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Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investigate protein-altering variants in ANGPTL4 among 58,124 participants in the DiscovEHR human genetics study, with follow-up studies in 82,766 T2D cases and 498,761 controls. Carriers of p.E40K, a variant that abolishes ANGPTL4 ability to inhibit lipoprotein lipase, have lower odds of T2D (odds ratio 0.89, 95% confidence interval 0.85–0.92, p = 6.3 × 10−10), lower fasting glucose, and greater insulin sensitivity. Predicted loss-of-function variants are associated with lower odds of T2D among 32,015 cases and 84,006 controls (odds ratio 0.71, 95% confidence interval 0.49–0.99, p = 0.041). Functional studies in Angptl4-deficient mice confirm improved insulin sensitivity and glucose homeostasis. In conclusion, genetic inactivation of ANGPTL4 is associated with improved glucose homeostasis and reduced risk of T2D., Genetic variation in ANGPTL4 is associated with lipid traits. Here, the authors find that predicted loss-of-function variants in ANGPTL4 are associated with glucose homeostasis and reduced risk of type 2 diabetes and that Angptl4−/− mice on a high-fat diet show improved insulin sensitivity.

AIM Pooled efficacy studies suggest that glycaemic responses to dipeptidyl-peptidase 4 inhibitors in type 2 diabetes are greatest in Asians, who may also respond better to alpha-glucosidase inhibitors. We assessed the glycaemic impact of sitagliptin by race in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), and whether this was enhanced in Asians with concomitant acarbose therapy. MATERIALS AND METHODS TECOS enrolled 14 671 patients with type 2 diabetes, cardiovascular disease and HbA1c of 48-64 mmol/mol (6.5%-8.0%), and randomized them, double-blind, to sitagliptin or placebo. There were 3265 patients (22.3%) from Asian countries. Background glucose-lowering therapies were unaltered for the first 4 months post randomization unless clinically essential, facilitating comparison of sitagliptin-associated effects in self-identified East Asian, Other (South) Asian, White Caucasian, Hispanic, Black and Indigenous groups. RESULTS Median baseline HbA1c by race was 54 to 57 mmol/mol (7.1%-7.4%). Mean 4-month reduction in placebo-adjusted HbA1c was greatest in East Asians (-6.6 mmol/mol [-0.60%] vs ≤6.0 mmol/mol [≤0.55%] in other groups), with significantly greater reduction vs the 2 largest groups (White Caucasians, Other Asians; P

Aims/Introduction Vascular adhesion protein‐1 (VAP‐1) is a membrane‐bound amine oxidase highly expressed in mature adipocytes and released into the circulation. VAP‐1 has been strongly implicated in several pathological processes, including diabetes, inflammation, hypertension, hepatic steatosis and renal diseases, and is an important disease marker and therapeutic target. Here, we aimed to identify the genetic loci for circulating VAP‐1 levels. Materials and Methods We carried out a genomic‐wide linkage scan for the quantitative trait locus of circulating VAP‐1 levels in 1,100 Han Chinese individuals from 398 families in the Stanford Asian Pacific Program for Hypertension and Insulin Resistance study. Regional association fine mapping was carried out using additional single‐nucleotide polymorphisms. Results The estimated heritability of circulating VAP‐1 levels is high (h 2 = 69%). The most significant quantitative trait locus for circulating VAP‐1 was located at 38 cM on chromosome 20, with a maximum empirical logarithm of odds score of 4.11 (P = 6.86 × 10−6) in females. Regional single‐nucleotide polymorphism fine mapping within a 1‐unit support region showed the strongest association signals in the MACRO domain containing 2 (MACROD2) gene in females (P = 5.38 × 10−6). Knockdown of MACROD2 significantly suppressed VAP‐1 expression in human adipocytes, as well as the expression of key adipogenic genes. Furthermore, MACROD2 expression was found to be positively associated with VAP‐1 in human visceral adipose tissue. Conclusion MACROD2 is a potential genetic determinant of serum VAP‐1 levels, probably through transcriptional regulation of adipogenesis.

Subclinical hypothyroidism has been associated with dyslipidemia, hypertension, and increased risk of coronary artery disease. However, limited is known for its effect on renal function. Here we aimed to investigate whether subclinical hypothyroidism is associated with reduced estimated glomerular filtration rate (eGFR) and proteinuria in the general population. A cross-sectional cohort of 74,356 adults aged ≥20 year participating in voluntary health examinations without previous thyroid diseases were recruited in Taiwan. The mean eGFR of persons with euthyroidism, subclinical, and overt hypothyroidism are 87.99, 83.46, and 72.22 mL/min/1.73 m2, respectively (P-for- trend

Aims To compare the incidence of hyperglycaemia among participants with low, elevated and normal serum thyroid-stimulating hormone concentration, as well as the incidence of abnormal thyroid function test results among participants with normal blood glucose and those with hyperglycaemia. Methods In a prospective study, a cohort of 72 003 participants with normal, low and elevated serum thyroid-stimulating hormone concentration were followed from the study beginning to the first report of diabetes and prediabetes. A proportional hazards regression model was used to calculate the hazard ratios and 95% CIs for each outcome, adjusting for age, sex, education level, smoking, alcohol consumption and obesity. Analyses for the association between dysglycaemia and incident abnormal thyroid function test were also conducted. Results During a median 2.6 year follow-up, the incident rates for dysglycaemia, particularly prediabetes, were substantially higher in participants with elevated thyroid-stimulating hormone concentrations at baseline, while the rates for participants with normal and low thyroid-stimulating hormone were similar. After controlling for risk factors, participants with elevated thyroid-stimulating hormone retained a 15% increase in risk of prediabetes (adjusted hazard ratio 1.16, 95% CI 1.05–1.28), but were not at greater risk of diabetes (adjusted hazard ratio 1.04, 95% CI 0.68–1.52). By contrast, participants with normal and low thyroid-stimulating hormone concentrations had similar dysglycaemia risks. Participants with diabetes and prediabetes were not at greater risks of developing abnormal thyroid function test results when compared with participants with euglycaemia. Conclusions People with elevated serum thyroid-stimulating hormone concentration are at greater risk of developing prediabetes. Whether this includes a greater risk of developing frank diabetes may require an extended period of follow-up to clarify. This article is protected by copyright. All rights reserved.

Objective To examine the reliability and validity of the Chinese version of the 19-item Audit of Diabetes-Dependent Quality of Life for Taiwan (ADDQoL-CnTW). Methods Linguistic validation procedures for patient-reported outcome measures were used to translate the Taiwan version from the original 19-item UK-English ADDQoL. The psychometric properties of the ADDQoL-CnTW were evaluated in a convenience sample, recruited from outpatient facilities, of 260 patients diagnosed with diabetes mellitus. Results The forced one-factor solution supported one general 19-item factor with all items loading above 0.43, accounting for 51.5% of the variance, although the results of confirmatory factory analysis did not strictly adhere to a one-factor structure. Using Kaiser's Criterion, exploratory factor analysis identified four sub-dimensions but the pattern of loading also confirmed the presence of a large general factor with 11 of 19 items loading ≥0.4 on the first component, accounting for 49.73% of the variance. Internal consistency for the entire scale was 0.94. Convergent and discriminant validity were suggested by a stronger correlation of average weighted impact (AWI) scores with the overview Diabetes-specific QoL item than with the Present QoL item. The Present QoL item correlated better with the World Health Organization Quality of Life-BREF(TW) dimension scores than the Diabetes-specific QoL scores or the AWI scores. Insulin-treated patients reported significantly more negative AWI scores and Diabetes-specific QoL scores than those treated with tablets and/or diet, demonstrating known-groups validity. Conclusions The ADDQoL-CnTW revealed excellent internal consistency reliability, and showed evidence of validity for use in Taiwanese people with diabetes.

Large-scale meta-analyses of genome-wide association studies (GWAS) have identified >175 loci associated with fasting cholesterol levels, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). With differences in linkage disequilibrium (LD) structure and allele frequencies between ancestry groups, studies in additional large samples may detect new associations. We conducted staged GWAS meta-analyses in up to 69,414 East Asian individuals from 24 studies with participants from Japan, the Philippines, Korea, China, Singapore, and Taiwan. These meta-analyses identified (P

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate ≥25 mL/min/1.73 m2 and albuminuria (urinary albumin-to-creatinine ratio ≥30 to ≤5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level α = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049.

Aims Insulin resistance (IR) changes over time during the development of type 2 diabetes. Some reports showed that obesity was associated with progression of IR. However, no study has explored if change of IR predicts incident diabetes, and no study has investigated other factors associated with the change. Methods In this study, 1184 subjects without diabetes at baseline were enrolled in 2006–2016 with a median follow-up period of 4.5 years. Diabetes was diagnosed by oral glucose tolerance test and hemoglobin A1c, or if anti-diabetic agents were used. HOMA2-IR and ISI0,120 were used to estimate IR. Results The annual changes of HOMA2-IR(ΔHOMA2-IR/year) and ISI0,120(ΔISI0,120/year) were associated with BMI, waist circumference(WC), glucose, HbA1c, triglyceride and HDL-cholesterol. Subjects with pre-diabetes or metabolic syndrome were associated with a more rapid increase of IR. ΔHOMA2-IR/year and ΔISI0,120/year were correlated with annual changes of BMI and WC. The hazard ratios for ΔHOMA2-IR/year and ΔISI0,120/year to predict incident diabetes were 1.39 (95% CI 1.22–1.59, p Conclusions Change of IR can be used as a surrogate marker of incident diabetes. The progression of IR is an important pathophysiologic link between risk factors and the incidence of diabetes.

Purpose: To develop a deep learning image assessment software VeriSee™ and to validate its accuracy in grading the severity of diabetic retinopathy (DR). Methods: Diabetic patients who underwent single-field, nonmydriatic, 45-degree color retinal fundus photography at National Taiwan University Hospital between July 2007 and June 2017 were retrospectively recruited. A total of 7524 judgeable color fundus images were collected and were graded for the severity of DR by ophthalmologists. Among these pictures, 5649 along with another 31,612 color fundus images from the EyePACS dataset were used for model training of VeriSee™. The other 1875 images were used for validation and were graded for the severity of DR by VeriSee™, ophthalmologists, and internal physicians. Area under the receiver operating characteristic curve (AUC) for VeriSee™, and the sensitivities and specificities for VeriSee™, ophthalmologists, and internal physicians in diagnosing DR were calculated. Results: The AUCs for VeriSee™ in diagnosing any DR, referable DR and proliferative diabetic retinopathy (PDR) were 0.955, 0.955 and 0.984, respectively. VeriSee™ had better sensitivities in diagnosing any DR and PDR (92.2% and 90.9%, respectively) than internal physicians (64.3% and 20.6%, respectively) (P

Objective Diabetic patients have an elevated risk of infection, but the optimal level of glycemic control with the lowest infection risk remains unclear, especially among the elderly. We aimed to investigate the relation between fasting plasma glucose (FPG) level and risk of infection-related morbidity and mortality. Method The participants were from a community-based health screening program in northern Taiwan during 2005–2008 (n = 118 645) and were followed up until 2014. Incidence of hospitalization for infection and infection-related death was ascertained from the National Health Insurance Database and National Death Registry. Cox proportional hazards regression modelling was used to estimate the hazard ratio (HR) between FPG and risk of infection. Results During a median follow-up of 8.1 years, the incidence rate of hospitalization for any infection was 36.33 and 14.26 per 1000 person-years among diabetics and nondiabetics, respectively, in the total study population, but increased to 70.02 and 45.21 per 1000 person-years, respectively, in the elderly. In the Cox regression analysis, the adjusted HR comparing diabetics to nondiabetics was 1.59 (95% confidence interval [CI], 1.52–1.67) for any hospitalization for infection and 1.71 (95% CI, 1.36–2.16) for infection-related mortality. The hazard for infection morbidity and mortality was higher at both extremes (200 mg/dl) of FPG. The excess risk associated with FPG ≤ 90 mg/dl was attenuated after controlling for multiple comorbidities. Conclusions Poor glycemic control (FPG > 200 mg/dl) was associated with a higher risk of infection-related morbidity and mortality, especially in the elderly population where the baseline infection risk was high., Few studies have longitudinally assessed the association between glycemic control and risk of infection mortality. In this study, a U-shaped relation between fasting plasma glucose level and infection-related outcome was observed. After controlling for multiple comorbidities, the increased risk among those with a low fasting glucose level were attenuated, suggesting that comorbidities may play a role in the excess risk associated with low fasting plasma glucose level, in particular among elderly diabetic patients.

SUMMARYMeta-analyses of genome-wide association studies (GWAS) have identified >240 loci associated with type 2 diabetes (T2D), however most loci have been identified in analyses of European-ancestry individuals. To examine T2D risk in East Asian individuals, we meta-analyzed GWAS data in 77,418 cases and 356,122 controls. In the main analysis, we identified 298 distinct association signals at 178 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 56 loci newly implicated in T2D predisposition. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. New associations include signals in/near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect muscle and adipose differentiation. At another locus, eQTLs at two overlapping T2D signals act through two genes, NKX6-3 and ANK1, in different tissues. Association studies in diverse populations identify additional loci and elucidate disease genes, biology, and pathways.Type 2 diabetes (T2D) is a common metabolic disease primarily caused by insufficient insulin production and/or secretion by the pancreatic β cells and insulin resistance in peripheral tissues1. Most genetic loci associated with T2D have been identified in populations of European (EUR) ancestry, including a recent meta-analysis of genome-wide association studies (GWAS) of nearly 900,000 individuals of European ancestry that identified >240 loci influencing the risk of T2D2. Differences in allele frequency between ancestries affect the power to detect associations within a population, particularly among variants rare or monomorphic in one population but more frequent in another3,4. Although smaller than studies in European populations, a recent T2D meta-analysis in almost 200,000 Japanese individuals identified 28 additional loci4. The relative contributions of different pathways to the pathophysiology of T2D may also differ between ancestry groups. For example, in East Asian (EAS) populations, T2D prevalence is greater than in European populations among people of similar body mass index (BMI) or waist circumference5. We performed the largest meta-analysis of East Asian individuals to identify new genetic associations and provide insight into T2D pathogenesis.

Background: Diabetic patients have an elevated risk of infection, but the optimal level of glycemic control with the lowest infection risk remains unclear, especially among the elderly. We conducted a cohort study to investigate the relation between fasting plasma glucose (FPG) level and risk of infection-related morbidity and mortality. Methods: Data of participants from a community-based health screening program in Taiwan during 2005-2008 (n=118,645) were analyzed. Incidence of hospitalization for infection and infection-related death was ascertained from the National Health Insurance Database and National Death Registry. Cox proportional hazards regression modelling was used to estimate the hazard ratio (HR) between FPG and risk of infection, adjusting for major risk factors of infection. Separate analyses were also performed to evaluate the risk of hospitalization among the elderly (> 65 years). Results: During a median follow-up of 8.13 years, 14,372 cases of hospitalization for infection and 422 infection-related deaths occurred. The incidence rate of hospitalization for any infection was 36.33 and 14.26 per 1,000 person-years among diabetics and nondiabetics in the total study population, but increased to 70.02 and 45.21 per 1,000 person-years in the elderly. In the Cox regression analysis, the adjusted HR comparing diabetics to nondiabetics was 1.59 (95% CI: 1.52-1.67) for any hospitalization for infection and 1.71 (95% CI: 1.36-2.16) for infection-related mortality. The hazard for infection morbidity and mortality was higher at both extremes (200 mg/dl) of FPG. The above relations were consistently observed in older people and across different sites of infection. Conclusion: The U-shape association between glycemic control and infection risk suggested that very tight glucose control may not provide additional benefits in risk reduction. In older adults, the absolute risk of infection associated with diabetes was high. Disclosure C. Chang: None. J. Wang: None. L. Wu: None. L. Chuang: None. H. Lin: None. Funding Taiwan Ministry of Science and Technology (MOST105-2628-B-002-025-MY3)

Background/Purpose: Several new antidiabetic drugs have been introduced in Taiwan. However, the trends in antidiabetic treatment remain unexamined. Methods: We studied data from the Taiwan National Health Insurance Database to identify outpatient prescriptions for antidiabetic drugs from 2005 to 2014. The patterns in antidiabetic treatment and the number of different classes of antidiabetic drugs were analyzed. The proportions of prescriptions of antidiabetic monotherapy, combination therapy, or insulin therapy were further analyzed. Results: The total and mean prescriptions gradually increased during the study period. Prescription of oral antidiabetic drugs (OADs) only or insulin-only therapy decreased slightly. Prescriptions of monotherapy and dual therapy decreased, whereas those of triple or higher order combinations increased. Prescriptions of sulfonylureas (SUs) decreased, whereas those of metformin and dipeptidyl peptidease-4 (DPP4) inhibitors increased. Insulin prescriptions increased but accounted for only 13.07% of prescriptions in 2014. Among monotherapy prescriptions, SU prescriptions decreased, but metformin and DPP4 inhibitor prescriptions increased. Among dual OAD prescriptions, those including SUs decreased, and those of metformin and DPP4 inhibitors increased. Although prescriptions of the metformin–SU combination decreased, they remained the most common among all dual OAD prescriptions, followed by the metformin–DPP4 inhibitor combination. Prescriptions of human insulin decreased and those of insulin analogs increased considerably; those of basal insulin increased, and those of mixed insulin decreased. However, mixed insulin was prescribed more than basal–bolus insulin. Conclusion: Antidiabetic treatment has become complex in Taiwan. Although combination therapy would become the major treatment strategy gradually, the underuse of insulin therapy must improve. Keywords: Antidiabetic drugs, Diabetes, Insulin, Oral antidiabetic drugs

Background/Purpose: Diabetes mellitus has become a major cause of death worldwide. Many technologies have become available for managing diabetes and its complications. This study investigated the mortality trends in people with diabetes in Taiwan between 2005 and 2014. Methods: We used data from Taiwan's National Health Insurance Research Database, which is linked to the National Death Registry. Patients with at least three outpatient visits in 1 year or at least one hospital admission with the diagnosis of diabetes (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] 250.x) were defined as diabetic patients. The main causes of death were classified using ICD-9-CM or ICD-10-CM. Results: In 2005–2014, the number of diabetic patients increased from 1.3 to 2.2 million in Taiwan, and all-cause mortality in the patients decreased continuously across sexes and age groups (all, 3.45%–3.00%; women, 3.07%–2.70%; men, 3.82%–3.28%, all p

Aim To investigate the appropriate fasting plasma glucose threshold by which to define prediabetes in children and adolescents, based on its ability to predict incident paediatric diabetes. Methods In a nationwide survey of diabetes and renal disease conducted between 1992 and 2000 in all school-aged children in Taiwan, those with abnormal results in repeated urine tests received further physical examination and blood tests. Students who had blood tests for at least two time points were selected for the present study (N = 12 119). The incidence of paediatric diabetes, adjusted hazard ratio and predictive power of fasting plasma glucose were analysed. Results The incidence of paediatric diabetes increased with increasing fasting plasma glucose levels. Groups with fasting plasma glucose >5.6 mmol/l had a higher adjusted hazard ratio. The adjusted hazard ratio of incident diabetes for participants with higher fasting plasma glucose rose continuously when using a higher threshold for fasting plasma glucose. The area under the receiver-operating characteristic curve for fasting plasma glucose was 0.628 for predicting paediatric diabetes. The association between fasting plasma glucose and incident paediatric diabetes and the area under the receiver-operating characteristic curve were similar in boys and girls and were higher in the age group 12-18 years. According to receiver-operating characteristic curve analysis, the optimal thresholds, sensitivity and specificity were 4.75 mmol/l, 65% and 51%, respectively, for those aged 6-11 years and 5.19 mmol/l, 60% and 73%, respectively, for those aged 12-18 years. Conclusion Fasting plasma glucose is associated with the incidence of paediatric diabetes. The results of the present study can be used as reference data to suggest a cut-off value to define paediatric prediabetes.

Key Points Question What are the effects of a quality improvement intervention on the care and cardiometabolic risk factors of patients with type 2 diabetes in low- and middle-income countries in the Asia-Pacific region? Findings In this randomized clinical trial of 20 834 patients with type 2 diabetes in 8 Asia-Pacific countries, the intervention group received a technology-guided structured evaluation, automated personalized reports to encourage patient empowerment, and nurse reminders to increase patient engagement over a 12-month period. Clinical events were similar between the control and intervention groups at 12 months; however, the intervention group was more likely to experience reductions in multiple risk factors and increases in the attainment of diabetes-associated targets. Meaning The study’s findings indicate that the use of information and communications technology and nurses to empower and engage patients did not change the number of clinical events but did reduce cardiometabolic risk factors among patients with type 2 diabetes in low- and middle-income countries., Importance Many health care systems lack the efficiency, preparedness, or resources needed to address the increasing number of patients with type 2 diabetes, especially in low- and middle-income countries. Objective To examine the effects of a quality improvement intervention comprising information and communications technology and contact with nonphysician personnel on the care and cardiometabolic risk factors of patients with type 2 diabetes in 8 Asia-Pacific countries. Design, Setting, and Participants This 12-month multinational open-label randomized clinical trial was conducted from June 28, 2012, to April 28, 2016, at 50 primary care or hospital-based diabetes centers in 8 Asia-Pacific countries (India, Indonesia, Malaysia, the Philippines, Singapore, Taiwan, Thailand, and Vietnam). Six countries were low and middle income, and 2 countries were high income. The study was conducted in 2 phases; phase 1 enrolled 7537 participants, and phase 2 enrolled 13 297 participants. Participants in both phases were randomized on a 1:1 ratio to intervention or control groups. Data were analyzed by intention to treat and per protocol from July 3, 2019, to July 21, 2020. Interventions In both phases, the intervention group received 3 care components: a nurse-led Joint Asia Diabetes Evaluation (JADE) technology-guided structured evaluation, automated personalized reports to encourage patient empowerment, and 2 or more telephone or face-to-face contacts by nurses to increase patient engagement. In phase 1, the control group received the JADE technology–guided structured evaluation and automated personalized reports. In phase 2, the control group received the JADE technology–guided structured evaluation only. Main Outcomes and Measures The primary outcome was the incidence of a composite of diabetes-associated end points, including cardiovascular disease, chronic kidney disease, visual impairment or eye surgery, lower extremity amputation or foot ulcers requiring hospitalization, all-site cancers, and death. The secondary outcomes were the attainment of 2 or more primary diabetes-associated targets (glycated hemoglobin A1c, This randomized clinical trial examines the effects of a quality improvement intervention comprising information and communications technology and increased contact with nurses on the clinical care and cardiometabolic risk factors of patients with type 2 diabetes in Asia-Pacific countries.

OBJECTIVE The purpose of this study was to determine the relationship between chronic kidney disease (CKD) and cardiovascular autonomic neuropathy (CAN). RESEARCH DESIGN AND METHODS From October 2008 to May 2011, we enrolled 218 patients with diabetes and 62 nondiabetic subjects. Heart rate variability was represented as the maximal heart rate minus the minimal heart rate (HRmax-min) during a one-minute deep breathing test. Normal, impaired cardiovascular autonomic function and CAN were defined as s HRmax-min > 15 beats/min, HRmax-min of 10-15 beats/min and HRmax-min

Diet-induced obesity can be caused by impaired thermogenesis of beige adipocytes, the brown-like adipocytes in white adipose tissue (WAT). Promoting brown-like features in WAT has been an attractive therapeutic approach for obesity. However, the mechanism underlying beige adipocyte formation is largely unknown. N-α-acetyltransferase 10 protein (Naa10p) catalyzes N-α-acetylation of nascent proteins, and overexpression of human Naa10p is linked to cancer development. Here, we report that both conventional and adipose-specific Naa10p deletions in mice result in increased energy expenditure, thermogenesis, and beige adipocyte differentiation. Mechanistically, Naa10p acetylates the N terminus of Pgc1α, which prevents Pgc1α from interacting with Pparγ to activate key genes, such as Ucp1, involved in beige adipocyte function. Consistently, fat tissues of obese human individuals show higher NAA10 expression. Thus, Naa10p-mediated N-terminal acetylation of Pgc1α downregulates thermogenic gene expression, making inhibition of Naa10p enzymatic activity a potential strategy for treating obesity.

Objective: Previous research has suggested that peroxisome proliferator-activated receptor-gamma (PPAR-γ) may play an important role in immunomodulation. We examined whether PPAR-γ agonists (thiazolidinediones) were associated with the incidence of bacterial abscess among patients with type 2 diabetes. Research Design and Methods: This retrospective cohort study included 46,986 propensity-matched patients diagnosed with type 2 diabetes between 2000 and 2010. We compared the incidence of bacterial abscess and the incidences of two subclasses: liver and non-liver abscesses, between groups treated with either metformin plus a thiazolidinedione (M+T, N=7831) or metformin plus a sulfonylurea (M+S, N=39,155). Data were retrieved from a population-based Taiwanese database. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) with Cox proportional hazard regression models. Results: During a median follow-up of 4.5 years, the adjusted rate of incident bacterial abscess was lower with M+T than with M+S treatment (1.89 vs. 3.15 per 1000 person-years). M+T was associated with a reduced risk of bacterial abscess (adjusted HRs: 0.58, 95% CI: 0.42-0.80 for bacterial abscess; 0.54, 95% CI: 0.28-1.07 for liver abscess; and 0.59, 95% CI: 0.41-0.85 for non-liver abscess). The results did not change materially, after accounting for unmeasured confounding factors and differential censoring between the two treatment groups. Rosiglitazone and pioglitazone, in combination with metformin, produced similar reductions in risk for all abscess outcomes. Conclusions: We found that M+T had a substantial protective effect in reducing the incidence of bacterial abscesses. These findings merit further investigation. Disclosure C. Chang: None. J. Wang: None. Y. Dong: None. W. Ko: None. L. Wu: None. L. Chuang: None. P. Chen: None.

Inflammation, oxidative stress, and the formation of advanced glycated end-products (AGEs) are important components of atherosclerosis. Vascular adhesion protein-1 (VAP-1) participates in inflammation. Its enzymatic activity, semicarbazide-sensitive amine oxidase (SSAO), can catalyze oxidative deamination reactions to produce hydrogen peroxide and aldehydes, leading to the subsequent generation of AGEs. This study aimed to investigate the effect of VAP-1/SSAO inhibition on atherosclerosis. In our study, immunohistochemical staining showed that atherosclerotic plaques displayed higher VAP-1 expression than normal arterial walls in apolipoprotein E-deficient mice, cholesterol-fed New Zealand White rabbits and humans. In cholesterol-fed rabbits, VAP-1 was expressed on endothelial cells and smooth muscle cells in the thickened intima of the aorta. Treatment with PXS-4728A, a selective VAP-1/SSAO inhibitor, in cholesterol-fed rabbits significantly decreased SSAO-specific hydrogen peroxide generation in the aorta and reduced atherosclerotic plaques. VAP-1/SSAO inhibition also lowered blood low-density lipoprotein cholesterol, reduced the expression of adhesion molecules and inflammatory cytokines, suppressed recruitment and activation of macrophages, and decreased migration and proliferation of SMC. In conclusion, VAP-1/SSAO inhibition reduces atherosclerosis and may act through suppression of several important mechanisms for atherosclerosis.

The global incidence and prevalence of type 2 diabetes have been escalating in recent decades. Patients with type 2 diabetes have an increased risk of atherosclerotic cardiovascular disease (ASCVD). About two-thirds of death in type 2 diabetes are due to ASCVD, including 40% from coronary heart disease (CHD), 15% from heart failure (HF), and 10% from stroke. The association between hyperglycemia and elevated CV risk has been demonstrated in multiple cohort studies. However, clinical trials of intensive glucose reduction did not significantly reduce macrovascular outcomes. It remains unclear whether the absence of demonstrable benefits is attributed to the inclusion of patients with far advanced ASCVD in whom a short treatment period is barely enough for CV protective effects to be shown, or complications associated with the treatment such as hypoglycemia hamper the beneficial effects to manifest, or simply glucose-lowering per se is ineffective. Since the US FDA issued a mandate in December 2008 that every new anti-diabetic agent requires rigorous assessments of its CV safety, there have been more than 200,000 patients enrolled in a number of randomized controlled trials (RCTs), and around half of them have been completed and published. The results of these CV outcome trials are important for clinicians in their clinical practice, and also provide an opportunity for academic society to formulate treatment guidelines or consensus to provide specific recommendations for glucose control in various CV diseases. The Taiwan Society of Cardiology (TSOC) and the Diabetes Association of Republic of China (DAROC), aiming to formulate a treatment consensus in type 2 diabetic patients with CVD, have appointed a jointed consensus group for the 2018 Consensus of TSOC/DAROC (Taiwan) on the Pharmacological Management of Patients with Type 2 Diabetes and CV Diseases. The consensus is comprised of 5 major parts: 1) Treatment of diabetes in patients with hypertension, 2) Treatment of diabetes in patients with CHD, 3) Treatment of diabetes in patients with stage 3 chronic kidney disease, 4) Treatment of diabetes in patients with a history of stroke, and 5) Treatment of diabetes in patients with HF. The members of the consensus group comprehensively reviewed all the evidence, mainly RCTs, and also included meta-analyses, cohort studies, and studies using claim data. The treatment targets of HbA1c were provided. The anti-diabetic agents were ranked according to their clinical evidence. The consensus is not mandatory. The final decision may need to be individualized and based on clinicians' discretion.

Aims/Introduction To determine the efficacy and safety of ipragliflozin in combination with metformin in Asian patients with type 2 diabetes mellitus. Materials and Methods This phase 3, multicenter, placebo-controlled, double-blind, parallel-group study was carried out at 18 sites in Korea and 12 sites in Taiwan. After an 8-week washout period for patients using drugs other than metformin and a 2-week run-in period, patients were randomized to either 50 mg ipragliflozin or a placebo for 24 weeks while continuing metformin. Efficacy outcomes included the changes in hemoglobin A1c, fasting plasma glucose (FPG) and bodyweight from baseline to the end of treatment (with last observation carried forward). Safety outcomes included treatment-emergent adverse events. Results Between November 2011 and January 2013, 171 patients were randomized to and administered ipragliflozin (n = 87) or a placebo (n = 83). The mean changes (standard deviation) in hemoglobin A1c were −0.94% (0.75%) and −0.47% (0.81%) in the ipragliflozin and placebo groups, respectively (between-group difference −0.46%, P < 0.001). The changes in fasting plasma glucose and bodyweight were also significantly greater in the ipragliflozin group, with between-group differences of −14.1 mg/dL and −1.24 kg, respectively (both P < 0.001). The most common treatment-emergent adverse events (ipragliflozin vs placebo) were upper respiratory tract infection (9.2% vs 12.0%) and urinary tract infection (6.9% vs 2.4%). Conclusions These results show that ipragliflozin is effective and well tolerated when used in combination with metformin in Asian patients with type 2 diabetes mellitus.

Aims/Introduction The International Association of the Diabetes and Pregnancy Study Group (IADPSG) criteria for gestational diabetes are associated with increased prevalence. However, it remains unknown if intervention for more women with gestational diabetes mellitus by the IADPSG criteria results in better pregnancy outcomes than adopting the Carpenter and Coustan (C&C) criteria in Asian populations. Materials and Methods This was a retrospective cohort study. A total of 1,840 women, 952 subjects by the IADPSG criteria and 888 subjects by the C&C criteria, who delivered singletons in 2011 in a single tertiary center, were included in the study. The same therapeutic interventions were offered to women with gestational diabetes mellitus by the two criteria. Maternal and neonatal outcomes were evaluated. Results Adopting the IADPSG criteria increased the prevalence of gestational diabetes mellitus diagnosis to 13.44%, compared with 2.59% by the C&C criteria. The diagnosis was made 3 weeks earlier by the IADPSG criteria (27 vs 30.5 weeks, P 90th percentile, jaundice, admission to neonatal intensive care unit, birth trauma, neonatal hypoglycemia and fetal death. Conclusions Adopting the IADPSG criteria is associated with improved pregnancy outcomes, at the expense of increased prevalence of gestational diabetes mellitus diagnosis.

Aim To compare the cardiovascular risks associated with second-line oral antidiabetic agents added to initial metformin therapy in a large nationwide observational study. Methods We conducted a nationwide retrospective cohort study using the Taiwan National Health Insurance database. A total of 36 118 users of different add-on oral antidiabetic agents (sulphonylureas, glinides, pioglitazone, α-glucosidase inhibitors and dipeptidyl peptidase-4 inhibitors) after initial metformin therapy were included in the analysis. The reference group was sulphonylureas added to metformin, the most commonly used combination regimen. The main outcomes of interest were hospitalizations for any cardiovascular event including acute myocardial infarction, congestive heart failure and ischaemic stroke. In the main analysis, all patients were followed within their initiation groups until the study end, disregarding any changes in treatment status over time. Results In intention-to-treat analyses, there was no difference in the risk of any cardiovascular event among the add-on combination treatment groups, but significantly lower risks of acute myocardial infarction were found for the glinides plus metformin treatment group (crude hazard ratio 0.52, adjusted hazard ratio 0.39; 95% CI 0.20–0.75) and for the α-glucosidase inhibitors plus metformin treatment group (crude hazard ratio 0.63, adjusted hazard ratio 0.54; 95% CI 0.31–0.95). No difference in risk of congestive heart failure or ischaemic stroke risk was found among the combination treatment groups. In secondary as-treated analyses, similar but less significant associations were found as compared with the primary intention-to-treat analyses for all treatment groups. Conclusion There were no differences in overall cardiovascular risks among several add-on second-line oral antidiabetic agents; however, glinide plus metformin and α-glucosidase inhibitors plus metformin combination therapies might be associated with lower risks of acute myocardial infarction.

Background Smoking is a strong risk factor of metabolic syndrome. Zinc α2-glycoprotein (ZAG) is a protein involved in metabolic syndrome. This study aims to investigate the effect of smoking on plasma ZAG levels and its relations to metabolic syndrome. Materials and methods A group of 41 cigarette smokers and 47 non-smokers were enrolled. ZAG levels were measured to correlate to participants’ demographic and metabolic parameters. Results Plasma ZAG levels of smokers were higher than those of controls (P

Metformin is the first-line oral therapy for type 2 diabetes with proven benefits against cardiovascular risk. Recent evidence suggested that acarbose might be similar to metformin in glucose-lowering efficacy and cardiovascular risk reduction. Therefore, international guidelines have suggested the use of acarbose as alternative first-line antidiabetic therapy.To compare the cardiovascular outcomes in the first-line users of acarbose vs metformin. DESIGN, SETTING, PATIENTS, AND OUTCOME MEASURES: A nationwide cohort study was conducted by analyzing the Taiwan National Health Insurance (NHI) Database. A total of 17,366 acarbose initiators and 230,023 metformin initiators were identified between January 1, 2009 and December 31, 2010. The primary outcome is hospitalization due to any cardiovascular events, including acute myocardial infarction, congestive heart failure, and ischemic stroke. The propensity score method was used to adjust for baseline differences between the two groups. Patients were followed from drug initiation to the earliest of outcome occurrence, death or disenrollment from NHI, or study termination.In intention-to-treat analyses, acarbose was associated with a higher risk of any cardiovascular event (adjusted hazard ratio [HR]: 1.05; 95% confidence interval [CI], 1.01-1.09), heart failure (HR, 1.08; 95% CI, 1.00-1.16), and ischemic stroke (HR, 1.05, 95% CI, 1.00-1.10) than metformin. No significant difference in risk was found in subgroups of patients with or without underlying hypertension, ischemic heart disease, or cerebrovascular disease. Similar results were found in auxiliary as-treated analyses or analyses stratified by propensity score quintiles.Our data do not support that acarbose has a cardio-protective effect similar to metformin as a first-line antidiabetic agent.

BACKGROUND Noninvasive stress tests for the diagnosis of significant coronary arterial stenosis requiring intervention are not perfect. We investigated whether plasma metabolome during the oral glucose tolerance test (OGTT) can improve the diagnosis. METHODS A total of 117 subjects with positive stress test results who received coronary angiography were recruited. After excluding subjects with a history of myocardial infarction and subjects who did not receive OGTT, the 18 subjects without significant stenosis were selected as controls. Another 18 age- and sex-matched subjects with significant stenosis were selected as cases. Plasma metabolome from samples obtained in fasting, 30 and 120 min after OGTT was measured using liquid chromatography combined with time-of-flight mass spectrometry. RESULTS We found five metabolites which can identify patients with significant stenosis independent to clinical risk factors, including diabetes, hypertension, hypercholesterolaemia, smoking and history of percutaneous coronary intervention (all P

The genetic basis of complex diseases often involves multiple causative loci. Under such a disease etiology, assuming one disease locus in linkage disequilibrium mapping is likely to induce bias and lead to efficiency loss in disease locus estimation. An approach is needed for simultaneously localizing multiple functional loci within the same region. However, due to the increasing number of parameters accompanying disease loci, these estimates can be computationally infeasible. To circumvent this problem, we propose to estimate the main and two-adjacent-locus joint effects and a nuisance parameter at the disease loci separately through a linear approximation. Estimates of the genetic effects are entered into a generalized estimating equation to estimate disease loci, and the procedure is conducted iteratively until convergence. The proposed method provides estimates and confidence intervals (CIs) for the disease loci, the genetic main effects, and the joint effects of two adjacent disease loci, with the CIs for the disease loci providing useful regions for further fine-mapping. We apply the proposed approach to a data example of case-control studies. Results of the simulations and data example suggest that the developed method performs well in terms of bias, variance, and coverage probability under scenarios with up to three disease loci.

The prevalence of diabetes is increasing in young adults in Asia, but little is known about metabolic control or the burden of associated complications in this population. We assessed the prevalence of young-onset versus late-onset type 2 diabetes, and associated risk factors and complication burdens, in the Joint Asia Diabetes Evaluation (JADE) cohort.JADE is an ongoing prospective cohort study. We enrolled adults with type 2 diabetes from 245 outpatient clinics in nine Asian countries or regions. We classified patients as having young-onset diabetes if they were diagnosed before the age of 40 years, and as having late-onset diabetes if they were diagnosed at 40 years or older. Data for participants' first JADE assessment was extracted for cross-sectional analysis. We compared clinical characteristics, metabolic risk factors, and the prevalence of complications between participants with young-onset diabetes and late-onset diabetes.Between Nov 1, 2007, and Dec 21, 2012, we enrolled 41,029 patients (15,341 from Hong Kong, 9107 from India, 7712 from Philippines, 5646 from China, 1751 from South Korea, 705 from Vietnam, 385 from Singapore, 275 from Thailand, 107 from Taiwan). 7481 patients (18%) had young-onset diabetes, with age at diagnosis of mean 32·9 years [SD 5·7] versus 53·9 years [9·0] with late-onset diabetes (n=33,548). Those with young-onset diabetes had longer disease duration (median 10 years [IQR 3-18]) than those with late-onset diabetes (5 years [2-11]). Fewer patients with young-onset diabetes achieved HbA1c concentrations lower than 7% compared to those with late-onset diabetes (27% vs 42%; p0·0001) Patients with young-onset diabetes had higher mean concentrations of HbA1c (mean 8·32% [SD 2·03] vs 7·69% [1·82]; p0·0001), LDL cholesterol (2·78 mmol/L [0·96] vs 2·74 [0·93]; p=0·009), and a higher prevalence of retinopathy (1363 [20%] vs 5714 (18%); p=0·011) than those with late-onset diabetes, but were less likely to receive statins (2347 [31%] vs 12,441 [37%]; p0·0001) and renin-angiotensin-system inhibitors (1868 [25%] vs 9665 [29%]; p=0·006).In clinic-based settings across Asia, one in five adult patients had young-onset diabetes. Compared with patients with late-onset diabetes, metabolic control in those with young-onset diabetes was poor, and fewer received organ-protective drugs. Given the risk conferred by long-term suboptimum metabolic control, our findings suggest an impending epidemic of young-onset diabetic complications.The Asia Diabetes Foundation (ADF) and Merck.

Prior cross-sectional analyses have demonstrated an association between subclinical hypothyroidism and metabolic syndrome and selected components. However, the temporal relation between metabolic syndrome and declining thyroid function remains unclear. In a prospective study, an unselected cohort of 66,822 participants with and without metabolic syndrome were followed. A proportional hazards regression model was used to estimate hazard ratios (HRs) and 95% CIs for hypothyroidism. Exploratory analyses for the relation between components of metabolic syndrome and declining thyroid function were also undertaken. During an average follow-up of 4.2 years, the incident rates for subclinical hypothyroidism were substantially higher in participants who began the study with metabolic syndrome compared with metabolically normal controls. After controlling for risk factors, patients with metabolic syndrome were at a 21% excess risk of developing subclinical hypothyroidism (adjusted HR 1.21; 95% CI 1.03–1.42). When individual components were analyzed, an increased risk of subclinical hypothyroidism was associated with high blood pressure (1.24; 1.04–1.48) and high serum triglycerides (1.18; 1.00–1.39), with a trend of increasing risk as participants had additional more components. Individuals with metabolic syndrome are at a greater risk for developing subclinical hypothyroidism, while its mechanisms and temporal consequences of this observation remain to be determined.

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed drugs for mood disorders. Long term use of SSRIs is associated with an increased risk of diabetes, but the underlying mechanism(s) remains elusive. E-cadherin-mediated cell-cell adhesion and elevated [Ca2+]i are important for insulin release and pancreatic β cell functions. This study aims to investigate whether a SSRI, fluoxetine (Prozac), induces pancreatic β cell dysfunction through affecting E-cadherin and/or [Ca2+]i. Here we show that fluoxetine significantly reduces glucose stimulated insulin secretion (GSIS). MIN6 cells, an established murine immortalized β cell line, form smaller colonies of loosely packed cells with reduced cell-cell contact after fluoxetine treatment. Immunofluorescence staining reveals that fluoxetine increases cytoplasmic accumulation of E-cadherin and reduces the membrane-localized E-cadherin probably due to increase of its endocytosis. Fluoxetine inhibits spreading of β cells on E-cad/Fc coated slides and also disrupts E-cadherin-mediated actin filaments. Additionally, fluoxetine significantly suppresses endoplasmic reticulum (ER) calcium release and store-operated calcium entry (SOCE) activation, probably through reduction of ER calcium storage and inhibition of stromal interaction molecule 1 (STIM1) trafficking. These data suggest that exposure to fluoxetine results in impaired β cell functions, occurring in concert with reduction of E-cadherin-dependent cell adhesion and alterations of calcium homeostasis.

Objectives The aim of this study was to examine the characteristics of patients, physicians, and medical facilities, and their association with prescriptions that do not include metformin as the initial oral antidiabetic agent. Study design Observational, cross-sectional study. Methods Patients with incident type 2 diabetes between January 1, 2006, and December 31, 2010, were identified from the Taiwan National Insurance Research Database. We describe trends in the initial prescription of antidiabetic medications that do not contain metformin during the study period. A multivariable logistic model and a multilevel linear model were used in the analysis of factors at a range of levels (patient, physician, and medical facility), which may be associated with the selection of oral antidiabetic drugs. Results During the study period, the proportion of prescriptions that did not include metformin declined from 43.8% to 26.2%. Male patients were more likely to obtain non-metformin prescriptions (adjusted odds ratio [OR]: 1.15; 95% confidence interval [CI]: 1.08–1.23), and the likelihood that a patient would be prescribed a non-metformin prescription increased with age. Physicians aged ≥35 years and those with specialties other than endocrinology tended to prescribe non-metformin prescriptions. Metformin was less commonly prescribed in for-profit hospitals (adjusted OR: 1.34, 95% CI: 1.11–1.61) and hospitals in smaller cities (adjusted OR: 1.28, 95% CI: 1.05–1.57) and rural areas (adjusted OR: 1.83, 95% CI: 1.32–2.54). Conclusions Disparities continue to exist in clinical practice with regard to the treatment of diabetes. These inequalities appear to be linked to a variety of factors related to patients, physicians, and medical facilities. Further study will be required to understand the effects of continuing medical education in enhancing adherence to clinical guidelines.

Gastric atrophy results in lower plasma ghrelin, higher gastrin secretion, a change in gut microbiota, and altered dietary nutrient absorption, which may be associated with the incidence of diabetes. Helicobacter pylori (H. pylori) infection is a major cause of gastric atrophy and is associated with diabetes in some reports. Since there is no study which investigates the impact of gastric atrophy on diabetes, we conduct a prospective cohort study to examine the relationship between H. pylori infection, gastric atrophy, and incident diabetes. In this study, subjects with gastric atrophy had a lower risk of incident diabetes, compared to those without gastric atrophy. The extent of gastric atrophy, measured by serum pepsinogen (PG) I/II ratio, was correlated with age, H. pylori IgG titer, HOMA2-IR, and HOMA2%B. When gastric atrophy is more extensive, presented as a lower serum PG I/II ratio, the risk of incident diabetes is lower. On the other hand, there was no significant association between H. pylori infection and the incidence of diabetes. In conclusion, the presence and the extent of gastric atrophy, but not H. pylori infection, are associated with incident diabetes. Further studies are needed to investigate the detailed mechanisms and the potential applications of the findings to guide diabetes screening and treatment strategies.

Background: Serum vascular adhesion protein-1 (VAP-1) predicts cancer-related mortality in diabetic subjects. However, whether serum VAP-1 predicts cancer incidence or cancer progression remains unclear. We conducted a cohort study to investigate whether serum VAP-1 and related clinical variables predict incident cancers in type II diabetic subjects. Methods: From 1996 to 2003, we enrolled 568 type II diabetic subjects who were free of cancer at baseline. Serum VAP-1 at enrollment was measured by time-resolved immunofluorometric assay. Chronic kidney disease (CKD) was defined as estimated glomerular filtration rate Results: During a mean follow-up of 11.3 years, 71 subjects developed incident cancers. The HRs for incident cancers in subjects with highest tertile of serum VAP-1 and in subjects with CKD were 2.95 [95% confidence interval (CI), 1.31–6.63; P = 0.009] and 2.29 (95% CI, 1.18–4.44; P = 0.015), respectively, after multivariate adjustment. There was an interaction between serum VAP-1 and CKD on the risk of incident cancers (P = 0.01 for log-transformed VAP-1 × CKD). The relationship among serum VAP-1, CKD, and incident cancers was similar if death was considered in the competing risk models or if subjects with shorter follow-up period were excluded. Conclusions: Higher serum VAP-1 and CKD can independently predict future development of cancers in type II diabetic subjects. Impact: Physicians should be aware of the early signs of cancer in diabetic individuals with elevated VAP-1 or renal dysfunction. More aggressive treatment strategies might be considered. Cancer Epidemiol Biomarkers Prev; 23(7); 1366–73. ©2014 AACR.

Biphasic insulin aspart 30 allows fewer daily injections versus basal-bolus insulin regimens, which may improve adherence and treatment outcome. This sub-analysis of the observational A1chieve study assessed clinical safety and effectiveness of biphasic insulin aspart 30 in people with type 2 diabetes previously receiving basal-bolus insulin regimens.A1chieve was an international, open-label, 24-week study in people with type 2 diabetes starting/switching to biphasic insulin aspart 30, insulin detemir or insulin aspart. This sub-analysis assessed patients switching from insulin glargine- or neutral protamine Hagedorn insulin-based basal-bolus insulin regimens to biphasic insulin aspart 30.1024 patients were included. At 24 weeks, glycated haemoglobin and fasting plasma glucose were significantly reduced from baseline in both cohorts (all p0.001). The proportion reporting any hypoglycaemia, major hypoglycaemia or nocturnal hypoglycaemia was significantly reduced after 24 weeks (all p0.05). No serious adverse drug reactions were reported. Both cohorts had significantly improved health-related quality of life (HRQoL; p0.001).24 weeks after switching from basal-bolus insulin regimens to biphasic insulin aspart 30, glycaemic control and HRQoL were significantly improved, and hypoglycaemia was significantly reduced. This suggests that people with type 2 diabetes inadequately controlled on basal-bolus insulin regimens can consider biphasic insulin aspart 30.

Fasting plasma glucose (FPG) is the preferred test in diagnosis of diabetes mellitus (DM) to 2-h post-challenged plasma glucose (2hPG). There is little information available on the comparison between FPG and 2hPG diagnostic criteria. This study included adult participants (≥18 years old) of the NHANES 2005–2010 with FPG, 2hPG, and BMI measured. Subjects with established DM were excluded. The sensitivity of FPG and 2hPG diagnostic criteria was compared as the main outcome measure. Among 5,782 subjects, 476 subjects (8.23 %) were diagnosed with DM by either FPG, 2hPG, or both criteria. Among the subjects meeting the criterion of FPG, those with 2hPG

Patients with Type 2 diabetes mellitus are at a higher risk of colorectal cancer (CRC). The objective of our study was to examine the inter-relationship among infection sites, systemic antibiotic use and risk of CRC among patients with Type 2 diabetes mellitus. From a diabetic cohort from the Taiwan's National Health Insurance claims database, we identified 3,593 incident colon cancer cases, 1,979 rectal cancer cases and 22,288 controls and conducted a nested case-control study to examine the association between antibiotic use and CRC incidence. Logistic regression models were applied to estimate the odds ratio (OR) and the 95% confidence interval (95% CI) between infection sites, antibiotic use and CRC incidence. Patients with intra-abdominal infection were significantly associated with increased risk for colon cancer (OR = 2.01, 95% CI = 1.73-2.35) and rectal cancer (OR = 1.59, 95% CI = 1.26-2.00). Any antianaerobic antibiotic use was associated with a higher risk of colon cancer (OR = 2.31, 95% CI = 2.12-2.52) and rectal cancer (OR = 1.69, 95% CI = 1.50-1.90) but without an obvious dose-response relationship for cumulative use. Antianaerobic antibiotics also increased the risks for those with nonintra-abdominal infection. No association was found between antiaerobic agent use and the CRC risk. The results suggest intra-abdominal infections and antianaerobic antibiotic use may be a marker for precancerous lesions or early CRC, although the possibility of antianaerobic antibiotics playing an additional role cannot be excluded. Further research examining the relationship between intra-abdominal infection, antianaerobic antibiotics use and possible change of microbiota leading to colorectal carcinogenesis is warranted.

To access publisher's full text version of this article click on the hyperlink at the bottom of the page To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry. Canadian Institutes of Health Research Medical Research Council UK G0601261 Mexico Convocatoria SSA/IMMS/ISSSTE-CONACYT 2012-2 clave 150352 IMSS R-2011-785-018 CONACYT Salud-2007-C01-71068 US National Institutes of Health DK062370 HG000376 DK085584 DK085545 DK073541 DK085501 Wellcome Trust WT098017 WT090532 WT090367 WT098381 WT081682 WT085475 info:eu-repo/grantAgreement/EC/FP7/201413

Silencing of acid-labile subunit (ALS) improved glucose metabolism in animal models. The aim of this study is to evaluate the effects of rosiglitazone (RSG) on ALS levels in individuals with type 2 diabetes. A randomized, double-blind, placebo-controlled trial was conducted. Subjects with type 2 diabetes mellitus were randomly distributed to an RSG-treated(n=30)or a placebo(n=31)group. Patients were evaluated prior to treatment at baseline and at 12 and 24 weeks after treatment. At baseline, ALS levels were negatively associated with low-density lipoprotein cholesterol (LDLc) levels and homeostatic model assessment version 2 insulin sensitivity (HOMA2-%S). Over 24 weeks, there was a significantly greater reduction in ALS levels in the nonobese RSG-treated individuals than placebo-treated group. The effect of RSG on ALS was not significant in obese individuals. Fasting plasma glucose and hemoglobin A1c were reduced, but total cholesterol and LDLc were increased, in patients on RSG. Change in ALS levels predicted changes in total cholesterol and HOMA2-%S over time. This study suggested a BMI-dependent effect of RSG treatment on ALS levels. Reduction of ALS by RSG increases the risk of atherosclerosis in individuals with type 2 diabetes.

(1) Background: Overt and subclinical hypothyroidism has been associated with increased cardiometabolic risks. Here we further explore whether thyroid function within normal range is associated with cardiometabolic risk factors in a large population-based study. (2) Methods: We screened 24,765 adults participating in health examinations in Taiwan. Participants were grouped according to high-sensitive thyroid-stimulating hormone (hsTSH) level as: &lt, 50th percentile (0.47&ndash, 1.48 mIU/L, the reference group), 50&ndash, 60th percentile (1.49&ndash, 1.68 mIU/L), 60&ndash, 70th percentile (1.69&ndash, 1.94 mIU/L), 70&ndash, 80th percentile (1.95&ndash, 2.3 mIU/L), 80&ndash, 90th percentile (2.31&ndash, 2.93 mIU/L), and &gt, 90th percentile (&gt, 2.93 mIU/L). Cardiometabolic traits of each percentile were compared with the reference group. (3) Results: Elevated hsTSH levels within normal range were dose-dependently associated with increased body mass index, body fat percentage, waist circumferences, blood pressure, hemoglobin A1c (HbA1c), fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), high homeostasis model of assessment of beta-cell (HOMA-&beta, ), triglycerides, total cholesterols, fibrinogen, and uric acids (p-for-trend &lt, 0.001), but not with fasting glucose levels. The association remained significant after adjustment of age, sex, and lifestyle. As compared to the reference group, subjects with the highest hsTSH percentile had significantly increased risk of being overweight (adjusted odds ratio (adjOR): 1.35), increased body fat (adjOR: 1.29), central obesity (adjOR: 1.36), elevated blood pressure (adjOR: 1.26), high HbA1c (adjOR: 1.20), hyperinsulinemia (adjOR: 1.75), increased HOMA-IR (adjOR: 1.45), increased HOMA-&beta, (adjOR: 1.40), hypertriglyceridemia (adjOR: 1.60), hypercholesterolemia (adjOR: 1.25), elevated hsCRP (adjOR: 1.34), increased fibrinogen (adjOR: 1.45), hyperuricemia (adjOR: 1.47), and metabolic syndrome (adjOR: 1.42), but significant risk of low fasting glucose (adjOR: 0.89). Mediation analysis indicates that insulin resistance mediates the majority of the association between thyroid hormone status and the metabolic syndrome. (4) Conclusion: Elevated hsTSH within the normal range is a cardiometabolic risk marker associated with central obesity, insulin resistance, elevated blood pressure, dyslipidemia, hyperuricemia, inflammation, and hypercoagulability.