CVD) mortality among type 2 diabetes (T2D) patients is sparse. Here, we aimed to evaluate the longitudinal associations between 11 essential metals levels in plasma and all-cause mortality and CVD mortality among T2D patients. Our study included 5278 T2D patients from the Dongfeng-Tongji cohort. LASSO penalized regression analysis was used to select the all-cause and CVD mortality-associated metals from 11 essential metals (iron, copper, zinc, selenium, manganese, molybdenum, vanadium, cobalt, chromium, nickel, and tin) measured in plasma. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: With a median follow-up of 9.8 years, 890 deaths were documented, including 312 deaths of CVD. LASSO regression models and the multiple-metals model revealed that plasma iron and selenium were negatively associated with all-cause mortality (HR: 0.83; 95%CI: 0.70, 0.98; HR: 0.60; 95%CI: 0.46, 0.77), whereas copper was positively associated with all-cause mortality (HR: 1.60; 95%CI: 1.30, 1.97). Only plasma iron has been significantly associated with decreased risk of CVD mortality (HR: 0.61; 95%CI: 0.49, 0.78). The dose-response curves for the association between copper levels and all-cause mortality followed a J shape (Pfor nonlinear = 0.01). Our study highlights the close relationships between essential metals elements (iron, selenium, and copper) and all-cause and CVD mortality among diabetic patients.

Diabetes mellitus is a complex disorder characterized by insufficient insulin production or insulin resistance, which results in a lifelong dependence on glucose-lowering drugs for almost all patients. During the fight with diabetes, researchers are always thinking about what characteristics the ideal hypoglycemic drugs should have. From the point of view of the drugs, they should maintain effective control of blood sugar, have a very low risk of hypoglycemia, not increase or decrease body weight, improve β-cell function, and delay disease progression. Recently, the advent of oral peptide drugs, such as semaglutide, brings exciting hope to patients with chronic diabetes. Legumes, as an excellent source of protein, peptides, and phytochemicals, have played significant roles in human health throughout human history. Some legume-derived peptides with encouraging anti-diabetic potential have been gradually reported over the last two decades. Their hypoglycemic mechanisms have also been clarified at some classic diabetes treatment targets, such as the insulin receptor signaling pathway or other related pathways involved in the progress of diabetes, and key enzymes including α-amylase, α-glucosidase, and dipeptidyl peptidase-IV (DPP-4). This review summarizes the anti-diabetic activities and mechanisms of peptides from legumes and discusses the prospects of these peptide-based drugs in type 2 diabetes (T2D) management.

Although the relationship between type 2 diabetes (T2D) and the increased risk of colorectal carcinogenesis is widely defined in clinical studies, the therapeutic methods and molecular mechanism of T2D-induced colon cancer and how does hyperglycemia affect the progression is still unknown. Here, we studied the function of lactoferrin (LF) in suppressing the progression of colon cancer in T2D mice, and uncovered the related molecular mechanisms in DNA 5mC and RNA m6A levels.
We examined the effects of LF (50% iron saturation) on the migration and invasion of colon tumor cells under high concentration of glucose. Then, transcriptomics and DNA methylation profilings of colon tumor cells was co-analyzed to screen out the special gene (NT5DC3), and the expression level of NT5DC3 in 75 clinical blood samples was detected by q-PCR and western blot, to investigate whether NT5DC3 was a biomarker to distinguish T2D patients and T2D-induced colon cancer patients from healthy volunteers. Futhermore, in T2D mouse with xenografted colon tumor models, the inhibitory effects of LF and NT5DC3 protein on colon tumors were investigated. In addition, epigenetic alterations were measured to examine the 5mC/m6A modification sites of NT5DC3 regulated by LF. Utilizing siRNA fragments of eight m6A-related genes, the special gene (WTAP) regulating m6A of NT5DC was proved, and the effect of LF on WTAP/NT5DC3/HKDC1 axis was finally evaluated.
A special gene NT5DC3 was screened out through co-analysis of transcriptomics and DNA methylation profiling, and HKDC1 might be a downstream sensor of NT5DC3. Mechanistically, LF-dependent cellular DNA 5mC and RNA m6A profiling remodeling transcriptionally regulate NT5DC3 expression. WTAP plays a key role in regulating NT5DC3 m6A modification and subsequently controls NT5DC3 downstream target HKDC1 expression. Moreover, co-treatment of lactoferrin and NT5DC3 protein restrains the growth of colon tumors by altering the aberrant epigenetic markers. Strikingly, clinical blood samples analysis demonstrates NT5DC3 protein expression is required to direct the distinction of T2D or T2D-induced colon cancer with healthy humans.
Together, this study reveals that lactoferrin acts as a major factor to repress the progression of colon cancer under hyperglycemia, thus, significantly expanding the landscape of natural dietary mediated tumor suppression.

Although increasing evidence shows the association between type 2 diabetes (T2D) and colorectal cancer, the related mechanism remains unclear. This study examined the suppressive effect of lactoferrin (LF) on the development of T2D-induced colon cancer. First, a co-cultured cell model consisting of NCM460 and HT29 cells was constructed to mimic the progression of T2D into colon cancer. The migration ability of NCM460 cells increased significantly (p < 0.05) after cultivation in HT29 cell medium (high glucose), while LF suppressed the progression of T2D to colon cancer by regulating the 5′-nucleotidase domain-containing 3 (NT5DC3) protein and the PI3K/AKT/mTOR signaling pathway in diabetic BALB/c mice and in cell models. A mutation assay of the phosphorylation site in the NT5DC3 protein and a surface plasmon resonance (SPR) protein binding test were performed to further ascertain a mechanistic link between LF and the NT5DC3 protein. The results indicated that LF specifically bound to the NT5DC3 protein to activate its phosphorylation at the Thr6 and Ser11 sites. Next, metabolic-specific staining and localization experiments further confirmed that LF acted as a phosphate donor for NT5DC3 protein phosphorylation by regulating the downstream metabolic pathway in T2D-induced colon tumors, which was specifically accomplished by controlling Thr6/Ser11 phosphorylation in NT5DC3 and its downstream effectors. These data on LF and NT5DC3 protein may suggest a new therapeutic strategy for cancer prevention, especially in T2D patients susceptible to colon cancer.

UNASSIGNED: Depression and type 2 diabetes (T2D) are both serious public health problems, with morbidity and mortality in people increasing year by year, resulting in a heavy economic burden. A correlation between dietary fiber and both has been reported. Nevertheless, few data are available concerning dietary fiber and the risk of depression with or without T2D, which deserve further attention.
UNASSIGNED: We assessed the relationship between dietary fiber intake and risk of depression with or without T2D in the 2007-2014 National Health and Nutrition Examination Survey (NHANES) population. A 24-h dietary review was used to assess fiber intake. The Patient Health Questionnaire-9 was used to assess depression. Stability of the results was assessed using restricted cubic spline models and logistic regression, as well as sensitivity analyses.
UNASSIGNED: A total of 17,866 adults aged 20 years and older with a mean age of 49.3 ± 17.7 years were included in this study, of whom 49.5% were male. After adjusting for covariates, the association of dietary fiber intake with the risk of depression appeared to differ between non-T2D group and T2D group (OR, 0.987; 95% CI, 0.979-0.995 vs. OR, 1.003; 95% CI, 0.988-1.017). Furthermore, when dietary fiber was converted to a categorical variable, there was evidence of interaction between T2D status and fiber intake on decreasing the prevalence of depression (P-value for interaction = 0.015). Sensitivity analysis showed stable results.
UNASSIGNED: Our findings indicated that whether a patient has T2D may affect the relationship between dietary fiber intake and the risk of depression, which still needs to be confirmed by further randomized controlled trials.