Using Hashimoto thyroiditis as gold standard to determine the upper limit value of thyroid stimulating hormone in a Chinese cohort.

BACKGROUND: Subclinical hypothyroidism, commonly caused by Hashimoto thyroiditis (HT), is a risk factor for cardiovascular diseases. This disorder is defined as merely having elevated serum thyroid stimulating hormone (TSH) levels. However, the upper limit of reference range for TSH is debated recently. This study was to determine the cutoff value for the upper normal limit of TSH in a cohort using the prevalence of Hashimoto thyroiditis as "gold" calibration standard. METHODS: The research population was medical staff of 2856 individuals who took part in health examination annually. Serum free triiodothyronine (FT3), free thyroxine (FT4), TSH, thyroid peroxidase antibody (TPAb), thyroglobulin antibody (TGAb) and other biochemistry parameters were tested. Meanwhile, thyroid ultrasound examination was performed. The diagnosis of HT was based on presence of thyroid antibodies (TPAb and TGAb) and abnormalities of thyroid ultrasound examination. We used two different methods to estimate the cutoff point of TSH based on the prevalence of HT. RESULTS: Joinpoint regression showed the prevalence of HT increased significantly at the ninth decile of TSH value corresponding to 2.9 mU/L. ROC curve showed a TSH cutoff value of 2.6 mU/L with the maximized sensitivity and specificity in identifying HT. Using the newly defined cutoff value of TSH can detect patients with hyperlipidemia more efficiently, which may indicate our approach to define the upper limit of TSH can make more sense from the clinical point of view. CONCLUSIONS: A significant increase in the prevalence of HT occurred among individuals with a TSH of 2.6-2.9 mU/L made it possible to determine the cutoff value of normal upper limit of TSH.

Neck circumference as a measure of neck fat and abdominal visceral fat in Chinese adults.

BACKGROUND: Visceral adipose tissue (VAT) is a unique pathogenic fatty deposit, in that it is closely correlated with risk of cardiovascular diseases. The present study is to investigate the usefulness of neck circumference (NC) to indicate VAT. METHODS: Participants aged 35 to 75 years who had taken abdomen and neck computer tomography (CT) examination were included in this study. Neck adipose tissue, abdominal VAT and subcutaneous adipose tissue (SAT) areas, as well as sagittal abdominal diameter (SAD) were measured by CT. Body anthropometrics and metabolic parameters including blood glucose, lipid profiles and blood pressure were also measured. RESULTS: A lower abdomen CT examination was carried out on a total of 177 patients (87 male and 90 female) with a mean age of 59 years. Of the 177 participants, 15 men and 15 women also took a neck CT examination. With a comparable age and BMI, neck adipose area was correlated with abdominal VAT area significantly in men (r = 0.57, p = 0.028) and women (r = 0.53, p = 0.041). NC is positively correlated with VAT both in men (r = 0.49, p < 0.001) and women (r = 0.25, p = 0.012). Meanwhile, SAD is the best predictor for visceral fat both in men (r = 0.83, p < 0.001) and women (r = 0.73, p < 0.001). Body mass index (BMI), waist circumference (WC), and waist to height ratio (WHtR) correlated significantly with VAT both in men and women (r = 0.68, 0.42, 0.46 in men and 0.50, 0.23, 0.39 in women, p < 0.001), while waist hip ratio (WHR) displayed the weakest least correlation in men (r = 0.32, p = 0.001) and no correlation in women (r = 0.08, p = 0.442). Additionally, BMI was more strongly correlated with VAT than NC in both sexes (both p < 0.01). CONCLUSION: Significant correlation between NC and VAT was present in Chinese men and women, which may be accounted by the fact that neck fat area is significantly correlated with abdominal VAT. Meanwhile, SAD is the best predictor for visceral fat in the Chinese population.

A high TSH level is associated with diabetic macular edema: a cross-sectional study of patients with type 2 diabetes mellitus.

Aims: In this study, we determined the association between thyroid-stimulating hormone (TSH) and diabetic macular edema (DME) by assessing the prevalence and risk factors for DME in type 2 diabetes mellitus (T2DM) patients with different thyroid dysfunctions. Methods: This was a retrospective cross-sectional study including 1003 euthyroid and 92 subclinical hypothyroidism (SCH) T2DM patients. DME status was detected by optical coherence tomography (OCT). The association between TSH and DME and the impact of TSH on DME were analyzed. Results: The DME prevalence was 28.3% in the SCH patients and 14.0% in the euthyroid population. The serum FT4 (P = 0.001) and FT3 (P < 0.001) levels were significantly higher in the non-DME group than in the DME group, and the TSH level (P < 0.001) was significantly lower. Four subgroups (G1-G4) were divided by TSH level, and the chi-square test indicated that even in the normal range, the TSH level was positively related to DME prevalence (P = 0.001). Subgroup data indicated that the association between TSH and DME detected by OCT (P = 0.001) was stronger than the correlation between TSH and diabetic retinopathy detected by digital retinal photographs (P = 0.027). The logistic regression model confirmed that elevated TSH was an independent risk factor for DME. The odds ratio was 1.53 (P = 0.02). Conclusions: A high TSH level was an independent risk factor for DME. More attention should be given to the TSH level in T2DM patients due to its relationship with diabetic complications.

Association of obesity with diabetic retinopathy in US adults with diabetes in a national survey.

OBJECTIVE: There is a lack of consensus on whether a high BMI increases the risk of diabetic retinopathy (DR). We aimed to investigate the association between BMI, overweight, obesity, and DR using the data of diabetes respondents in the 2015 US Behavioral Risk Factor Surveillance System survey. METHODS: Diabetes respondents aged over 18-year-old with complete information as well as undergone fundus examination in the past 2 years or had been diagnosed with DR were included. Weighted logistic regression analyses were used to identify the association of BMI with DR. RESULTS: Among the 21,647 diabetes respondents, 4588 respondents had DR with a weighted prevalence of 22.5%. The mean BMI of all diabetes respondents was 31.50 ± 6.95 kg/m2 with 18,498 (86.5%) overweight and 11,353 (54.6%) obese. The mean BMI of the DR group (31.83 ± 7.41 kg/m2) was significantly higher than that of the non-DR group (31.41 ± 6.81 kg/m2, P < 0.05). The proportion of obese respondents in the DR group was higher than the non-DR group (54.3%, P < 0.001). The weighted prevalence of DR was 0.8, 13.8, 29.7, and 55.7% for the emaciation group, the normal weight group, the overweight group, and the obesity group, respectively (P < 0.001). Weighted logistic regression analysis showed that both BMI (adjusted OR = 1.004, 95% CI 1.003-1.004) and obesity (adjusted OR = 1.051, 95% CI 1.048-1.055) were associated with DR after adjusting for the confounding variables. However, overweight was not significantly associated with DR. CONCLUSION: The prevalence of DR in the normal weight, overweight, and obesity groups increased gradually. Obesity, rather than overweight, was significantly associated with increased DR prevalence.

The effects of acarbose therapy on reductions of myocardial infarction and all-cause death in T2DM during 10-year multifactorial interventions (The Beijing Community Diabetes Study 24).

To investigate the potential benefits of acarbose therapy on cardiovascular events (CVD) in Type 2 diabetes (T2DM) in an urban community over 10-year follow-up. The study population of Beijing Community Diabetes Study (BCDS) were type 2 diabetes (T2DM) living in 21 communities in Beijing. All patients received comprehensive intervention in accordance with the Chinese guidelines for the prevention and treatment of diabetes. Professors in endocrinology from top tier hospitals regularly visited the communities for consultations, which was a feature of this study. A total of 1797 T2DM in BCDS study had complete screening data, including blood glucose, blood pressure, lipid profiles and acarbose continuous therapy. After 10-year follow-up, the risks of CVD outcomes were assessed according to whether patients had received acarbose therapy or not. All patients were followed-up to assess the long-term effects of the multifactorial interventions. At baseline, compared with the acarbose therapy free in T2DM, there was no significant difference in achieving the joint target control in patients with acarbose therapy. From the beginning of 8th year follow-up, the joint target control rate in patients with acarbose therapy was significantly higher than that of acarbose therapy free. During the 10-year follow-up, a total of 446 endpoint events occurred, including all-cause death, cardiovascular events, cerebrovascular events. The incidences of myocardial infarction (from the 4th year of follow-up) and all-cause death (from the 2nd year of follow-up) in patients who received acarbose therapy were significantly lower than that of acarbose therapy free respectively. In Cox multivariate analyses, there were significant differences in incidences of myocardial infarction and all-cause death between afore two groups during the 10-year follow-up, and the adjusted HRs were 0.50 and 0.52, respectively. After multifactorial interventions, T2DM with acarbose therapy revealed significant reductions of myocardial infarction and all-cause death. The long-term effects of with acarbose therapy on improving joint target control might be one of the main reasons of myocardial infarction and all-cause death reduction.Trial Registration: ChiCTR-TRC-13003978, ChiCTR-OOC-15006090.

Neck circumference and waist circumference associated with cardiovascular events in type 2 diabetes (Beijing Community Diabetes Study 23).

Obesity increases the risk of developing cardiovascular disease and other metabolic diseases. We intended to compare three different anthropometric indicators of obesity, in predicting the incidence of cardiovascular events in Chinese type 2 diabetes. Beijing Community Diabetes Study was a prospective multi-center study conducted in Beijing community health centers. Type 2 diabetes patients from fourteen community health centers were enrolled at baseline. The primary endpoint was cardiovascular events. The upper quartile of neck circumference (NC) was set as greater NC. A total of 3299 diabetes patients were enrolled. In which, 941 (28.52%) had cardiovascular disease at baseline. Logistic analysis showed that central obesity (waist circumference (WC) above 90 cm in men and 85 cm in women) and greater NC were all related to baseline cardiovascular disease (adjusted OR = 1.49, and 1.55). After 10-year follow-up, 340 (10.31%) had cardiovascular events. Compared with patients without cardiovascular events, those having cardiovascular events had higher BMI, larger WC and NC. Cox regression analysis showed that greater WC and NC were all associated with the occurrence of cardiovascular events (adjusted HR = 1.41, and 1.38). A higher NC and WC might increase the risk of cardiovascular events by about 40% in type 2 diabetes patients in Beijing communities.

Association between subclinical hypothyroidism and proliferative diabetic retinopathy in type 2 diabetic patients: a case-control study.

Subclinical hypothyroidism (SCH) is defined as an asymptomatic state characterized by normal serum levels of free thyroxine and elevated serum concentrations of thyrotropin (> 4.0 µU/ml). The association between SCH and type 2 diabetes has been well established. Proliferative diabetic retinopathy (PDR) that is characterized by neovascularization is a leading cause of visual loss in adults worldwide. However, whether SCH is related to PDR has not been studied. This study thus aimed to evaluate the relationship between SCH and PDR in type 2 diabetes. A total of 371 type 2 diabetic subjects were enrolled: 187 subjects with PDR and 184 subjects without diabetic retinopathy (with HbA1c above 6.5% and at least 10 years of diabetes duration). Subjects with PDR had higher blood pressure, higher serum levels of total cholesterol, low-density lipoprotein cholesterol and thyrotropin, and higher urinary albumin excretion rate. Of the 371 diabetics, 83 subjects (22.4%) were diagnosed as SCH (male 12.1% and female 29.9%). The prevalence of SCH in the PDR group (51/187, 27.3%) was higher than that in the subjects without diabetic retinopathy (32/184, 17.4%). Logistic regression analysis showed that after adjusting for compounding variables, SCH was independently related with PDR (p = 0.032, adjusted OR = 2.485). These results indicate that type 2 diabetic patients with PDR are at an increased risk of SCH. A routine screening for thyroid function may thus be considered advisable in PDR subjects. This may be helpful in investigating new strategies preventing or treating PDR in clinical practice.

Comparison of Coronary Heart Disease and Stroke in Association with Diabetic Retinopathy in Adults with Diabetes Using a National Survey.

OBJECTIVE: Diabetic retinopathy (DR) was reported to have higher prevalence of coronary heart disease (CHD) and stroke compared with people without DR. However, whether DR had similar effects on CHD and stroke in US adults with diabetes was not well known. This study was to compare the association between DR, CHD and stroke in US adults with diabetes using the 2015 Behavioral Risk Factor Surveillance System (BRFSS). METHODS: Respondents with diabetes aged over 18 years and undergone a fundus examination over the past 2 years were included in this study. DR, CHD and stroke were self-reported. A weighted hierarchical logistic regression was used to examine the association of DR with CHD and stroke. RESULTS: A total of 21,049 respondents with diabetes aged over 18 years having undergone a fundus examination over the past 2 years were included in the analysis. There were 4690 people reported having CHD, accounting for the weighted prevalence 22.1%. The weighted prevalence of stroke was 9.6%. There was 28.3% of CHD people who had DR which was higher than that in people without CHD. Differences in weighted frequency distributions of gender, age category (over 45 years or not), current smoking, hypercholesterolemia, hypertension and insulin treatment were significantly different between the CHD and without CHD groups (p<0.001). Similar results were found in people with stroke. Logistic analysis showed that DR was related to CHD and stroke (crude OR =1.876, 2.263, respectively, p all <0.001). After adjusting other variables, these associations persisted (Adjusted OR=1.632 (95% CI=1.625-1.639), 1.846 (95% CI=1.836-1.856), respectively, p all<0.001). CONCLUSION: The BRFSS 2015 data indicated that DR was not only associated with CHD but also associated with stroke in US adults with diabetes, independently of other risk factor. DR might be more strongly associated with stroke than with CHD.

Improved Framingham Risk Scores of Patients with Type 2 Diabetes Mellitus in the Beijing Community: A 10-Year Prospective Study of the Effects of Multifactorial Interventions on Cardiovascular Risk Factors (The Beijing Communities Diabetes Study 22).

INTRODUCTION: To date, research is lacking on the development of a cardiovascular disease (CVD) risk assessment tool for people with diabetes mellitus, in general, and for Chinese patients with diabetes in particular. We have explored CVD risk assessment tools for Chinese patients with diabetes. Here, we report our investigation of cardiovascular risk assessment using the improved Framingham Risk Score (I-FRS) in patients with type 2 diabetes mellitus (T2DM) in Beijing communities. METHODS: A total of 3232 patients with T2DM attending Beijing community health centers were enrolled in this study. FRS were used to predict CVD risk in all patients at baseline using the following risk scores for glycated hemoglobin (HbA1c) categories: 0 = HbA1c ≤ 7.0%; 1 = 7.0% < HbA1c ≤ 7.9%;      2 = 8.0% < HbA1c ≤ 8.9%; and 3 = HbA1c > 9.0%. The I-FRS was use to stratify all patients into low (I-FRS < 10%), medium (I-FRS 10-20%), and high (I-FRS > 20%) FRS strata. All treatments administered in the Beijing Communities Diabetes Study were in accordance with national guidelines for T2DM in China, and patients regularly attended clinical consultations with professors in endocrinology, who were experts in their respective speciality, from top tier hospitals. After 10 years, patients were followed-up to assess the long-term effects of the multifactorial interventions. Statistical analysis was performed using SAS® software (SAS Institute, Inc., Cary, NC, USA). RESULTS: The receiver operating characteristic curve of the I-FRS showed significant prediction accuracy for the actual incidence of CVD events. At baseline, subjects in the high FRS stratum for diabetes were more prone to be elderly and to have a longer duration of T2DM, higher systolic blood pressure, and higher lipid profiles. Subjects in the medium and high FRS strata had a higher incidence of CVD events than those in the no-complications group (DM group with no blood pressure issues) (P < 0.001). The 10-year hazard ratios for CVD events in diabetic patients with I-FRS score > 20% was 12.5-fold higher than that of patients with I-FRS score < 10%. Multifactorial intervention significantly reduced the I-FRS of the three FRS strata in patients with T2DM. The post-intervention I-FRS for the hypertension and CVD groups of patients were significantly lower than the respective baseline I-FRS. Cox multivariate analyses revealed that patients in the medium and high FRS strata had higher incidences of endpoint events than those in the low FRS stratum. CONCLUSIONS: The I-FRS plays an important role in predicting CVD in patients with T2DM. Multifactorial interventions for CVD risk factors over 10-year follow-up lowered the estimated 10-year risk for CVD events in persons with diabetes. We suggest the use of the I-FRS score to stratify a patient's risk of CVD when analyzing the efficacy of diabetes management. Aggressive risk reduction should be focused on those individuals with a high I-FRS score. TRIAL REGISTRATION: ChiCTR-TRC-13003978 and ChiCTR-OOC-15006090.

Effects of pre-gestational diabetes mellitus and gestational diabetes mellitus on macrosomia and birth defects in Upstate New York.

AIMS: To evaluate the effects of pre-gestational diabetes mellitus (PGDM) and gestational diabetes mellitus (GDM) on macrosomia and birth defects. METHODS: Existing birth registry data from the Perinatal Data System in Upstate New York was analysed. 650,914 women with a singleton term pregnancy (≥37 weeks) aged 18-55 years from 2004 to 2016 were included. RESULTS: The prevalence of macrosomia in infants born to women with PGDM and GDM were 26.0% and 16.4%, respectively, higher than that in the controls (11.2%). Compared with the controls (0.8%), the PGDM and GDM groups had higher prevalence of any birth defect (1.8% and 1.0%). The PGDM group had the highest prevalence of cyanotic heart disease (0.6%). Moreover, the PGDM group had higher prevalence of cleft lip and palate, cleft palate alone, hypospadias and limb reduction defect compared to the GDM and control groups (p < 0.05). However, these birth defects in the GDM group were similar to those in the controls. Both the PGDM and GDM groups had significantly elevated odds of macrosomia, cyanotic heart disease and any birth defect than controls. The PGDM group had higher odds of cleft lip and palate, cleft palate alone, hypospadias and limb reduction defect. CONCLUSIONS: Using the Perinatal Data System database, PGDM and GDM, especially PGDM, was associated with higher prevalence of macrosomia, cyanotic heart disease and any birth defect in singleton term pregnancy in Upstate New York. PGDM, not GDM had higher prevalence of cleft lip and palate, cleft palate alone, hypospadias and limb reduction defect.

Association between diabetes, metabolic syndrome and heart attack in US adults: a cross-sectional analysis using the Behavioral Risk Factor Surveillance System 2015.

OBJECTIVES: Diabetes mellitus (DM) and metabolic syndrome (MS) are both associated with heart attack. Evidence regarding which condition-MS or DM-is better associated with heart attack, however, is limited. The purpose of this study is to examine DM and MS, and their comparative associations with heart attack, using the 2015 Behavioral Risk Factor Surveillance System (BRFSS). DESIGN: Cross-sectional study. METHODS: A total of 332 008 subjects aged over 18 years were included in the analysis. All subjects were classified into four groups based on their DM and MS status: neither DM nor MS, DM without MS, MS without DM, and both DM and MS. A weighted hierarchical logistic regression was used to examine the difference between the four groups in their association with the risk of a heart attack. RESULTS: Differences in weighted frequency distributions of gender, age category (over 45 years or not), smoking status, education, race, physical activity and daily vegetable and fruit consumption were significantly different across the four groups (p<0.05). The weighted prevalence of heart attack was 5.2% for neither DM nor MS group, 8.5% for DM without MS group, 11.0% for MS without DM group and 16.1% for both DM and MS group. The weighted prevalence of heart attack in MS without DM group was significantly higher than that in the DM without MS group (p<0.01). After adjusting for confounding variables, DM without MS and MS without DM were both found to be independently associated with heart attack compared with those without DM nor MS (DM without MS, OR=2.09; MS without DM, OR=2.58, all p<0.01). CONCLUSION: The BRFSS 2015 data indicated that MS without DM and DM without MS had comparable effects on heart attack, and the odds of risk are doubled than US adults with neither DM nor MS.

Association Between Neck Circumference and Coronary Heart Disease: A Meta-analysis.

Aims: Neck circumference (NC) was found to be related to the risk factors for coronary heart disease (CHD). However, the effects of NC on CHD are still controversial. To evaluate the relationship between NC and CHD, a meta-analysis of observational studies was performed. Method: Eligible studies on the association between NC and CHD were searched in Medline, Embase, Ovid, and Web of Science databases published in English from January 1980 to December 2016. Moreover, studies published in Chinese in Wanfang and China Hospital Knowledge databases were also searched. Random effects models in the metafor package in statistical analysis software R 3.3.3 were used for the meta-analysis. Heterogeneity was analyzed with Q statistics. Results: Eight studies were selected for the meta-analysis. A larger NC was associated with a higher prevalence of CHD (OR = 1.18, 95% CI 1.04-1.34, p = 0.0108). The eight studies were further divided into three subgroups according to the criteria for diagnosing CHD. In the subgroup of coronary angiography, NC was also found to be associated with the prevalence of CHD with low heterogeneity (OR = 1.17, 95% CI 1.07-1.28, p = 0.0007, I 2 = 17.02%). However, in the subgroup of computed tomography or past history, no association between NC and CHD was found. In addition, subgroup analyses were also conducted according to the regions of the study. No association between NC and CHD was identified in either Chinese studies or Brazil studies (OR = 1.20, 95% CI 0.96-1.49; OR = 1.31, 95% CI 0.82-2.09, respectively). Conclusion: Larger NC is associated with increased risk of CHD, especially when coronary angiography was taken to diagnose CHD.

Association between Neck Circumference and the Occurrence of Cardiovascular Events in Type 2 Diabetes: Beijing Community Diabetes Study 20 (BCDS-20).

BACKGROUND: Neck circumference (NC) was found to be related to the risk factors of cardiovascular disease. However, the effects of NC on cardiovascular disease are still controversial. A prospective study of Chinese patients with type 2 diabetes was performed to evaluate the relationship between NC and cardiovascular disease. METHODS: A multicenter prospective study with eight-year follow-up was conducted in Beijing communities. Cardiovascular events were defined as myocardial infarction, unstable angina pectoris, hospitalization for heart failure, coronary revascularization, cardiac death, stroke, transient ischemic attack, and cerebral hemorrhage. RESULTS: A total of 3,009 diabetic patients were recruited. Following an eight-year follow-up, 211 patients with cardiovascular events (105 in men and 106 in women) were identified. All patients were categorized into two groups according to the upper quartile of NC (43 cm in men and 39 cm in women). The prevalence of cardiovascular events in men with an NC >43 cm (16.48%) was higher than that in the group with an NC <43 cm (8.16%, p=0.007). The prevalence of cardiovascular events in women with the NC >39 cm (10.67%) was higher compared to the group with NC <39 cm (5.31%, p=0.004). The longitudinal prevalence of cardiovascular events in groups with different NC increased with the increasing duration of follow-up (p < 0.001). Cox regression analysis showed that higher NC was associated with the occurrence of cardiovascular events after adjusting for confounding variables (adjusted HR = 2.305 (1.535-3.460)). CONCLUSIONS: NC was associated with the occurrence of cardiovascular events in type 2 diabetes in Chinese communities, and greater NC may increase the risk of cardiovascular events by about 2.3-fold.

The Association between Metabolic Syndrome and Morbid Events in Type 2 Diabetes after a 7-Year Community Management: Beijing Community Diabetes Study 17.

BACKGROUND: To examine the association between morbid events and metabolic syndrome (MS) in patients with type 2 diabetes mellitus (T2DM). METHODS: A prospective, longitudinal, multicenter study was conducted at 13 community health centers associated with Beijing Tongren Hospital. From 2008 to 2015, there have been 3,525 T2DM patients being managed based on the Chinese guideline for T2DM. The morbid events included macrovascular events, diabetic kidney disease, ophthalmologic events, cancer, and all-cause death. RESULTS: At baseline, there were 2,708 people with MS and 817 without MS. After a seven-year management, there were 351 (12.96%) events in MS people and 74 (9.06%) events in people without MS (p = 0.003). The prevalence of macrovascular events (6.06%) was much higher in MS people than in people without MS (3.79%, p = 0.013). Cox regression analysis showed an association between MS and morbid events even after adjusting for confounding variables (adjusted hazard ratio = 1.44). MS was also associated with macrovascular events (adjusted hazard ratio = 1.96). The occurrence of morbid events and macrovascular events was increased when the numbers of metabolic abnormalities were 1, 2, 3, and 4 (p < 0.001). There was no continuously statistically significant difference in the cumulative prevalence of morbid events between patients with MS and patients without MS during the first five years. However, after six or seven years, the cumulative prevalence of morbid events in patients with MS was continuously significantly higher than that in patients without MS (11.00% vs. 8.20%, 12.96% vs. 9.06%, p < 0.05). CONCLUSIONS: T2DM with MS had higher incidence of morbid events, especially cardiovascular events, even after integrated management. The occurrence of morbid and macrovascular events increased as the number of metabolic abnormalities increased. MS was associated with increased risk of morbid events by 44% and macrovascular events by 96%. It would take at least six years to observe the association between MS and morbid events in T2DM.

The effects of cardiovascular risk factor combined anti-platelet therapy and the risk of cerebrovascular events in patients with T2DM in an urban community over 96-months follow-up: The Beijing communities diabetes study 19.

OBJECTIVE: We investigated the prognostic significance of metabolic risk scores and aspirin with respect to cerebrovascular events. METHODS: A total of 25 communities of diabetic patients were enrolled in Beijing Community Diabetes Study (BCDS) from 2008. 3413 patients with T2DM in BCDS have complete screening data, including blood glucose, blood pressure, lipid profiles and anti-platelet therapy, which were assigned metabolic score (MS) and add up to the total metabolic score (TMS). According to the total metabolic score (TMS), the patients were divided into four equal groups: Group 1 (24 < TMS < 40), Group 2 (40 < TMS < 47), Group 3 (47 < TMS < 55) and Group 4 (55 < TMS < 87). After 96 months, patients were followed-up to assess the long-term effects of the multifactorial interventions. RESULTS: During 96-months follow-up, a total of 91 cerebrovascular events occurred, including acute cerebral infarction, acute cerebral hemorrhage and transient ischemic attack (TIA). The incidence of cerebrovascular events was higher in the Group 4 than in the Group 1. In Cox multivariate analyses, there are significant differences in incidences of cerebral infarction events among the four groups during the 96-months follow-up. Cox proportional hazards analysis revealed that, HbA1c (p ≤ 0.001), systolic pressure (p ≤ 0.001), aspirin free treatment (P = 0.0023) are independent predictor for cerebrovascular events in diabetic patients. CONCLUSIONS: This study indicates that total metabolic score (TMS) influences the incidence of cerebrovascular events in diabetic patients. In addition to good control of blood glucose, blood pressure and lipid profiles, anti-platelet therapy is important for the prevention of cerebrovascular events in T2DM. TRIAL REGISTRATION: ChiCTR-TRC-13003978, ChiCTR-OOC-15006090.

The effects of AER and eGFR on outcomes of CVD in patients with T2DM in an urban community over 8 years of multifactorial treatment: the Beijing Communities Diabetes Study 18.

OBJECTIVE: It is well known that diabetic kidney disease is a risk factor for cardiovascular diseases (CVD) in patients with type 2 diabetes mellitus (T2DM). In this study, the effects of urine albumin excretion rate (AER) and estimated glomerular filtration rate (eGFR) on CVD outcomes were analyzed in a population of T2DM. METHODS: The study was carried out using recorded information of a cohort study. A total of 1,914 patients with T2DM with no prevalent CVD were enrolled in an 8 years prospective study and received multifactorial intervention. The risk of CVD outcomes was assessed according to chronic kidney disease staging, which was categorized using AER (mg/d) and eGFR (mL/min/1.73 m2). The effects of AER and eGFR on risk of CVD onset were also analyzed. RESULTS: During the follow-up period (median 6.8 years), 71 CVD events occurred. At baseline, those with AER ≥300 mg/d and coexisting eGFR 60-89 mL/min/1.73 m2 or <60 mL/min/1.73 m2 showed increased risk for CVD outcomes when compared with "no chronic kidney disease" (AER <30 mg/d and eGFR ≥90 mL/min/1.73 m2). The increased CVD risk was observed in patients who progressed to AER ≥30 mg/d during the follow-up period, whereas patients who progressed to eGFR <90 mL/min/1.73 m2 alone showed no increased CVD risk. During the follow-up period, after multifactorial intervention, 8.7% patients with microalbuminuria and 1.8% patients with overt nephropathy reversed to normoalbuminuria or microalbuminuria. CONCLUSION: AER is a more sensitive predictor than eGFR for CVD outcomes in T2DM patients. Overt nephropathy can be reversed after multifactorial intervention.

From Hyper- to Hypoinsulinemia and Diabetes: Effect of KCNH6 on Insulin Secretion.

Glucose-stimulated insulin secretion from islet ß cells is mediated by KATP channels. However, the role of non-KATP K+ channels in insulin secretion is largely unknown. Here, we show that a non-KATP K+ channel, KCNH6, plays a key role in insulin secretion and glucose hemostasis in humans and mice. KCNH6 p.P235L heterozygous mutation co-separated with diabetes in a four-generation pedigree. Kcnh6 knockout (KO) or Kcnh6 p.P235L knockin (KI) mice had a phenotype characterized by changing from hypoglycemia with hyperinsulinemia to hyperglycemia with insulin deficiency. Islets from the young KO mice had increased intracellular calcium concentration and increased insulin secretion. However, islets from the adult KO mice not only had increased intracellular calcium levels but also had remarkable ER stress and apoptosis, associated with loss of ß cell mass and decreased insulin secretion. Therefore, dysfunction of KCNH6 causes overstimulation of insulin secretion in the short term and ß cell failure in the long term.

A three-step programmed method for the identification of causative gene mutations of maturity onset diabetes of the young (MODY).

To establish a three-step programmed method to find gene mutations related to maturity onset diabetes of the young (MODY). Target region capture and next-generation sequencing (NGS) were performed using customized oligonucleotide probes designed to capture suspected genes for MODY in 11 probands with clinically diagnosed MODY. The suspected associations of certain genes with MODY were then confirmed by Sanger sequencing in the probands and their family members. Finally, to validate variants of one of the genes of interest (glucokinase, GCK) as pathogenic mutations, protein function editing by the variant genes was assessed. In the target region capture and NGS phase, a total of nine variants of seven genes (GCK, WFS1, SLC19A2, SH2B1, SERPINB4, RFX6, and GATA6) were identified in eight probands. Two heterozygous GCK mutations located on the same allele (p.Leu77Arg and p.Val101Met) were identified in a MODY family. Sanger sequencing was used to confirm the variants identified by NGS to be present in probands and their diabetic family members, but not in non-diabetic family members. Finally, enzyme kinetic and thermal stability analyses revealed that the p.Leu77Arg mutation or the p.Leu77Arg mutation in combination with the p.Val101Met mutation inactivates GCK function and stability, while mutation of p.Val101Met alone does not. The p.Leu77Arg but not p.Val101Met GCK mutation is therefore considered a pathogenic mutation associated with MODY. Genetic screening coupled with gene-editing protein function testing is an effective and reliable method by which causative gene mutations of MODY can be identified.

Pharmacokinetics and pharmacodynamics of a polyethylene glycol (PEG)-conjugated GLP-receptor agonist once weekly in Chinese patients with type 2 diabetes.

This multi-center, randomized, double-blind, multiple dose-escalation study was conducted to assess the pharmacokinetics and pharmacodynamics of a newly developed polyethylene glycol (PEG)-conjugated glucagon-like peptide-1 (GLP-1) receptor agonist, PEX168 once weekly in Chinese patients with type 2 diabetes (T2DM). Fifty patients aged 20-65 years, either treatment-naive or having been treated with single oral antidiabetic agents were eligible. Antidiabetic agents were stopped for 14 days before the study was initiated. Patients were allocated randomly into groups with subcutaneous PEX168 or placebo once-weekly for 8 weeks followed by 6 weeks observation. From baseline to 8 weeks, HbA1c were decreased by up to 0.0, 0.2, 0.6, 0.9, and -0.4% in the 50, 100, 200, 300 µg PEX168 groups, and placebo group respectively. The mean elimination half-life of PEX168 was 131.8-139.8 hours. The mean tmax was 67.3 hours. Steady-state plasma PEX168 concentrations were attained after 4 weeks. PEX168 once-weekly were tolerable by the patients: adverse effects reported ranged from 'mild' to 'moderate'. The most frequent drug-related adverse effects were nausea, vomiting, and diarrhea of mild to moderate severity. Administration of the PEG-conjugated GLP-1 receptor agonist PEX168 resulted in dose-proportional pharmacokinetic and antidiabetic pharmacodynamic activity.