Gestational age-specific reference intervals for androgens in pregnancy.

BACKGROUND: Androgen could impact cervical remodelling during pregnancy, and a higher level is associated with adverse pregnancy outcomes. A population-based gestation age-specific reference interval (RI) of total testosterone (TT), androstenedione (A4), and 17-hydroxyprogesterone (17-OHP) can help to diagnose maternal hyperandrogenism. METHODS: We enrolled 600 healthy Chinese women to obtain longitudinal serum samples across gestation. The serum androgen profile was measured by liquid chromatography-tandem mass spectrometry. The equations for medians of TT, A4, and 17-OHP were generated by MedCal, and the variances adjusted for 2-level modeling were generated by MLwiN, a system for the specification and analysis of a range of multilevel models. RESULTS: A4 and TT levels increased across the gestation, and they closely correlated with each other (R = 0.90, P=<0.001), whereas 17-OHP level decreased from 5th gestational week to 16th gestational week and then increased afterward towards the end of pregnancy. Women diagnosed with preeclampsia (PE) were found to have a significantly higher level of A4, TT, and 17-OHP when compared with non-PE cases with p ≤0.01, whereas mothers carrying male versus female fetuses have comparable levels of A4, TT, and 17-OHP. CONCLUSION: The study highlights a methodology for constructing gestational age-specific TT, A4, and 17-OHP levels to provide a better interpretation of results in a cohort of healthy Chinese women. The observation in PE supports previous findings, and the higher levels of TT, A4, and 17-OHP were observed before the onset of PE.

Precision Medicine to Redefine Insulin Secretion and Monogenic Diabetes-Randomized Controlled Trial (PRISM-RCT) in Chinese patients with young-onset diabetes: design, methods and baseline characteristics.

INTRODUCTION: We designed and implemented a patient-centered, data-driven, holistic care model with evaluation of its impacts on clinical outcomes in patients with young-onset type 2 diabetes (T2D) for which there is a lack of evidence-based practice guidelines. RESEARCH DESIGN AND METHODS: In this 3-year Precision Medicine to Redefine Insulin Secretion and Monogenic Diabetes-Randomized Controlled Trial, we evaluate the effects of a multicomponent care model integrating use of information and communication technology (Joint Asia Diabetes Evaluation (JADE) platform), biogenetic markers and patient-reported outcome measures in patients with T2D diagnosed at ≤40 years of age and aged ≤50 years. The JADE-PRISM group received 1 year of specialist-led team-based management using treatment algorithms guided by biogenetic markers (genome-wide single-nucleotide polymorphism arrays, exome-sequencing of 34 monogenic diabetes genes, C-peptide, autoantibodies) to achieve multiple treatment goals (glycated hemoglobin (HbA1c) <6.2%, blood pressure <120/75 mm Hg, low-density lipoprotein-cholesterol <1.2 mmol/L, waist circumference <80 cm (women) or <85 cm (men)) in a diabetes center setting versus usual care (JADE-only). The primary outcome is incidence of all diabetes-related complications. RESULTS: In 2020-2021, 884 patients (56.6% men, median (IQR) diabetes duration: 7 (3-12) years, current/ex-smokers: 32.5%, body mass index: 28.40±5.77 kg/m2, HbA1c: 7.52%±1.66%, insulin-treated: 27.7%) were assigned to JADE-only (n=443) or JADE-PRISM group (n=441). The profiles of the whole group included positive family history (74.7%), general obesity (51.4%), central obesity (79.2%), hypertension (66.7%), dyslipidemia (76.4%), albuminuria (35.4%), estimated glomerular filtration rate <60 mL/min/1.73 m2 (4.0%), retinopathy (13.8%), atherosclerotic cardiovascular disease (5.2%), cancer (3.1%), emotional distress (26%-38%) and suboptimal adherence (54%) with 5-item EuroQol for Quality of Life index of 0.88 (0.87-0.96). Overall, 13.7% attained ≥3 metabolic targets defined in secondary outcomes. In the JADE-PRISM group, 4.5% had pathogenic/likely pathogenic variants of monogenic diabetes genes; 5% had autoantibodies and 8.4% had fasting C-peptide <0.2 nmol/L. Other significant events included low/large birth weight (33.4%), childhood obesity (50.7%), mental illness (10.3%) and previous suicide attempts (3.6%). Among the women, 17.3% had polycystic ovary syndrome, 44.8% required insulin treatment during pregnancy and 17.3% experienced adverse pregnancy outcomes. CONCLUSIONS: Young-onset diabetes is characterized by complex etiologies with comorbidities including mental illness and lifecourse events. TRIAL REGISTRATION NUMBER: NCT04049149.

One-hour post-load plasma glucose level predicts future type 2 diabetes in a community-based study of Hong Kong Chinese workforce.

BACKGROUND: We compared performance of high 1-hour PG level, impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) in predicting type 2 diabetes in a longitudinal community-based cohort of Hong Kong Chinese. METHODS: Between 2001 and 2003, 472 adults aged 18-55 years without diabetes underwent 75-gram oral glucose tolerance test (OGTT). Between 2012 and 2014, progression to diabetes was ascertained by reviewing medical records or repeating OGTT and HbA1c. We defined high 1-hour PG as PG ≥ 8.6 mmol/L at 1-hour. RESULTS: In this cohort, 23.5% had normal glucose tolerance and high 1-hour PG, 10.0% had isolated IGT, 4.2% had isolated IFG. Over 12-year follow-up, 9.3% developed type 2 diabetes. In logistic regression, high 1-hour PG was associated with progression to type 2 diabetes with adjusted odds ratio (95% CI) of 4.20 (1.60, 12.40), independent of IFG, IGT and other clinical variables. Areas under ROC (95% CI) for type 2 diabetes were similar between 1-hour (0.84 [0.78, 0.89], 2-hour (0.79 [0.72, 0.86]) and fasting PG (0.79 [0.71, 0.86]). CONCLUSION: High 1-hour PG identified young Chinese with 5-fold increased risk of type 2 diabetes independent of other intermediate hyperglycaemia status and clinical factors. 1-hour PG is similar to fasting and 2-hour PG in predicting type 2 diabetes.

Enhanced prediction of abnormal glucose tolerance using an extended non-invasive risk score incorporating routine renal biochemistry.

INTRODUCTION: Type 2 diabetes is preventable in subjects with impaired glucose tolerance based on 2-hour plasma glucose (2hPG) during 75 g oral glucose tolerance test (OGTT). We incorporated routine biochemistry to improve the performance of a non-invasive diabetes risk score to identify individuals with abnormal glucose tolerance (AGT) defined by 2hPG≥7.8 mmol/L during OGTT. RESEARCH DESIGN AND METHODS: We used baseline data of 1938 individuals from the community-based "Better Health for Better Hong Kong - Hong Kong Family Diabetes Study (BHBHK-HKFDS) Cohort" recruited in 1998-2003. We incorporated routine biochemistry in a validated non-invasive diabetes risk score, and evaluated its performance using area under receiver operating characteristics (AUROC) with internal and external validation. RESULTS: The AUROC of the original non-invasive risk score to predict AGT was 0.698 (95% CI, 0.662 to 0.733). Following additional inclusion of fasting plasma glucose, serum potassium, creatinine, and urea, the AUROC increased to 0.778 (95% CI, 0.744 to 0.809, p<0.001). Net reclassification improved by 31.9% (p<0.001) overall, by 30.8% among people with AGT and 1.1% among people without AGT. The extended model showed good calibration (χ2=11.315, p=0.1845) and performance on external validation using an independent data set (AUROC=0.722, 95% CI, 0.680 to 0.764). CONCLUSIONS: The extended risk score incorporating clinical and routine biochemistry can be integrated into an electronic health records system to select high-risk subjects for evaluation of AGT using OGTT for prevention of diabetes.

The Association of Prenatal Vitamin D Status With Pregnancy and Neonatal Outcomes.

Context: Vitamin D inadequacy is globally prevalent among pregnant women; however, its impact on pregnancy remains inconclusive. Objective: This study aims to explore the associations of maternal and umbilical cord serum 25-hydroxyvitamin D (25(OH)D) levels with pregnancy and neonatal outcomes. Method: We used archived serum samples from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study participants in the Hong Kong center and assayed maternal 25(OH)D levels at midgestation and umbilical cord 25(OH)D at birth using liquid chromatography-tandem mass spectroscopy. Data regarding pregnancy and perinatal outcomes were extracted from the HAPO study dataset and the hospital computerized medical system. Results: Only 247 (16.4%) mothers and 66 (5.0%) neonates met the criteria for vitamin D sufficiency (ie, 25(OH)D ≥ 75 nmol/L). The ratio of umbilical cord to maternal vitamin D levels was positively associated with maternal age and ambient solar radiation at the month of delivery, while negatively associated with maternal serum total 25(OH)D at midgestation (all P < .001). Umbilical cord serum 25(OH)D was independently associated with a lower primary cesarean section rate (OR 0.990, 95% CI 0.982-0.999; P = .032). There were no associations of maternal and umbilical cord 25(OH)D levels with other adverse pregnancy and neonatal outcomes. Conclusion: Placental vitamin D transfer was found to be higher with a lower maternal vitamin D level, older maternal age, and higher ambient solar radiation at the time of the delivery. The protective effect of sufficient vitamin D in a cesarean section will require further studies.

Understanding diabetes heterogeneity: key steps towards precision medicine in diabetes.

Diabetes is a highly heterogeneous condition; yet, it is diagnosed by measuring a single blood-borne metabolite, glucose, irrespective of aetiology. Although pragmatically helpful, disease classification can become complex and limit advances in research and medical care. Here, we describe diabetes heterogeneity, highlighting recent approaches that could facilitate management by integrating three disease models across all forms of diabetes, namely, the palette model, the threshold model and the gradient model. Once diabetes has developed, further worsening of established diabetes and the subsequent emergence of diabetes complications are kept in check by multiple processes designed to prevent or circumvent metabolic dysfunction. The impact of any given disease risk factor will vary from person-to-person depending on their background, diabetes-related propensity, and environmental exposures. Defining the consequent heterogeneity within diabetes through precision medicine, both in terms of diabetes risk and risk of complications, could improve health outcomes today and shine a light on avenues for novel therapy in the future.

Association of insomnia with incident chronic cognitive impairment in older adults with type 2 diabetes mellitus: A prospective study of the Hong Kong Diabetes Register.

AIMS: To examine the risk association of insomnia with incident chronic cognitive impairment in older adults with type 2 diabetes mellitus (T2D). METHODS: Between July 2010 and June 2015, patients with T2D aged ≥60 years enrolled in the Hong Kong Diabetes Register completed the Insomnia Severity Index (ISI) questionnaire. Patients were considered having insomnia if they had ISI score > 14. We prospectively followed up the cohort and censored outcome through reviewing diagnoses and clinical notes entered by attending physicians in electronic medical record to identify incident cases of mild cognitive impairment and dementia. RESULTS: After excluding shift workers and those with established chronic cognitive impairment at baseline, we included 986 patients with T2D in this study (58.3 % men, mean age ± standard deviation: 62.5 ± 2.6 years, disease duration of diabetes: 10.7 ± 8.2 years, HbA1c: 7.4 ± 1.3 %, insulin users: 28.7 %, insomnia: 9.1 %). After a median follow-up of 7.6 (interquartile range = 2.0) years, 41 (4.2 %) developed chronic cognitive impairment. Using Cox regression analysis, insomnia (hazard ratio, HR 2.909, p = 0.012) and HbA1c ≥ 7 % (HR 2.300, p = 0.038) were positively associated with incident chronic cognitive impairment while insulin use (HR 0.309, p = 0.028) showed negative association. CONCLUSIONS: Insomnia, suboptimal glycemic control and non-insulin use are independent risk factors for incident chronic cognitive impairment in older adults with T2D.

Advanced liver fibrosis predicts heart failure and hospitalizations in people with type 2 diabetes: A prospective cohort study from Hong Kong Diabetes Register.

AIMS: We aimed to examine the impact of non-alcoholic fatty liver disease (NAFLD) on the clinical outcomes in patients with type 2 diabetes (T2D). METHODS: Between 2013 and 2014, 1,734 patients with T2D underwent transient elastography (TE) to assess liver status indicated by controlled attenuation parameter (CAP) and liver stiffness measurement (LSM). Liver steatosis was defined by CAP ≥ 248 dB/m and advanced liver fibrosis by LSM ≥ 10 kPa. In 2019, we assessed their clinical outcomes including hospitalizations and mortality. RESULTS: In this prospective cohort [56% men, mean (±standard deviation) age:60.8±11.5 years; glycated hemoglobin (HbA1c)7.8±1.6 %], 798 patients had liver steatosis, 296 patients had advanced liver fibrosis and 640 patients had normal liver at baseline. T2D with advanced liver fibrosis had higher body mass index, waist circumference, waist-hip ratio, fasting plasma glucose, HbA1c, blood pressure and lipid profiles than their counterparts with NAFLD or normal liver (all p < 0.05). After a median follow-up of 6.07 (interquartile range:5.84 to 6.30) years, there were 4,403 incident hospitalizations, 32,119 days of hospital stay, and 171 deaths. Using Cox regression analysis, advanced liver fibrosis was associated with increased risk of heart failure (hazard ratio [95% confidence interval] HR:3.07[1.08-8.68], p=0.035) and hospitalizations (HR:1.39[1.14-1.70], p=0.001) while liver steatosis was associated with reduced mortality (HR:0.60[0.41-0.87], p=0.007) compared to their counterparts with normal liver after adjustment for potential confounders. CONCLUSIONS: T2D comorbid with liver steatosis and advanced liver fibrosis are distinct clinical entities with differences in outcomes. Advanced liver fibrosis is an important predictor for worse outcomes including heart failure and hospitalizations in people with T2D.

The global burden of metabolic disease: Data from 2000 to 2019.

Global estimates of prevalence, deaths, and disability-adjusted life years (DALYs) from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019 were examined for metabolic diseases (type 2 diabetes mellitus [T2DM], hypertension, and non-alcoholic fatty liver disease [NAFLD]). For metabolic risk factors (hyperlipidemia and obesity), estimates were limited to mortality and DALYs. From 2000 to 2019, prevalence rates increased for all metabolic diseases, with the greatest increase in high socio-demographic index (SDI) countries. Mortality rates decreased over time in hyperlipidemia, hypertension, and NAFLD, but not in T2DM and obesity. The highest mortality was found in the World Health Organization Eastern Mediterranean region, and low to low-middle SDI countries. The global prevalence of metabolic diseases has risen over the past two decades regardless of SDI. Urgent attention is needed to address the unchanging mortality rates attributed to metabolic disease and the entrenched sex-regional-socioeconomic disparities in mortality.

SOX4 is a novel phenotypic regulator of endothelial cells in atherosclerosis revealed by single-cell analysis.

INTRODUCTION: Atherosclerotic complications represent the leading cause of cardiovascular mortality globally. Dysfunction of endothelial cells (ECs) often initiates the pathological events in atherosclerosis. OBJECTIVES: In this study, we sought to investigate the transcriptional profile of atherosclerotic aortae, identify novel regulator in dysfunctional ECs and hence provide mechanistic insights into atherosclerotic progression. METHODS: We applied single-cell RNA sequencing (scRNA-seq) on aortic cells from Western diet-fed apolipoprotein E-deficient (ApoE-/-) mice to explore the transcriptional landscape and heterogeneity of dysfunctional ECs. In vivo validation of SOX4 upregulation in ECs were performed in atherosclerotic tissues, including mouse aortic tissues, human coronary arteries, and human renal arteries. Single-cell analysis on human aortic aneurysmal tissue was also performed. Downstream vascular abnormalities induced by EC-specific SOX4 overexpression, and upstream modulators of SOX4 were revealed by biochemical assays, immunostaining, and wire myography. Effects of shear stress on endothelial SOX4 expression was investigated by in vitro hemodynamic study. RESULTS: Among the compendium of aortic cells, mesenchymal markers in ECs were significantly enriched. Two EC subsets were subsequently distinguished, as the 'endothelial-like' and 'mesenchymal-like' subsets. Conventional assays consistently identified SOX4 as a novel atherosclerotic marker in mouse and different human arteries, additional to a cancer marker. EC-specific SOX4 overexpression promoted atherogenesis and endothelial-to-mesenchymal transition (EndoMT). Importantly, hyperlipidemia-associated cytokines and oscillatory blood flow upregulated, whereas the anti-diabetic drug metformin pharmacologically suppressed SOX4 level in ECs. CONCLUSION: Our study unravels SOX4 as a novel phenotypic regulator during endothelial dysfunction, which exacerbates atherogenesis. Our study also pinpoints hyperlipidemia-associated cytokines and oscillatory blood flow as endogenous SOX4 inducers, providing more therapeutic insights against atherosclerotic diseases.

GCK-MODY in pregnancy: A pregnant woman with diabetes and a small-for-gestational-age fetus.

Glucokinase-maturity-onset diabetes of the young (GCK-MODY) is often misdiagnosed as other forms of diabetes. A 42-year-old pregnant lady with pre-existing diabetes was treated with insulin during first trimester. Fetal growth restriction was noted since mid-second trimester. Genetic testing suggested the diagnosis of GCK-MODY.

The roles of newborn anthropometrics in the association between maternal weight gain and childhood cardiovascular risks.

OBJECTIVE: The aim was to study the association between newborn anthropometrics and childhood cardiovascular risks and whether newborn anthropometrics mediate the effect of maternal gestational weight gain (GWG) on childhood risks. METHODS: Data of 926 mother-child dyads from the Hyperglycemia and Adverse Pregnancy Outcomes study were analyzed. Newborn anthropometrics were treated as predictors and mediators by using a regression model and causal mediation model, respectively. RESULTS: Newborn sum of skinfolds (SSF) was associated with childhood diastolic blood pressure (DBP) and pulse wave velocity (coefficients [95% CI]: 0.13 [0.06 to 0.20]; 0.08 [0.004 to 0.15]), whereas newborn ponderal index (PI) was inversely associated with childhood systolic blood pressure (SBP), DBP, and pulse wave velocity (-0.08 [-0.15 to -0.01]; -0.08 [-0.14 to -0.008]; -0.09 [-0.16 to -0.03]). Newborn SSF mediated the effects of maternal excessive GWG on childhood SSF and DBP (proportion of total effect 9% and 8%, respectively). In contrast, a significant negative mediation through newborn PI was found for the effect of maternal excessive GWG on childhood DBP (-8%) and its effect on childhood SBP through birth weight (-27%). CONCLUSIONS: Childhood cardiovascular risks are positively associated with newborn SSF but inversely associated with newborn PI. Newborn SSF mediates the impact of excessive maternal GWG on childhood BP, but birth weight and newborn PI negatively mediate it.

Dietary patterns of Chinese pregnant women in Hong Kong.

BACKGROUND AND OBJECTIVES: Maternal nutrition is important for healthy pregnancy, but it has not been well studied among pregnant women in Hong Kong. This study aims to examine the dietary pattern and nutritional intake of women in early pregnancy, and the associations between dietary patterns, dietary quality, and other health parameters. METHODS AND STUDY DESIGN: This is a prospective cohort study of healthy Chinese pregnant women, recruited at their first antenatal appointment. Dietary intakes were assessed by a locally validated food frequency questionnaire (FFQ) and dietary patterns were derived by principal component analysis. RESULTS: Of 160 women recruited, the mean age was 32.7±3.9 years and body mass index (BMI) before pregnancy was 22.6±3.8 kg/m2. The dietary analyses were restricted to 156 women who had completed the FFQ. 99% of women had excessive sodium intake and only 2.6% of women met the recommended fibre intake. Three dietary patterns identified were 'sweet and fast-food pattern', 'prudent pattern' and 'meat pattern', which altogether accounted for 23.5% of the total variation. The 'prudent pattern' was positively associated with dietary quality indices [Dietary Approaches to Stop Hypertension score, ρ=0.323, p<0.01; Dietary Quality Index-International, ρ=0.400, p<0.01; Mediterranean Diet Score, ρ=0.243, p=0.02]; and was inversely associated systolic (B=-3.71, 95% CI -7.06, -0.36) and diastolic blood pressure (B=-2.69, 95% CI -5.12, -0.26), suggesting this pattern represented a relatively healthier dietary option. CONCLUSIONS: Suboptimal dietary intake is a common issue among pregnant women in Hong Kong. Early dietary assessment and attention are warranted in this population.

Effects of RAS inhibitors on all-site cancers and mortality in the Hong Kong diabetes surveillance database (2002-2019).

BACKGROUND: Cancer is replacing cardiovascular-disease as a leading cause of death in type 2 diabetes (T2D). The association of RAS-inhibitors (RASi) and cancer, including differences between angiotensin-converting-enzyme-inhibitor (ACEi) and angiotensin-receptor-blocker (ARBs) as well as their associations independent of blood pressure lowering, remains inconclusive in T2D. METHODS: We conducted a cohort study with new-user design in 253,491 patients in the Hong-Kong-Diabetes-Surveillance-Database (HKDSD) in 2002-2019. We evaluated the associations of time-varying RASi use (ACEi and ARBs) with all-site cancer, diabetes-related cancers, and cancer-specific mortality including comparison with new-users of calcium-channel-blockers (CCBs) as an active-comparator group. FINDINGS: Of 253,491, 133,730 (52.8%) were new-RASi and 119,761 (47.2%) were non-RASi users with a median follow-up period of 6.3 (interquartile ragne: 3.4-9.2) years (1,678,719 patient-years). After propensity-score weighting and adjustment for time-varying covariables, RASi use was associated with lower risk of all-site cancer (HR=0.76, 95%CI: 0.74-0.79), diabetes-related cancer (HR=0.79, 95%CI: 0.75-0.84), cancer-specific mortality (HR=0.50, 95%CI: 0.47-0.53), and diabetes-related cancer mortality (HR=0.49, 95%CI: 0.45-0.54) versus non-RASi. Amongst RASi users, ARBs use was associated with lower risk of cancer-specific mortality versus ACEi (HR=0.77, 95%CI: 0.66-0.91). Use of RASi was associated with an estimated-prevention of 2.6 (95%CI: 2.3-3.0) all-site cancer per-1000-person-years and 2.2 (95%CI: 2.0-2.5) cancer-related mortality per-1000-person-years. Lower risk of cancer-specific mortality was similarly observed in new-RASi compared with new-CCBs users. INTERPRETATION: RASi use was independently associated with lower cancer risk in T2D with stronger associations in users of ARBs than ACEi. The benefits of RASi in patients with diabetes might go beyond cardiovascular-renal protection if confirmed by other real-world studies and trials. FUNDING: Dr. Aimin Yang was supported by a CUHK Impact-Research-Fellowship Scheme.

Endothelial UCP2 Is a Mechanosensitive Suppressor of Atherosclerosis.

BACKGROUND: Inflamed endothelial cells (ECs) trigger atherogenesis, especially at arterial regions experiencing disturbed blood flow. UCP2 (Uncoupling protein 2), a key mitochondrial antioxidant protein, improves endothelium-dependent relaxation in obese mice. However, whether UCP2 can be regulated by shear flow is unknown, and the role of endothelial UCP2 in regulating inflammation and atherosclerosis remains unclear. This study aims to investigate the mechanoregulation of UCP2 expression in ECs and the effect of UCP2 on endothelial inflammation and atherogenesis. METHODS: In vitro shear stress simulation system was used to investigate the regulation of UCP2 expression by shear flow. EC-specific Ucp2 knockout mice were used to investigate the role of UCP2 in flow-associated atherosclerosis. RESULTS: Shear stress experiments showed that KLF2 (Krüppel-like factor 2) mediates fluid shear stress-dependent regulation of UCP2 expression in human aortic and human umbilical vein ECs. Unidirectional shear stress, statins, and resveratrol upregulate whereas oscillatory shear stress and proinflammatory stimuli inhibit UCP2 expression through altered KLF2 expression. KLF2 directly binds to UCP2 promoter to upregulate its transcription in human umbilical vein ECs. UCP2 knockdown induced expression of genes involved in proinflammatory and profibrotic signaling, resulting in a proatherogenic endothelial phenotype. EC-specific Ucp2 deletion promotes atherogenesis and collagen production. Additionally, we found endothelial Ucp2 deficiency aggravates whereas adeno-associated virus-mediated EC-Ucp2 overexpression inhibits carotid atherosclerotic plaque formation in disturbed flow-enhanced atherosclerosis mouse model. RNA-sequencing analysis revealed FoxO1 (forkhead box protein O1) as the major proinflammatory transcriptional regulator activated by UCP2 knockdown, and FoxO1 inhibition reduced vascular inflammation and disturbed flow-enhanced atherosclerosis. We showed further that UCP2 level is critical for phosphorylation of AMPK (AMP-activated protein kinase), which is required for UCP2-induced inhibition of FoxO1. CONCLUSIONS: Altogether, our studies uncover that UCP2 is novel mechanosensitive gene under the control of fluid shear stress and KLF2 in ECs. UCP2 expression is critical for endothelial proinflammatory response and atherogenesis. Therapeutic strategies enhancing UCP2 level may have therapeutic potential against atherosclerosis.

Comparing IADPSG and NICE Diagnostic Criteria for GDM in Predicting Adverse Pregnancy Outcomes.

OBJECTIVE: To compare the performance of diagnostic criteria for gestational diabetes mellitus (GDM) proposed by the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) with those endorsed by the National Institute for Health and Care Excellence (NICE) in predicting adverse pregnancy outcomes. RESEARCH DESIGN AND METHODS: We performed a secondary data analysis of the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study participants in five study centers. Logistic regression analyses were performed, and Akaike information criterion were applied for the comparison of different statistical prediction models. We further analyzed the performance by four racial/ethnic subgroups, namely, Whites, Hispanics, Asians, and Blacks. RESULTS: Among all, IADPSG criteria diagnosed 267 (4.1%) more women with GDM, but predicted primary caesarean section (CS) and large for gestational age (LGA) and neonatal adiposity better than did NICE criteria after adjustment for potential confounders. Among Whites, IADPSG criteria diagnosed 65 (2.5%) more subjects with GDM and predicted LGA and neonatal adiposity better, but predicted hypertensive disorders, primary CS and clinical neonatal hypoglycemia worse. Among Hispanics, the IADPSG criteria diagnosed 203 (12.1%) more with GDM but performed better in predicting hypertensive disorders, LGA, neonatal adiposity, and hyperinsulinemia. Among Asians, the IADPSG criteria diagnosed 34 (2.0%) fewer subjects with GDM but predicted hypertensive disorders better in the unadjusted model. In Blacks, IADPSG criteria diagnosed 34 (10.5%) more women with GDM. CONCLUSIONS: IADPSG criteria appear to be more favorable than NICE for identification of adverse pregnancy outcomes among Hispanic and Asian women, while they are comparable to NICE among White women.

A randomized clinical trial of genetic testing and personalized risk counselling in patients with type 2 diabetes receiving integrated care -The genetic testing and patient empowerment (GEM) trial.

AIMS: We evaluated the effect of personalized risk counseling incorporating clinical and genetic risk factors on patient empowerment and risk factor control in diabetes. METHODS: Patients with type 2 diabetes (T2D) with suboptimal glycaemic control (HbA1c ≥ 7.5%) were randomized to a genetic counselling (GC) or control group. All patients underwent genetic testing for alleles at three loci associated with diabetic complications. The GC group received additional explanation of the joint associations of genetic and modifiable risk factors on risk of complications. All patients were reassessed at 12 months including validated questionnaires for patient reported outcomes. The primary outcome was proportion of patients reaching ≥ 3 of 5 predefined treatment targets (HbA1c < 7%, BP < 130/80 mmHg, LDL-C < 2.6 mmol/L, Triglyceride < 2.0 mmol/L, use of renin-angiotensin system inhibitors). Secondary outcomes included new-onset chronic kidney disease or microalbuminuria and patient reported outcome measures. RESULTS: A total of 435 patients were randomized and 420 patients were included in the modified intention-to-treat analysis. At 12 months, the proportion of patients who attained ≥ 3 targets increased from 41.6% to 52.3% in the GC group (p = 0.007) versus 49.5% to 62.6% in the control group (p = 0.003), without between-group difference. Both groups had similar reduction in HbA1c, LDL-C and increased use of medications. In per protocol analysis, the GC group had higher diabetes empowerment, with reduced diabetes distress. In the GC group, the greatest improvement in positive attitude and self-care activities was observed in the intermediate to high genetic risk score (GRS) groups. CONCLUSIONS: In patients with T2D receiving integrated care, additional counselling on genetic risk of complications did not further improve risk factor control, although the improvement in self-efficacy warrants long-term evaluation.

Endothelial PPARδ facilitates the post-ischemic vascular repair through interaction with HIF1α.

Rationale: Restoration of vascular perfusion in peripheral arterial disease involves a combination of neovessel formation and the functional restoration of vascular endothelium. Previous studies indicated that ligand-dependent PPARδ activation enhances angiogenesis. However, how PPARδ is triggered by hypoxia and its downstream effects during post-ischemic vascular repair was not well understood. Methods: We induced experimental hindlimb ischemia in endothelial cell selective Ppard knockout induced by Cdh5-Cre mediated deletion of floxed Ppard allele in mice and their wild type control and observed blood perfusion, capillary density, vascular relaxation, and vascular leakage. Results: Deletion of endothelial Ppard delayed perfusion recovery and tissue repair, accompanied by delayed post-ischemic angiogenesis, impaired restoration of vascular integrity, more vascular leakage and enhanced inflammatory responses. At the molecular level, hypoxia upregulated and activated PPARδ in endothelial cells, whereas PPARδ reciprocally stabilized HIF1α protein to prevent its ubiquitin-mediated degradation. PPARδ directly bound to the oxygen-dependent degradation domain of HIF1α at the ligand-dependent domain of PPARδ. Importantly, this HIF1α-PPARδ interaction was independent of PPARδ ligand. Adeno-associated virus mediated endothelium-targeted overexpression of stable HIF1α in vivo improved perfusion recovery, suppressed vascular inflammation, and enhanced vascular repair, to counteract with the effect of Ppard knockout after hindlimb ischemia in mice. Conclusions: In summary, hypoxia-induced, ligand-independent activation of PPARδ in ECs stabilizes HIF1α and serves as a critical regulator for HIF1α activation to facilitate the post-ischemic restoration of vascular homeostasis.

Quantitation of plasma angiotensin II in healthy Chinese subjects by a validated liquid chromatography tandem mass spectrometry method.

Quantitation of plasma angiotensin (Ang) II, the active mediator of the renin-angiotensin system, is challenging owing to its low physiological concentration. We report a validated liquid chromatography-mass spectrometry (LCMS) method to overcome this challenge. Ang II was extracted from EDTA plasma by an offline solid-phase extraction procedure with a Waters MAX µElution plate. LCMS quantitation was performed on the Waters TQS system, monitoring the 3+ ions of the peptide. The analytical performance of the LCMS method was validated. The stability of Ang II was studied with or without the presence of a protease inhibitor. Local reference intervals were established from 143 healthy normotensive subjects (57% female, 21-60 years old). The Ang II LCMS method had a measurable range of 3.3-700 pmol/L. The between-batch precision coefficient of variation was <7% over Ang II concentrations of 8.6-110 pmol/L. No significant matrix interference and carryover were observed. There was no significant difference in Ang II concentration in EDTA blood and plasma for at least 2h and 1 h at room temperature, respectively. Ang II was stable for at least 1 year when stored at -80°C, with or without the protease inhibitor. Age-dependent Ang II reference intervals were established: 4.4-17.7 pmol/L (21-30 years) and 3.9-12.8 pmol/L (31-60 years). The present LCMS method is suitable for quantitation of plasma Ang II to study the renin-angiotensin system.

Maternal and Neonatal 3-epi-25-hydroxyvitamin D Concentration and Factors Influencing Their Concentrations.

BACKGROUND: Little is known about the presence of 3-epi-25 hydroxyvitamin D in maternal and neonatal circulation, the extent of its contribution to total 25 hydroxyvitamin D, or factors influencing its levels. METHODS: A total of 1502 and 1321 archived maternal and umbilical cord serum samples from the Hyperglycemia and Adverse Pregnancy Outcome Study cohort from Hong Kong were assayed for 25(OH)D2, 25(OH)D3, and isomeric form of 25(OH)D3 (3-epi-25(OH)D3) by a liquid chromatography-tandem mass spectrometry method. RESULTS: Vitamin D deficiency (total serum 25(OH)D level < 50 nmol/L) and severe vitamin D deficiency (total serum 25(OH)D level < 25 nmol/L) occurred in 590 (39.3%) and 25 (1.7%) mothers, respectively. 3-epi-25(OH)D3 could be detected in 94.5% of maternal and 92.1% of neonatal umbilical sera, with the highest 3-epi-25(OH)D3 levels contributing to 19.9% and 15.3% of the maternal and umbilical cord sera 25(OH)D3 levels, respectively. Pregnancy with a male fetus, ambient solar radiation, and maternal glycemia and 25(OH)D3 levels were independent factors associated with maternal 3-epi-25(OH)D3 level. Advanced maternal age, multiparity, maternal gestational weight gain below the Institute of Medicine recommendation, maternal glycemic status, and earlier gestational age at delivery were significantly associated with higher umbilical cord serum 3-epi-25(OH)D3. CONCLUSIONS: 3-epi-25(OH)D3 accounted for a significant portion of total 25(OH)D in maternal and neonatal circulations. Further study is needed to determine the possible mechanism underlying this observation.