Stevioside Ameliorates Palmitic Acid-Induced Abnormal Glucose Uptake via the PDK4/AMPK/TBC1D1 Pathway in C2C12 Myotubes.

BACKGROUND: Stevioside (SV) with minimal calories is widely used as a natural sweetener in beverages due to its high sweetness and safety. However, the effects of SV on glucose uptake and the pyruvate dehydrogenase kinase isoenzyme (PDK4) as an important protein in the regulation of glucose metabolism, remain largely unexplored. In this study, we used C2C12 skeletal muscle cells that was induced by palmitic acid (PA) to assess the effects and mechanisms of SV on glucose uptake and PDK4. METHODS: The glucose uptake of C2C12 cells was determined by 2-NBDG; expression of the Pdk4 gene was measured by quantitative real-time PCR; and expression of the proteins PDK4, p-AMPK, TBC1D1 and GLUT4 was assessed by Western blotting. RESULTS: In PA-induced C2C12 myotubes, SV could significantly promote cellular glucose uptake by decreasing PDK4 levels and increasing p-AMPK and TBC1D1 levels. SV could promote the translocation of GLUT4 from the cytoplasm to the cell membrane in cells. Moreover, in Pdk4-overexpressing C2C12 myotubes, SV decreased the level of PDK4 and increased the levels of p-AMPK and TBC1D1. CONCLUSION: SV was found to ameliorate PA-induced abnormal glucose uptake via the PDK4/AMPK/TBC1D1 pathway in C2C12 myotubes. Although these results warranted further investigation for validation, they may provide some evidence of SV as a safe natural sweetener for its use in sugar-free beverages to prevent and control T2DM.

Relationship between trajectories of dietary iron intake and risk of type 2 diabetes mellitus: evidence from a prospective cohort study.

BACKGROUND: The association between dietary iron intake and the risk of type 2 diabetes mellitus (T2DM) remains inconsistent. In this study, we aimed to investigate the relationship between trajectories of dietary iron intake and risk of T2DM. METHODS: This study comprised a total of 61,115 participants without a prior T2DM from the UK Biobank database. We used the group-based trajectory model (GBTM) to identify different dietary iron intake trajectories. Cox proportional hazards models were used to evaluate the relationship between trajectories of dietary iron intake and risk of T2DM. RESULTS: During a mean follow-up of 4.8 years, a total of 677 T2DM events were observed. Four trajectory groups of dietary iron intake were characterized by the GBTM: trajectory group 1 (with a mean dietary iron intake of 10.9 mg/day), 2 (12.3 mg/day), 3 (14.1 mg/day) and 4 (17.6 mg/day). Trajectory group 3 was significantly associated with a 38% decreased risk of T2DM when compared with trajectory group 1 (hazard ratio [HR] = 0.62, 95% confidence interval [CI]: 0.49-0.79), while group 4 was significantly related with a 30% risk reduction (HR = 0.70, 95% CI: 0.54-0.91). Significant effect modifications by obesity (p = 0.04) and history of cardiovascular disease (p < 0.01) were found to the relationship between trajectories of dietary iron intake and the risk of T2DM. CONCLUSIONS: We found that trajectories of dietary iron intake were significantly associated with the risk of T2DM, where the lowest T2DM risk was observed in trajectory group 3 with a mean iron intake of 14.1 mg/day. These findings may highlight the importance of adequate dietary iron intake to the T2DM prevention from a public health perspective. Further studies to assess the relationship between dietary iron intake and risk of T2DM are needed, as well as intervention studies to mitigate the risks of T2DM associated with dietary iron changes.

Relationship between metabolic status, physical activity and cardiovascular disease in participants with obesity.

OBJECTIVE: We aimed to investigate the independent and joint associations between metabolic status, PA (physical activity) and risk of CVD (cardiovascular disease) in participants with obesity. METHODS: We included 109,301 adults with obesity free of baseline CVD enrolled from 2006 to 2010 in the UK Biobank cohort (aged 56 ± 7.9 years). Based on metabolic status, obesity was grouped into metabolically healthy obesity (MHO; free of hypertension, hypercholesterolemia and diabetes; n = 26,989; BMI 33 ± 3.3 kg/m2) and metabolically unhealthy obesity (MUO; n = 82,312; BMI 34 ± 4.0 kg/m2). PA was categorized into four groups according to moderate-to-vigorous PA (MVPA): none, low, medium, and high. Multivariable Cox regression models were used for the main analyses adjusting for sociodemographic factors, lifestyles and comorbidities. RESULTS: There were 8,059 CVD events during a median follow-up of 8.1 years. MHO was associated with a 42% reduced risk of CVD compared with MUO (HR = 0.58, 95% CI: 0.53-0.63). A significant interaction effect between PA and metabolic status on CVD risk was found. Among MUO participants, individuals with PA had significantly decreased CVD risk when compared with no MVPA (HR = 0.87, 95% CI: 0.81-0.94 for low PA; HR = 0.85, 95% CI: 0.78-0.93 for medium PA; and HR = 0.86, 95% CI: 0.80-0.92 for high PA). The lowest CVD risk was observed in MHO & medium PA group when compared with MUO & no MVPA (HR = 0.45, 95% CI: 0.37-0.56). CONCLUSIONS: Both MHO and any MVPA were associated with reduced risk of CVD in adults with obesity, while PA could modify the relationship between metabolic status and CVD risk.

Relationship Between Lipoprotein(a), Renal Function Indicators, and Chronic Kidney Disease: Evidence From a Large Prospective Cohort Study.

BACKGROUND: Chronic kidney disease (CKD) poses a significant global public health challenge. While lipoprotein(a) (Lp[a]) has been established as a significant factor in cardiovascular disease, its connection to CKD risk remains a topic of debate. Existing evidence indicates diverse risks of kidney disease among individuals with various renal function indicators, even when within the normal range. OBJECTIVE: This study aims to investigate the joint associations between different renal function indicators and Lp(a) regarding the risks of incident CKD in the general population. METHODS: The analysis involved a cohort of 329,415 participants without prior CKD who were enrolled in the UK Biobank between 2006 and 2010. The participants, with an average age of 56 (SD 8.1) years, included 154,298/329,415 (46.84%) males. At baseline, Lp(a) levels were measured using an immunoturbidimetric assay and classified into 2 groups: low (<75 nmol/L) and high (≥75 nmol/L). To assess participants' baseline renal function, we used the baseline urine albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR). The relationship between Lp(a), renal function indicators, and the risk of CKD was evaluated using multivariable Cox regression models. These models were adjusted for various factors, including sociodemographic variables, lifestyle factors, comorbidities, and laboratory measures. RESULTS: A total of 6003 incident CKD events were documented over a median follow-up period of 12.5 years. The association between elevated Lp(a) levels and CKD risk did not achieve statistical significance among all participants, with a hazard ratio (HR) of 1.05 and a 95% CI ranging from 0.98 to 1.13 (P=.16). However, a notable interaction was identified between Lp(a) and UACR in relation to CKD risk (P for interaction=.04), whereas no significant interaction was observed between Lp(a) and eGFR (P for interaction=.96). When compared with the reference group with low Lp(a) and low-normal UACR (<10 mg/g), the group with high Lp(a) and low-normal UACR exhibited a nonsignificant association with CKD risk (HR 0.98, 95% CI 0.90-1.08; P=.74). By contrast, both the low Lp(a) and high-normal UACR (≥10 mg/g) group (HR 1.16, 95% CI 1.08-1.24; P<.001) and the high Lp(a) and high-normal UACR group (HR 1.32, 95% CI 1.19-1.46; P<.001) demonstrated significant associations with increased CKD risks. In individuals with high-normal UACR, elevated Lp(a) was linked to a significant increase in CKD risk, with an HR of 1.14 and a 95% CI ranging from 1.03 to 1.26 (P=.01). Subgroup analyses and sensitivity analyses consistently produced results that were largely in line with the main findings. CONCLUSIONS: The analysis revealed a significant interaction between Lp(a) and UACR in relation to CKD risk. This implies that Lp(a) may act as a risk factor for CKD even when considering UACR. Our findings have the potential to provide valuable insights into the assessment and prevention of CKD, emphasizing the combined impact of Lp(a) and UACR from a public health perspective within the general population. This could contribute to enhancing public awareness regarding the management of Lp(a) for the prevention of CKD.

Relationship between remnant cholesterol and risk of heart failure in participants with diabetes mellitus.

BACKGROUND: Evidence about the association between calculated remnant cholesterol (RC) and risk of heart failure (HF) in participants with diabetes mellitus (DM) remains sparse and limited. METHODS: We included a total of 22 230 participants with DM from the UK Biobank for analyses. Participants were categorized into three groups based on their baseline RC measures: low (with a mean RC of 0.41 mmol/L), moderate (0.66 mmol/L), and high (1.04 mmol/L). Cox proportional hazards models were used to evaluate the relationship between RC groups and HF risk. We performed discordance analysis to evaluate whether RC was associated with HF risk independently of low-density lipoprotein cholesterol (LDL-C). RESULTS: During a mean follow-up period of 11.5 years, there were a total of 2232 HF events observed. The moderate RC group was significantly related with a 15% increased risk of HF when compared with low RC group (hazard ratio [HR] = 1.15, 95% confidence interval [CI]: 1.01-1.32), while the high RC group with a 23% higher HF risk (HR = 1.23, 95% CI: 1.05-1.43). There was significant relationship between RC as a continuous measure and the increased HF risk (P < 0.01). The association between RC and risk of HF was stronger in participants with HbA1c level ≥ 53 mmol/mol when compared with HbA1c < 53 mmol/mol (P for interaction = 0.02). Results from discordance analyses showed that RC was significantly related to HF risk independent of LDL-C measures. CONCLUSIONS: Elevated RC was significantly associated with risk of HF in patients with DM. Moreover, RC was significantly related to HF risk independent of LDL-C measures. These findings may highlight the importance of RC management to HF risk in patients with DM.

Consumption of Non-Nutritive Sweetener during Pregnancy and Weight Gain in Offspring: Evidence from Human Studies.

The relationship between the consumption of maternal non-nutritive sweeteners (NNS) during pregnancy and the risk of obesity in offspring remains inconsistent. We aimed to systematically evaluate and clarify the relationship between NNS intake during pregnancy and weight gain in offspring based on evidence from population and clinical research. Databases including PubMed (via Medline), EMBASE, and the Cochrane Library were systematically searched for eligible human studies. The primary outcome was the differences in body mass index (BMI) z-scores between offspring at 1 year of age who were with and without NNS intake during pregnancy or between offspring with different NNS intake levels during pregnancy. A random-effects meta-analysis was conducted for data synthesis to calculate the weighted mean difference (WMD). A total of six prospective cohort studies were eligible for inclusion, among which three were used for pooled analysis of the BMI z-score. A significant increase was found in an offspring's weight at 1 year of age in the NNS group when compared with the control group: WMD in BMI z-score = 0.19 (95% CI: 0.07, 0.31), p-value = 0.002. Results from the dose-response analysis showed a linear relationship between NNS intake during pregnancy and WMD at 1 year of age: beta = 0.02 (95% CI: 0.001, 0.04) for per serving/week increase in NNS consumption. The whole body of evidence for the review was rated as low quality. In summary, maternal NNS intake during pregnancy was found to be associated with increased weight gain in offspring based on evidence from human studies. Further well-designed and adequately powered studies are needed to confirm this relationship.

Genome-wide identification and functional analysis of Cellulose synthase gene superfamily in Fragaria vesca.

The Cellulose synthase (CesA) and Cellulose synthase-like (Csl) gene superfamilies encode key enzymes involved in the synthesis of cellulose and hemicellulose, which are major components of plant cell walls, and play important roles in the regulation of fruit ripening. However, genome-wide identification and functional analysis of the CesA and Csl gene families in strawberry remain limited. In this study, eight CesA genes and 25 Csl genes were identified in the genome of diploid woodland strawberry (Fragaria vesca). The protein structures, evolutionary relationships, and cis-acting elements of the promoter for each gene were investigated. Transcriptome analysis and quantitative real-time PCR (qRT-PCR) results showed that the transcript levels of many FveCesA and FveCsl genes were significantly decreased during fruit ripening. Moreover, based on the transcriptome analysis, we found that the expression levels of many FveCesA/Csl genes were changed after nordihydroguaiaretic acid (NDGA) treatment. Transient overexpression of FveCesA4 in immature strawberry fruit increased fruit firmness and reduced fresh fruit weight, thereby delaying ripening. In contrast, transient expression of FveCesA4-RNAi resulted in the opposite phenotypes. These findings provide fundamental information on strawberry CesA and Csl genes and may contribute to the elucidation of the molecular mechanism by which FveCesA/Csl-mediated cell wall synthesis regulates fruit ripening. In addition, these results may be useful in strawberry breeding programs focused on the development of new cultivars with increased fruit shelf-life.

Association between metabolically healthy obesity and risk of atrial fibrillation: taking physical activity into consideration.

The modification of physical activity (PA) on the metabolic status in relation to atrial fibrillation (AF) in obesity remains unknown. We aimed to investigate the independent and joint associations of metabolic status and PA with the risk of AF in obese population. Based on the data from UK Biobank study, we used Cox proportional hazards models for analyses. Metabolic status was categorized into metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO). PA was categorized into four groups according to the level of moderate-to-vigorous PA (MVPA): none, low, medium, and high. A total of 119,424 obese participants were included for analyses. MHO was significantly associated with a 35% reduced AF risk compared with MUO (HR = 0.65, 95% CI: 0.57-0.73). No significant modification of PA on AF risk among individuals with MHO was found. Among the MUO participants, individuals with medium and high PA had significantly lower AF risk compared with no MVPA (HR = 0.84, 95% CI: 0.74-0.95, and HR = 0.87, 95% CI: 0.78-0.96 for medium and high PA, respectively). As the severity of MUO increased, the modification of PA on AF risk was elevated accordingly. To conclude, MHO was significantly associated with a reduced risk of AF when compared with MUO in obese participants. PA could significantly modify the relationship between metabolic status and risk of AF among MUO participants, with particular benefits of PA associated with the reduced AF risk as the MUO severity elevated.

Twenty-year trends in racial and ethnic enrollment in large diabetes randomized controlled trials.

BACKGROUND: Lack of representativeness in Black, Indigenous, and People of Colour (BIPOC) enrollment could compromise the generalizability of study results and health equity. This study aimed to examine trends in BIPOC groups enrollment in diabetes randomized controlled trials (RCTs) and to explore the association between trial factors and high-enrollment of BIPOC groups. METHODS: We systematically searched the literature on large diabetes RCTs with a sample size of ≥ 400 participants published between 2000 and 2020. We assessed temporal trends in enrollment of racial and ethnic groups in the included trials. Logistic and linear regression analyses were used to explore the relationship between trial factors and the high-enrollment defined by median enrollment rate. RESULTS: A total of 405 RCTs were included for analyses. The median enrollment rate of BIPOC groups was 24.0%, with 6.4% for the Black group, 11.2% for Hispanic, 8.5% for Asian, and 3.0% for other BIPOC groups respectively. Over the past 20 years, the BIPOC enrollment showed an increased trend in the diabetes RCTs, ranging from 20.1 to 28.4% (P for trend = 0.041). A significant trend towards increased enrollment for Asian group was observed. We found that weekly or daily intervention frequency (OR = 0.48, 95% CI: 0.26, 0.91) and duration of intervention > 6.5 month (OR = 0.59, 95% CI: 0.37, 0.95) were significantly related to decreased odds of high-enrollment, while type 2 diabetes (OR = 1.44, 95% CI: 1.04, 1.99) was associated with high-enrollment of BIPOC groups. CONCLUSIONS: The enrollment of BIPOC was found to increase in large diabetes RCTs over the past two decades; some trial factors may be significantly associated with BIPOC enrollment. These findings may highlight the importance of enrollment of BIPOC groups and provide insights into the design and implementation of future clinical trials in diabetes.

Changes in blood pressure and related risk factors among nurses working in a negative pressure isolation ward.

Objective: To observe changes in blood pressure (ΔBP) and explore potential risk factors for high ΔBP among nurses working in a negative pressure isolation ward (NPIW). Methods: Data from the single-center prospective observational study were used. Based on a routine practice plan, female nurses working in NPIW were scheduled to work for 4 days/week in different shifts, with each day working continuously for either 5 or 6 h. BP was measured when they entered and left NPIW. Multivariable logistic regression was used to assess potential risk factors in relation to ΔBP ≥ 5 mm Hg. Results: A total of 84 nurses were included in the analysis. The ΔBP was found to fluctuate on different working days; no significant difference in ΔBP was observed between the schedules of 5 and 6 h/day. The standardized score from the self-rating anxiety scale (SAS) was significantly associated with an increased risk of ΔBP ≥ 5 mm Hg (odds ratio [OR] = 1.12, 95% CI: 1.00-1.24). Working 6 h/day (vs. 5 h/day) in NPIW was non-significantly related to decreased risk of ΔBP (OR = 0.70), while ≥ 2 consecutive working days (vs. 1 working day) was non-significantly associated with increased risk of ΔBP (OR = 1.50). Conclusion: This study revealed no significant trend for ΔBP by working days or working time. Anxiety was found to be significantly associated with increased ΔBP, while no <2 consecutive working days were non-significantly related to ΔBP. These findings may provide some preliminary evidence for BP control in nurses who are working in NPIW for Coronavirus Disease 2019 (COVID-19).

Relationship between Serum 25-Hydroxyvitamin D Level and Risk of Recurrent Stroke.

Evidence for the association between vitamin D and risk of recurrent stroke remains sparse and limited. We aimed to assess the relationship between serum circulating 25-hydroxyvitamin D (25(OH)D) level and risk of recurrent stroke in patients with a stroke history, and to identify the optimal 25(OH)D level in relation to lowest recurrent stroke risk. Data from the nationwide prospective United Kingdom Biobank were used for analyses. Primary outcome was time to first stroke recurrence requiring a hospital visit during follow-up. We used Cox proportional hazards regression model with restricted cubic splines to explore 25(OH)D level in relation to recurrent stroke. The dose-response relationship between 25(OH)D and recurrent stroke risk was also estimated, taking the level of 10 nmol/L as reference. A total of 6824 participants (mean age: 60.6 years, 40.8% females) with a baseline stroke were included for analyses. There were 388 (5.7%) recurrent stroke events documented during a mean follow-up of 7.6 years. Using Cox proportional hazards regression model with restricted cubic splines, a quasi J-shaped relationship between 25(OH)D and risk of recurrent stroke was found, where the lowest recurrent stroke risk lay at the 25(OH)D level of approximate 60 nmol/L. When compared with 10 nmol/L, a 25(OH)D level of 60 nmol/L was related with a 48% reduction in the recurrent stroke risk (hazard ratio = 0.52, 95% confidence interval: 0.33-0.83). Based on data from a large-scale prospective cohort, we found a quasi J-shaped relationship between 25(OH)D and risk of recurrent stroke in patients with a stroke history. Given a lack of exploring the cause-effect relationship in this observational study, more high-quality evidence is needed to further clarify the vitamin D status in relation to recurrent stroke risk.

Trends in risk factor control in patients with gout: data from the National Health and Nutrition Examination Survey, 2007-2018.

OBJECTIVES: To explore trends in risk factor control (hypertension, diabetes mellitus, hyperlipidaemia) in patients with gout and medication use among those whose risk factor control targets were not achieved. METHODS: We used the data from National Health and Nutrition Examination Survey (NHANES) between 2007-2008 and 2017-2018 for analyses. The study samples were weighted so that they could be representative of the non-institutionalized US population. We conducted a cross-sectional analysis to assess trends in risk factor control and medication use, and employed logistic regression analyses to explore patient characteristics associated with risk factor control. RESULTS: The prevalence of participants in whom blood pressure control target was achieved decreased from 64.6% in 2007-2008 to 55.3% in 2017-2018 (P-value for trend = 0.03). The percentage of participants whose glycaemic, lipid or all three risk factor control targets were achieved remained stable temporally (P > 0.05). Some patient characteristics were significantly related to risk factor control, including age 45-64, age ≥65, Asian Americans, non-Hispanic Blacks, higher family income, and being overweight and obese. A trend towards increased use of glucose-lowering medication was found (from 71.0% in 2007-2008 to 94.7% in 2017-2018, P < 0.01), while the prevalence of taking blood pressure-lowering and lipid-lowering medications remained stable (P > 0.05). CONCLUSION: Based on NHANES data, a significant trend towards decreased blood pressure control was observed in patients with gout, while glycaemic and lipid control levelled off. These findings emphasize that more endeavours are needed to improve management of cardiovascular risk factors in patients with gout.

Relationship between diurnal temperature range and emergency ambulance dispatches due to stroke in Guangzhou, China.

BACKGROUND: The evidence between diurnal temperature range (DTR) and stroke remains controversial and sparse. We aimed to assess the relationship between DTR and emergency ambulance dispatches (EADs) due to stroke, and to explore whether there were effect modifications to the relationship. METHODS: A Quasi-Poisson generalized linear regression combined with a distributed lag non-linear model was used to examine the relationship between DTR and EADs for stroke between January 1st 2011 and June 30th 2018 in Guangzhou, China. We estimated the effects of the low DTR and high DTR (defined as DTR below and above 10 °C respectively) on EADs. The effects of minimum, maximum, 5th, 25th, 50th, 75th, and 95th percentiles of DTR compared with the DTR of 10 °C were also analyzed. RESULTS: A total of 20,275 EADs for stroke were included for analyses, among which 17,556 EADs were used in the model further adjusted for age and sex. A quasi-U-shaped relationship between DTR and EADs over lag0-2 days was observed. For the low DTR, per 1 °C decrease in DTR was significantly associated with an increase of 2.64% (RR = 1.03, 95% CI: 1.01-1.04) for EADs, while per 1 °C increase for the high DTR was non-significantly related with an increased risk of EADs (RR = 1.01, 95% CI: 0.90-1.13). Significant effects of the 5th and 25th percentiles of DTR on EADs were found when compared with the DTR of 10 °C. No significant effect modifications by age, sex or season were found to the association between DTR and EADs. CONCLUSIONS: We found a quasi-U-shaped relationship between DTR and EADs due to stroke in this study, while age, sex or season did not significantly modify the association between DTR and EADs. More high-quality evidence is needed to further explore and validate the relationship between DTR and stroke.

Association between bone turnover markers and the risk of imminent recurrent osteoporotic fracture.

The association between bone turnover markers (BTMs) and the risk of imminent recurrent osteoporotic fracture (ROF) in the elderly remains unclear. The present study thus aimed to explore BTMs in relation to imminent ROF in the elderly with an index OF. For this purpose, data from a prospective cohort study were used for analysis. Elderly patients hospitalized due to an index OF were included and followed-up. The BTMs included bone resorption marker (C-terminal telopeptide of type I collagen) and the bone formation markers, procollagen type I N propeptide, osteocalcin (OC) and total alkaline phosphatase. The outcome was the time to the first ROF following their index fracture. Cox regression analysis was used to assess the association between BTMs and ROF. Model discrimination was calculated to explore whether the BTMs had potential to improve fracture risk prediction. There were 169 eligible patients included in the analysis (median age, 72 years; 87.6% females). During a median follow-up period of 10.5 months, there were seven ROFs (4.1%) observed. Serum OC levels were found to be significantly associated with the risk of ROF [hazard ratio, 0.13; 95% confidence interval (CI) 0.018-0.90; P=0.039] for per-SD increase in OC from multivariable analysis. After incorporating OC into the model, a C-index of 0.83 (95% CI, 0.70-0.96; P<0.001) was observed, which outperformed the model with bone mineral density alone (improvement for C-index, 0.29; 95% CI, 0.028-0.55). On the whole, the present study demonstrates a significant association between serum OC and the decreased risk of imminent ROF in the elderly with index fractures. However, further high-quality evidence is required to further clarify and validate the BTMs in relation to the imminent risk of ROFs among the elderly.