Smoking timing, genetic susceptibility and the risk of incident type 2 diabetes: A cohort study from the UK Biobank.

AIM: To prospectively assess the association of smoking timing with the risk of type 2 diabetes (T2D) and examine whether smoking amount or genetic susceptibility might modify the relationship. MATERIALS AND METHODS: A total of 294 815 participants without diabetes from the UK Biobank, including non-smokers and smokers with data on the time from waking to first cigarette, were included. Cox proportional hazards models were used to evaluate the association between smoking timing and the risk of incident T2D. RESULTS: During a median follow-up time of 12 years, a total of 9937 incident cases of T2D were documented. Compared with non-smokers, a shorter time from waking to first cigarette was significantly associated with a higher risk of incident T2D (P for trend < .001). In the fully adjusted model, the hazard ratios (HRs) (95% confidence interval) associated with smoking timing were 1.46 (1.17-1.81) for more than 2 hours, 1.51 (1.21-1.87) for 1-2 hours, 1.58 (1.34-1.85) for 30-60 minutes, 1.86 (1.57-2.21) for 5-15 minutes and 2.01 (1.60-2.54) for less than 5 minutes. We found that even among those who reported being light smokers, those with the shortest time from waking to first cigarette had a 105% higher risk of T2D with an HR of 2.05 (1.52-2.76), which was comparable with heavy smokers. The genetic risk score for T2D did not modify this association (P-interaction = .51). CONCLUSIONS: Our findings indicate that shorter time from waking to first cigarette is significantly associated with a higher risk of incident T2D.

Risk factor control and incident cardiovascular disease in patients with diabetes: Sex-specific relations.

AIM: Women with diabetes are at higher risk of cardiovascular diseases (CVD) than men with diabetes; however, the sex difference in the association between the degree of risk factor control and the risk of CVD in patients with diabetes is unclear. METHODS: In total, 17 260 participants diagnosed with diabetes from the UK Biobank were included and matched with 86 300 non-diabetes controls based on age, sex and assessment centre. The main exposure was the number of risk factors within the target range, including glycated haemoglobin level <53 mol/mol (7%), blood pressure <140/90 mm/Hg, low-density lipoprotein cholesterol <100 mg/dl, non-current smoking and absence of microalbuminuria. RESULTS: During a median follow-up of 13.3 years, a total of 3338 incident CVD cases, including 2807 ischaemic heart disease and 793 strokes, were documented. A more stringent control of risk factors was significantly associated with a lower risk of incident CVD, and such an association was significantly stronger in women than men. Compared with non-diabetes participants, the diabetes-related risk of CVD appeared to be eliminated if more than three risk factors were well controlled among women and men with diabetes. Moreover, clinical biomarkers (e.g. glycated haemoglobin and blood pressure) showed greater relative importance than other factors in women, whereas socio-economic and psychological factors (e.g. education and depression) exhibited similar relative importance to clinical biomarkers in men with diabetes. CONCLUSION: Our findings highlighted the importance of raising awareness of sex differences in the management of CVD risk factors among patients with diabetes.

Cardiovascular Health and Life Expectancy Among Adults in the United States.

BACKGROUND: Cardiovascular disease may be the main reason for stagnant growth in life expectancy in the United States since 2010. The American Heart Association recently released an updated algorithm for evaluating cardiovascular health (CVH)-Life's Essential 8 (LE8) score. We aimed to quantify the associations of CVH levels, estimated by the LE8 score, with life expectancy in a nationally representative sample of US adults. METHODS: We included 23 003 nonpregnant, noninstitutionalized participants aged 20 to 79 years who participated in the National Health and Nutrition Examination Survey from 2005 to 2018 and whose mortality was identified through linkage to the National Death Index through December 31, 2019. The overall CVH was evaluated by the LE8 score (range, 0-100), as well as the score for each component of diet, physical activity, tobacco/nicotine exposure, sleep duration, body mass index, non-high-density lipoprotein cholesterol, blood glucose, and blood pressure. Life table method was used to estimate life expectancy by levels of the CVH. RESULTS: During a median of 7.8 years of follow-up, 1359 total deaths occurred. The estimated life expectancy at age 50 years was 27.3 years (95% CI, 26.1-28.4), 32.9 years (95% CI, 32.3-33.4), and 36.2 years (95% CI, 34.2-38.2) in participants with low (LE8 score <50), moderate (50≤ LE8 score <80), and high (LE8 score ≥80) CVH, respectively. Equivalently, participants with high CVH had an average 8.9 (95% CI, 6.2-11.5) more years of life expectancy at age 50 years compared with those with low CVH. On average, 42.6% of the gained life expectancy at age 50 years from adhering to high CVH was attributable to reduced cardiovascular disease death. Similarly significant associations of CVH with life expectancy were observed in men and women, respectively. Similarly significant associations of CVH with life expectancy were observed in White participants and Black participants but not in Mexican participants. CONCLUSIONS: Adhering to a high CVH, defined as the LE8 score, is related to a considerably increased life expectancy in US adults, but more research needs to be done in other races and ethnicities (eg, Hispanic and Asian).

Chemerin-Induced Down-Regulation of Placenta-Derived Exosomal miR-140-3p and miR-574-3p Promotes Umbilical Vein Endothelial Cells Proliferation, Migration, and Tube Formation in Gestational Diabetes Mellitus.

Gestational diabetes mellitus (GDM) leads to poor pregnancy outcomes and fetoplacental endothelial dysfunction; however, the underlying mechanisms remain unknown. This study aimed to investigate the effect of placenta-derived exosomal miRNAs on fetoplacental endothelial dysfunction in GDM, as well as to further explore the role of chemerin to this end. Placenta-derived exosomal miR-140-3p and miR-574-3p expression (next-generation sequencing, quantitative real-time PCR), its interactions with cell function (Cell Counting Kit-8, Transwell, tube formation assay), chemerin interactions (Western blotting), and placental inflammation (immunofluorescence staining, enzyme-linked immunosorbent assay) were investigated. Placenta-derived exosomal miR-140-3p and miR-574-3p were downregulated in GDM. Additionally, miR-140-3p and miR-574-3p inhibited the proliferation, migration, and tube formation ability of umbilical vein endothelial cells by targeting vascular endothelial growth factor. Interestingly, miR-140-3p and miR-574-3p expression levels were negatively correlated with chemerin, which induced placental inflammation through the recruitment of macrophage cells and release of IL-18 and IL-1ß. These findings indicate that chemerin reduces placenta-derived exosomal miR-140-3p and miR-574-3p levels by inducing placental inflammation, thereby promoting the proliferation, migration, and tube formation of umbilical vein endothelial cells in GDM, providing a novel perspective on the underlying pathogenesis and therapeutic targets for GDM and its offspring complications.

Perinatal exposure to maternal smoking and adulthood smoking behaviors in predicting cardiovascular diseases: A prospective cohort study.

BACKGROUND AND AIMS: Little is known about the associations between perinatal exposure to maternal smoking and cardiovascular disease (CVD) incidence in offspring, and whether such associations are modified by adulthood and genetically determined smoking behaviors. METHODS: A total of 414,588 participants without CVD at baseline were included from the UK Biobank in 2006-2010 and followed up through 2018. Cox-proportional hazard models were used to examine the association of perinatal maternal smoking with CVD, and both multiplicative and additive interaction analyses were performed to investigate the modification effects of own smoking behaviors. RESULTS: During a median follow-up of 8.93 years, we observed 10,860 incident CVD events, including 7006 myocardial infarction (MI) and 4147 stroke. We found that perinatal exposure to maternal smoking was associated with increased risks of CVD (HR: 1.10; 95% CI: 1.05-1.14), MI (1.10; 1.05-1.16) and stroke (1.10; 1.03-1.18). In addition, we observed significant interactions between perinatal exposure to maternal smoking and adulthood exposure to own smoking on CVD and MI on both the multiplicative and additive scales (all p < 0.05). The attributable proportions due to additive interaction between perinatal and adulthood exposure to smoking were 14% (9%-19%) for CVD and 16% (10%-22%) for MI, respectively. Perinatal exposure to maternal smoking also showed an interaction with genetically determined smoking on MI (p < 0.05), but no interactions were found on the total CVD and stroke. CONCLUSIONS: Our results indicate that perinatal exposure to maternal smoking is associated with increased risks of CVD events, and such relations are modified by adulthood smoking behaviors.

Glucosamine Use, Inflammation, and Genetic Susceptibility, and Incidence of Type 2 Diabetes: A Prospective Study in UK Biobank.

OBJECTIVE: Glucosamine is a widely used supplement typically taken for osteoarthritis and joint pain. Emerging evidence suggests potential links of glucosamine with glucose metabolism, inflammation, and cardiometabolic risk. We prospectively analyzed the association of habitual glucosamine use with risk of type 2 diabetes (T2D) and assessed whether genetic susceptibility and inflammation status might modify the association. RESEARCH DESIGN AND METHODS: This study analyzed 404,508 participants from the UK Biobank who were free of diabetes, cancer, or cardiovascular disease at baseline and completed the questionnaire on supplement use. Cox proportional hazards models were used to evaluate the association between habitual use of glucosamine and risk of incident T2D. RESULTS: During a median of 8.1 years of follow-up, 7,228 incident cases of T2D were documented. Glucosamine use was associated with a significantly lower risk of T2D (hazard ratio 0.83, 95% CI 0.78-0.89) after adjustment for age, sex, BMI, race, center, Townsend deprivation index, lifestyle factors, history of disease, and other supplement use. This inverse association was more pronounced in participants with a higher blood level of baseline C-reactive protein than in those with a lower level of this inflammation marker (P-interaction = 0.02). A genetic risk score for T2D did not modify this association (P-interaction = 0.99). CONCLUSIONS: Our findings indicate that glucosamine use is associated with a lower risk of incident T2D.

Chemerin-induced macrophages pyroptosis in fetal brain tissue leads to cognitive disorder in offspring of diabetic dams.

BACKGROUND: Chemerin is highly expressed in the serum, placenta tissue, and umbilical cord blood of diabetic mother; however, the impact of chemerin on cognitive disorders of offspring from mothers with diabetes in pregnancy remains unclear. METHODS: A diabetic phenotype in pregnant mice dams was induced by streptozocin (STZ) injection or intraperitoneal injection of chemerin. Behavioral changes in offspring of diabetic dams and nondiabetic controls were assessed, and changes in chemerin, two receptors of chemerin [chemerin receptor 23 (ChemR23) and chemokine (C-C motif) receptor-like 2 (CCRL2)], macrophages, and neurons in the brain tissue were studied to reveal the underlying mechanism of the behavioral changes. RESULTS: Chemerin treatment mimicked the STZ-induced symptom of maternal diabetes in mice along with the altered behavior of offspring in the open field test (OFT) assay. In the exploring process for potential mechanism, the brain tissues of offspring from chemerin-treated dams were observed with an increase level of macrophage infiltration and a decrease number of neuron cells. Moreover, an increased level of NOD-like receptor family pyrin domain containing 3 (NLRP3) and apoptosis-associated speck-like (Asc) protein as well as pyroptosis [characterized by increased active caspase-1 content and secretion of cytokines such as interleukin (IL) 1 beta (IL-1ß) and IL-18] more activated in macrophages is also observed in the brain of these diabetic dam's offspring, in the presence of ChemR23. In vitro, it was found that pyroptosis activation was increased in macrophages separated from the abdominal cavity of normal mice, after chemerin treatment. However, depletion of CCRL2 decreased the level of chemerin in the brain tissues of diabetic dams' offspring; depletion of ChemR23 decreased macrophage pyroptosis, and depletion of either receptor reversed chemerin-mediated neurodevelopmental deficits and cognitive impairment of offspring of diabetic pregnant dams. CONCLUSIONS: Chemerin induced diabetic pregnant disease and CCRL2 were required to enrich chemerin in the brain of offspring. Aggregation of chemerin could lead to macrophage recruitment, activation of pyroptosis, the release of inflammatory cytokines, a decrease in the number of neurons, and cognitive impairment in offspring in a ChemR23-dependent manner. Targeting CCRL2 and/or ChemR23 could be useful for treating neuropsychological deficits in offspring of dams with diabetes in pregnancy.

Lifestyle intervention modifies the effect of the MC4R genotype on changes in insulin resistance among women with prior gestational diabetes: Tianjin Gestational Diabetes Mellitus Prevention Program.

BACKGROUND: A history of gestational diabetes mellitus (GDM) has been related to an elevated risk of type 2 diabetes. The melanocortin-4 receptor (MC4R) genotype has been related to glycemic changes in women with prior GDM. OBJECTIVE: The objective of this study was to analyze whether lifestyle intervention modified the association between the MC4R genotype and changes in insulin sensitivity among women with prior GDM. METHODS: We genotyped MC4R rs6567160 and measured glucose and insulin in fasting plasma samples at baseline and during the first 2 follow-up visits in 1128 women with prior GDM. They were randomly assigned to either a 4-y lifestyle intervention involving both diet and physical activity or a control group from a randomized clinical trial, the Tianjin Gestational Diabetes Mellitus Prevention Program. We analyzed the interaction between the MC4R genotype and lifestyle intervention on changes in insulin resistance. RESULTS: From baseline to 1.28 y, the MC4R genotype was related to changes in fasting insulin, HOMA-IR, and homeostasis model assessment of ß cell function (HOMA-B) in the intervention group. Each risk allele (C) of rs6567160 was associated with a 0.08-unit greater decrease in log(insulin), log(HOMA-IR), and log(HOMA-B) (P = 0.02, 0.04, and 0.04, respectively), whereas in the control group, each C allele tended to be associated with a greater increase in HOMA-IR (P = 0.09). We found significant interactions between the MC4R genotype and lifestyle intervention on 1.28-y changes in fasting insulin and HOMA-IR (P = 0.006 and 0.008, respectively), and such interaction remained significant when we analyzed the trajectory of changes in insulin and HOMA-IR from baseline to 2.55 y (both P = 0.03). CONCLUSIONS: The exploratory results from the first 2 follow-up visits indicate that women with prior GDM carrying a diabetes-increasing MC4R genotype (CC or TC) may obtain better improvement than the TT genotype in insulin resistance through lifestyle intervention. This trial was registered at clinicaltrials.gov as NCT01554358.

Reproductive outcome following resectoscope metroplasty in women having a complete uterine septum with double cervix and vagina.

OBJECTIVE: To evaluate reproductive outcomes in women with complete uterine septum with double cervix and vagina following resectoscope metroplasty. METHODS: The pregnancy outcomes of 21 women who underwent vaginal and uterine septum resection were compared with those of 15 untreated women with similar clinical characteristics. The Fisher exact test and the Mann-Whitney test were used for statistical analysis. RESULTS: Cycle fecundity was better (33.4%+/-28.5% vs 12.2%+/-4.7%; P=0.046), the rate of term delivery significantly increased (P<0.05), and the rate of spontaneous abortion decreased (P<0.05) in the treatment group. CONCLUSION: Resectoscope metroplasty was found to improve the pregnancy outcomes of women having primary infertility or a history of pregnancy loss associated with a complete uterine septum with double cervix and vagina.

[Development of HPV16 positive cervical cancer model in the hu-PBL-SCID mouse and its immunological features].

OBJECTIVE: To develop a HPV16 positive cervical cancer model in the hu-PBL-SCID mouse and investigate its immunological features. METHODS: Thirty-two CB17SCID mice were randomly divided into 4 groups: group A (5 mice) subcutaneously injected with phosphate-buffered saline, group B (5 mice) intraperitoneally injected with human peripheral blood lymphocyte (PBL) for immune reconstruction, group C (11 mice) subcutaneously injected with human cervical carcinoma cell line SiHa, and group D (11 mice) intraperitoneally injected with PBL and subcutaneously injected with SiHa cells after 24 hours of PBL transplantation. The tumor growth, behaviors and status of xenogeneic graft versus host disease (XGVHD) were observed. Human immunoglobulins G (IgG) in mouse serum, the percentage of human CD3(+), CD4(+) and CD8(+) T cells in peripheral blood and spleen, spleen weight, tumor infiltrating lymphocytes and human CD4(+) T cells, and cytotoxicity test of spleen cells were detected. RESULTS: The rate of successful tumor transplantation was 100%. XGVHD was not found. On the 5th day, human IgG level in the group B (0.98 microg/ml +/- 0.20 microg/ml) and group D (1.39 microg/ml +/- 0.25 microg/ml) was significantly higher than that in the group A (t = 7.655, 9.937, both P = 0.000). Human IgG level in group D was significantly higher than that in the group B (t = 3.200, P = 0.006). Only very low levels of human serumal IgG were detected in the group C and group A with no significantly difference. The level of human serumal IgG was gradually elevated in all the humanized SCID mice as the the time after PBL transplantation went on, and was significantly higher than that in non-humanized mice (P < 0.05). The percentage of human CD3(+), CD4(+) and CD8(+) T cells was significantly increased in the peripheral blood and spleen of immunoreconstituted SCID mice. The weight of spleen was markedly increased in the group D. TIL infiltrating in the tumor were remarkable and human CD4(+) T cells was detected by immunohistochemistry in the group D but not in the group C. The spleen cells in the group D displayed stronger cytotoxicity to the target cells (P < 0.05). CONCLUSION: Human immune function can be successfully reconstructed in SCID mouse via intraperitoneally injecting with human PBL, and induce anti-tumor immune response to the transplantated tumor of HPV16 positive cervical cancer.