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Recently, some studies have focused on the relationship between dietary protein intake and the risk of type 2 diabetes mellitus (T2DM), but the conclusions have been inconsistent. Therefore, in this paper, a systematic review and meta-analysis of cohort studies regarding protein consumption and T2DM risk are conducted in order to present the association between them. We searched the PubMed and Embase databases for cohort studies on dietary protein, high-protein food consumption and risk of T2DM, up to July 2017. A summary of relative risks was compiled by the fixed-effect model or random-effect model. Eleven cohort studies regarded protein intake and T2DM (52,637 cases among 483,174 participants). The summary RR and 95% CI (Confidence Interval) of T2DM was 1.12 (1.08–1.17) in all subjects, 1.13 (1.04–1.24) in men, and 1.09 (1.04–1.15) in women for total protein;1.14 (1.09–1.19) in all subjects, 1.23 (1.09–1.38) in men, and 1.11 (1.03–1.19) in women for animal protein; 0.96 (0.88–1.06) in all subjects, 0.98 (0.72–1.34) in men, and 0.92 (0.86–0.98) in women for plant protein. We also compared the association between different food sources of protein and the risk of T2DM. The summary RR (Relative Risk) and 95% CI of T2DM was 1.22 (1.09–1.36) for red meat, 1.39 (1.29–1.49) for processed meat, 1.03 (0.89–1.17) for fish, 1.03 (0.64–1.67) for egg, 0.89 (0.84–0.94) for total dairy products, 0.87 (0.78–0.96) for whole milk, 0.83 (0.70–0.98) for yogurt, 0.74 (0.59–0.93) in women for soy. This meta-analysis shows that total protein and animal protein could increase the risk of T2DM in both males and females, and plant protein decreases the risk of T2DM in females. The association between high-protein food types and T2DM are also different. Red meat and processed meat are risk factors of T2DM, and soy, dairy and dairy products are the protective factors of T2DM. Egg and fish intake are not associated with a decreased risk of T2DM. This research indicates the type of dietary protein and food sources of protein that should be considered for the prevention of diabetes.

Type 2 diabetes mellitus (T2DM) patients with colon cancer have an increased incidence and poor prognosis, which may be closely related to advanced glycation end products (AGEs) and its receptor (RAGE), but the underlying mechanism is still unclear. The aim of this study is to investigate how the AGEs-RAGE axis inhibits ferroptosis in T2DM-associated colon cancer by regulating carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1). ELISA and Western blot were used to detect expression levels of CEACAM1 in 155 patients with colon cancer. In vitro experiments examined various parameters in CEACAM1 knockdown/overexpression cells co-cultured with AGEs. The molecular mechanism was validated using multiple detection methods following intervention with FPS-ZM1 and sabatolimab. Serum and tissue analyses revealed that CEACAM1 is up-regulated in colon cancer patients with T2DM. The AGEs-RAGE promotes colon cancer cell proliferation, migration and invasion by upregulating CEACAM1. CEACAM1 overexpression triggers IFN-γ pathway, thereby enhancing SLC7A11/GPX4-mediated ferroptosis resistance. Blockade of RAGE with FPS-ZM1 reverses CEACAM1 driven inhibition of ferroptosis by reducing GPX4. A nude mouse model of type 2 diabetic tumors was established to assess tumor growth. Furthermore, blockade of Tim-3 by sabatolimab disrupts its interaction with CEACAM1, restoring ferroptosis sensitivity and inhibiting subcutaneous tumor growth in these mice. The AGEs-RAGE axis inhibits ferroptosis by driving CEACAM1 overexpression and mediating IFN-γ/SLC7A11/GPX4 signaling pathway, which reveals a new mechanism by which AGEs-RAGE-CEACAM1 promotes tumor survival in diabetic environment. Sabatolimab may provide a therapeutic strategy for colon cancer patients with T2DM.

Background/Aims: Diabetic cardiomyopathy (DCM) is a common complication of diabetes and can cause heart failure, arrhythmia and sudden death. The pathogenesis of DCM includes altered metabolism, mitochondrial dysfunction, oxidative stress, inflammation, cell death and extracellular matrix remodeling. Recently, pyroptosis, a type of programmed cell death related to inflammation, was proven to be activated in DCM. However, the molecular mechanisms underlying pyroptosis in DCM remain elusive. The long non-coding RNA (lncRNA) Kcnq1ot1 participates in many cardiovascular diseases. This study aims to clarify whether Kcnq1ot1 affects cardiac pyroptosis in DCM. Methods: AC16 cells and primary cardiomyocytes were incubated with 5.5 and 50 mmol/L glucose. Diabetic mice were induced with streptozotocin (STZ). Kcnq1ot1 was silenced both in vitro and in vivo. qRT-PCR was used to detect the expression level of Kcnq1ot1. Immunofluorescence, qRT-PCR and western blot analyses were used to detect the degree of pyroptosis. Echocardiography, hematoxylin and eosin staining, and Masson’s trichrome staining were used to detect the cardiac function and morphology in mice. Cell death and function were detected using TUNEL staining, immunofluorescence staining and Ca 2+ measurements. Results: The expression of Kcnq1ot1 was increased in patients with diabetes, high glucose-induced cardiomyocytes and diabetic mouse cardiac tissue. Silencing Kcnq1ot1 alleviated pyroptosis by targeting miR-214-3p and caspase-1. Furthermore, silencing Kcnq1ot1 reduced cell death, cytoskeletal structure abnormalities and calcium overload in vitro and improved cardiac function and morphology in vivo. Conclusion: Kcnq1ot1 is overexpressed in DCM, and silencing Kcnq1ot1 inhibits pyroptosis by influencing miR-214-3p and caspase-1 expression. We clarified for the first time that Kcnq1ot1 could be a new therapeutic target for DCM.

Background This study aims to investigate potential interactions between maternal smoking around birth (MSAB) and type 2 diabetes (T2D) pathway-specific genetic risks in relation to the development of T2D in offspring. Additionally, it seeks to determine whether and how nutritional factors during different life stages may modify the association between MSAB and risk of T2D. Methods This study included 460,234 participants aged 40 to 69 years, who were initially free of T2D from the UK Biobank. MSAB and breastfeeding were collected by questionnaire. The Alternative health eating index(AHEI) and dietary inflammation index(DII) were calculated. The polygenic risk scores(PRS) of T2D and pathway-specific were established, including β-cell function, proinsulin, obesity, lipodystrophy, liver function and glycated haemoglobin(HbA1c). Cox proportion hazards models were performed to evaluate the gene/diet-MSAB interaction on T2D. The relative excess risk due to additive interaction (RERI) were calculated. Results During a median follow-up period of 12.7 years, we identified 27,342 cases of incident T2D. After adjustment for potential confounders, participants exposed to MSAB had an increased risk of T2D (HR=1.11, 95%CI:1.08-1.14), and this association remained significant among the participants with breastfeeding (HR= HR=1.10, 95%CI: 1.06-1.14). Moreover, among the participants in the highest quartile of AHEI or in the lowest quartile of DII, the association between MSAB and the increased risk of T2D become non-significant (HR=0.94, 95%CI: 0.79-1.13 for AHEI; HR=1.09, 95%CI:0.99-1.20 for DII). Additionally, the association between MSAB and risk of T2D became non-significant among the participants with lower genetic risk of lipodystrophy (HR=1.06, 95%CI:0.99-1.14), and exposed to MSAB with a higher genetic risk for β-cell dysfunction or lipodystrophy additively elevated the risk of T2D(RERI=0.18, 95%CI:0.06-0.30 for β-cell function; RERI=0.16, 95%CI:0.04-0.28 for lipodystrophy). Conclusions This study indicates that maintaining a high dietary quality or lower dietary inflammation in diet may reduce the risk of T2D associated with MSAB, and the combination of higher genetic risk of β-cell dysfunction or lipodystrophy and MSAB significantly elevate the risk of T2D in offspring.

Objective Little is known about the role of timing of physical activity in female reproductive disorders. These disorders include polycystic ovary syndrome (PCOS), heavy menstrual bleeding (HMB), endometriosis, infertility, and pregnancy-related disorders. This study aims to investigate the associations of activity patterns with female reproductive diseases. Methods A total of 49,540 female participants from the UK Biobank with valid accelerometer data were enrolled at baseline. Activity patterns were defined based on the timing of moderate-to-vigorous intensity physical activity (MVPA) throughout the day. Participants were categorized into four groups according to the timing of their MVPA: “morning, evening, mixed, midday-afternoon”, with the midday-afternoon group serving as the reference. Cox proportional hazards models were utilized to evaluate the association between activity patterns and female reproductive diseases. Results During a median follow-up of 12.6 years, a total of 1044 cases of female reproductive diseases were documented. After adjustment for potential confounders, compared to women with midday-afternoon exercise, women with morning exercise and mixed-timing exercise were associated with lower risks for female reproductive diseases (HR morning =0.81, 95% CI: 0.67–0.98; HR mixed =0.79, 95% CI: 0.69–0.91, P-trend < 0.05). Moreover, morning exercise and mixed-timing exercise had lower risks of PCOS (HR morning =0.38, 95% CI: 0.15–0.97; HR mixed =0.27, 95% CI: 0.13–0.57, P-trend<0.001), and mixed-timing exercise was associated with a lower risk for HMB (HR mixed =0.81, 95% CI: 0.70–0.95, P-trend < 0.05), compared with the reference group. Conclusions Compared with midday-afternoon group, morning and mixed MVPA timing groups, but not evening group, were associated with decreased risks for female reproductive diseases and PCOS. In addition, we found that women with mixed MVPA timing exercise had a lower risk of HMB, compared with the reference group.

Background Knowledge regarding the health impacts of daily eating frequency (DEF) and nighttime fasting duration (NFD) on mortality is very limited. Objective This study aimed to examine whether DEF and NFD are associated with CVD and all-cause mortality. Methods This was a prospective cohort study of a nationally representative sample from the United States, including 30,464 adults who participated in the National Health and Nutrition Examination Survey 2003–2014. Using 24-h dietary recall, DEF was assessed by the number of eating episodes, and NFD was calculated by the first and last eating time across a day. Death information was obtained from the National Death Index up to 2019. Weighted Cox proportional hazards regression models were used to assess survival relationships of DEF and NFD with mortality. Results During 307,686 person-years of follow-up, 4560 deaths occurred, including 1824 CVD cases. After adjustment for confounders, compared to DEF at 4–6 times, participants whose DEF was less than 3 times had greater CVD [hazard-ratio (HR) = 1.33, 95% confidence-interval (CI): 1.06–1.67] and all-cause (HR = 1.16, 95% CI: 1.01–1.33) mortality risks. Furthermore, compared to NFD of 10 to 11 h, participants whose NFD was shorter than 10 h had HRs of 1.30 (95% CI: 1.08–1.55) for CVD mortality and 1.23 (95% CI: 1.08–1.39) for all-cause mortality. NFD longer than 14 h was also related to CVD mortality (HR = 1.37, 95% CI: 1.12–1.67) and all-cause mortality (HR = 1.36, 95% CI: 1.19–1.54). Similar results for the association of NFD and DEF with heart-specific and stroke-specific mortality were observed. Conclusion This study found that DEF less than 3 times and NFD shorter than 10 h or longer than 14 h were independently associated with greater cardiovascular and all-cause mortality.

We evaluated temporal and genetic relationships between 176 food-liking-traits and cardio-metabolic diseases using data from the UK Biobank (N = 182,087) for observational analyses and summary-level GWAS data from FinnGen and other consortia (N = 406,565–977,323) for genetic analyses. Integrating observational and genetic results, we identified two detrimental food-liking-traits (bacon and diet-fizzy-drinks) and three protective food-liking-traits (broccoli, pizza, and lentils/beans). These food-liking-traits are associated with habitual food intake and influence cardio-metabolic proteins and biological processes. Notably, we found three genetic links: diet-fizzy-drinks with heart-failure, bacon with type-2-diabetes, and lentils/beans with type-2-diabetes, identifying 54 pleiotropic single-nucleotide-variants, impacting both phenotypes. Our data show the diet-fizzy-drinks and heart-failure link maybe not direct, as diet-fizzy-drinks liking correlates with sweet food consumption and shares variants linked to BMI, adiposity, platelet count and cardio-metabolic traits. The pleiotropic single-nucleotide-variants map to 251 tissue-specific genes, with four showing high druggability potential, highlighting personalized dietary strategies for cardio-metabolic diseases. This study explored genetic and temporal links between food liking and cardiometabolic diseases, identifying harmful (bacon, diet fizzy drinks) and protective (broccoli, pizza, lentils) traits linked via shared genetics and pleiotropic variants.

Background Menopausal women undergo substantial physiological changes that can impact their overall health. Objectives We examined relationships between circadian rest-activity rhythms (CRARs) and multimorbidity progression in this population. Methods We used UK Biobank data, involving 10,138 participants, who were initially free of chronic conditions. We primarily focused on the relative amplitude (RA) of CRARs, tracking incident first chronic conditions (FCC), multimorbidity, and all-cause mortality. Multimorbidity was indicated by the presence of any 2/35 chronic conditions during the follow-up period. We used a multi-state model to assess the RA impact on the multimorbidity progression trajectory, encompassing transition from health to an FCC, to consequent multimorbidity, and ultimately to mortality, in parallel with sensitivity analyses to ensure results stability and reliability. Results During a mean 8.13-year follow-up period, we identified 855 incident multimorbidity cases and recorded 88 deaths. In a multi-state model, a lower RA was associated with an increased risk of transition from health to FCC onset [hazard ratio (HR): 1.18, 95% confidence interval (CI): 1.07–1.31] and also from an FCC to multimorbidity development (HR: 1.34, 95% CI: 1.12–1.61), even after adjusting for several confounding factors. Conclusions Among menopausal women, circadian rhythm disturbance increased the risk of transitioning from health to a single chronic condition, as well as transitioning from a single chronic condition to multimorbidity.

Numerous risk factors for oesophageal cancer are linked to lifestyle habits, but the role of early-life factors in its incidence and mortality is unclear. Using UK Biobank data, we explore the association among breastfeeding, maternal smoking, smoking in offspring, and oesophageal cancer risk in adult offspring via multivariable Cox regression. Here, we show that being breastfed, compared with not being breastfed, is associated with a lower risk of oesophageal cancer incidence (HR: 0.83, 95% CI: 0.70–0.98) and mortality (HR: 0.74, 95% CI: 0.61–0.89) in adult offspring. Additionally, it is associated with a reduced impact of smoking in offspring on oesophageal cancer incidence (HR: 0.79, 95% CI: 0.64-0.96) and mortality (HR: 0.73, 95% CI: 0.59-0.91). We subsequently construct a polygenic risk score for oesophageal cancer to explore the influence of genetic factors. Our findings emphasize the importance of breastfeeding, and smoking cessation to prevent oesophageal cancer. Early life factors like breastfeeding and maternal smoking may influence oesophageal cancer risk in adults. Here, the authors analyse data from the UK biobank and show that breastfeeding is associated with reduced incidence and mortality of oesophageal cancer and reduced adverse effects of smoking in offspring.

ObjectiveThis study aimed to investigate the association between the trajectories of energy consumption at dinner versus breakfast and the risk of type 2 diabetes (T2D).DesignCohort study.SettingThe study was conducted in China.ParticipantsA total of 10 727 adults, including 5239 men and 5488 women, with a mean age of 42.7±11.2 years and a mean follow-up time of 9.1 years, met the study criteria and completed a questionnaire about energy intake and diabetes status from the China Health and Nutrition Survey in 1997–2011.Primary outcome measuresParticipants were divided into subgroups based on the trajectories of the ratio of energy consumption at dinner versus breakfast. Cox multivariate regression models were used to explore the associations between different trajectories and the risk of T2D after adjustment for confounders and their risk factors. Mediation analysis was performed to explore the intermediary effect of triacylglycerol (TG), total cholesterol (TC), uric acid (UA) and apolipoprotein B (ApoB) between the trajectories and the risk of T2D.ResultsFor energy consumption at dinner versus breakfast, compared with a low-stable trajectory, the adjusted HR of T2D in low-increasing from early-stage trajectory was 1.29 (95% CI 1.04 to 1.60). TG, TC, UA and ApoB were significantly higher in low-increasing from early-stage trajectory than other trajectories and play partial regulation roles between trajectories and T2D.ConclusionsThis study emphasised the harmful effect of a gradual increase in the ratio of energy consumption at dinner versus breakfast from early stage on the development of T2D and partially mediated by TG, TC, UA and ApoB, highlighting that it is necessary to intake more energy at breakfast compared with dinner to prevent T2D in adults.