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Context There is a medical need for effective insulin-independent antidiabetic drugs that can promote pancreatic β-cell function and have a low risk of hypoglycemia in type 2 diabetes mellitus (T2DM) patients. R-form verapamil (R-Vera), which is able to enhance the survival of β-cells and has higher cardiovascular safety margin compared with racemic verapamil, was developed as a novel approach for T2DM treatment. Objective This randomized, double-blind, placebo-controlled clinical trial was designed to evaluate the efficacy and safety of 3 dosages of R-Vera added to ongoing metformin therapy in T2DM patients who had inadequate glycemic control on metformin alone. Methods Participants were randomly assigned in an equal ratio to receive R-Vera 450, 300, or 150 mg per day, or matching placebo, in combination with metformin. The primary endpoint was change in hemoglobin A1c (HbA1c) after 12 weeks of treatment. Results A total of 184 eligible participants were randomized to receive either R-Vera or placebo plus metformin. At week 12, significant reductions in HbA1c were observed for R-Vera 300 mg/day (−0.36, P = 0.0373) and 450 mg/day (−0.45, P = 0.0098) compared with placebo. The reduction in HbA1c correlated with decreasing fasting plasma glucose levels and improved HOMA2-β score. Treatment with R-Vera was well tolerated with no hypoglycemic episodes occurring during the trial. Conclusion Addition of R-Vera twice daily to ongoing metformin therapy significantly improved glycemic control in T2DM patients. The favorable efficacy and safety profile of R-Vera 300 mg/day can be considered as the appropriate dose for clinical practice.

Heme oxygenase (HO)-1 is a rate-limiting enzyme for degrading heme into carbon monoxide. Longer (GT)n repeat of the HO-1 gene (HMOX1) promoter has a lower transcription rate. Subjects with longer GT repeats in the HMOX1 promoter are more likely to have coronary artery disease (CAD) and cardiovascular events. We retrospectively enrolled CAD subjects with an abnormal ejection fraction (EF) 30 repeats) (p

Early onset of type 2 diabetes and a high prevalence of co‐morbidities predispose the Asian population to a high risk for, and rapid progression of, diabetic kidney disease (DKD). Apart from renin‐angiotensin system inhibitors, sodium‐glucose co‐transporter‐2 (SGLT‐2) inhibitors have been shown to delay renal disease progression in patients with DKD. In this review article, we consolidate the existing literature on SGLT‐2 inhibitor use in Asian patients with DKD to establish contemporary guidance for clinicians. We extensively reviewed recommendations from international and regional guidelines, data from studies on Asian patients with DKD, global trials (DAPA‐CKD, CREDENCE and DELIGHT) and cardiovascular outcomes trials. In patients with DKD, SGLT‐2 inhibitor therapy significantly reduced albuminuria and the risk of hard renal outcomes (defined as the onset of end‐stage kidney disease, substantial decline in renal function from baseline and renal death), cardiovascular outcomes and hospitalization for heart failure. In all the cardiovascular and renal outcomes trials, there was an initial decline in the estimated glomerular filtration rate (eGFR), which was followed by a slowing in the decline of renal function compared with that seen with placebo. Despite an attenuation in glucose‐lowering efficacy in patients with low eGFR, there were sustained reductions in body weight and blood pressure, and an increase in haematocrit. Based on the available evidence, we conclude that SGLT‐2 inhibitors represent an evidence‐based therapeutic option for delaying the progression of renal disease in Asian patients with DKD and preserving renal function in patients at high risk of kidney disease.

Type 2 diabetes mellitus (T2DM) in East Asian population is characterized by phenotypes such as low body mass index, an index of β-cell dysfunction, and higher percentage of body fat, an index of insulin resistance. These phenotypes/pathologies may predispose people to early onset of diabetes with increased risk of stroke and renal disease. Less than 50% of patients with T2DM in East Asia achieve glycemic targets recommended by national or regional guidelines, which may be due to knowledge and/or implementation gaps. Herein, we review the latest evidence with special reference to East Asian patients with T2DM and present arguments for the need to use early combination therapy to intensify glycemic control. This strategy is supported by the 5-year worldwide VERIFY study, which has reported better glycemic durability in newly diagnosed patients with T2DM with a mean HbA1c of 6.9% treated with early combination therapy of vildagliptin plus metformin versus those treated with initial metformin monotherapy followed by addition of vildagliptin only with worsening glycemic control. This paradigm shift of early intensified treatment is now recommended by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). In order to translate these evidence to practice, increased awareness and strengthening of the healthcare system are needed to diagnose and manage patients with T2DM early for combination therapy. This article is protected by copyright. All rights reserved.

Objective: Better glycemic control for hospitalized diabetic patients significantly reduces health expenditures and improves disease outcomes. We developed a dynamic dashboard with a remote management system and evaluated its impact on inpatient glycemic control. Methods: This was an observational institution-wide study; study participants were enrolled from a 1,500-bed public medical center from 2016 to 2018. We evaluated the impact of a dynamic dashboard system, which analyzed and monitored all glucose data with virtual glycemic management recommendation by a team of endocrinologists, over 3 × 1-year periods: 2016 (pre-implementation), 2017 (development), and 2018 (implementation). Results: A total of 51,641 discharges with 878,159 blood glucose measurements were obtained during the 3-year period. After implementation of the dashboard system, the proportion of patients with poor glycemic control (hyperglycemia or hypoglycemia) was reduced by 31% (from 10.2 to 7.0 per day per 100 patients with glucose monitoring; P Conclusion: We successfully installed a dynamic, electronic medical records-based dashboard monitoring system to improve inpatient glycemic control. The system, supported by a team of endocrinologists via remote recommendations, could efficiently fill an important need for improved glycemic management among hospitalized adults. Abbreviations: CDE = certified diabetes educator; DM = diabetes mellitus; EMR = electronic medical record; POC = point-of-care; TCVGH = Taichung Veterans General Hospital; UCSF = University of California, San Francisco; U.S. = United States; vGMS = virtual glucose management service

Aims To explore the pattern of insulin use and glycaemic control in Asian people with type 2 diabetes, stratified by gender, young‐onset diabetes (YOD; diagnosed before age 40 years), and diabetic kidney disease (DKD; estimated glomerular filtration rate [eGFR]

Diabetes mellitus in Asia accounts for more than half of the global prevalence. There is a high prevalence of cardiovascular disease (CVD) in the region among people with type 2 diabetes mellitus (T2DM) and it is often associated with multiple risk factors including hypertension, renal disease and obesity. The early onset of T2DM and the eventual long disease duration portends an increasing proportion of the population to premature CVD. In addition to lowering blood glucose, sodium‐glucose co‐transporter‐2 (SGLT‐2) inhibitors exert favourable effects on multiple risk factors (including blood pressure, body weight and renal function) and provide an opportunity to reduce the risk of CVD in patients with T2DM. In this article, we consolidated the existing literature on SGLT‐2 inhibitor use in Asian patients with T2DM and established contemporary guidance for clinicians. We extensively reviewed recommendations from international and regional guidelines, published data from clinical trials in the Asian population (dapagliflozin, canagliflozin, empagliflozin, ipragliflozin, luseogliflozin and tofogliflozin), CVD outcomes trials (EMPAREG‐OUTCOME, CANVAS and DECLARE‐TIMI 58) and real‐world evidence studies (CVD‐REAL, EASEL, CVD‐REAL 2 and OBSERVE‐4D). A series of clinical recommendations on the use of SGLT‐2 inhibitors in Asian patients with T2DM was deliberated among experts with multiple rounds of review and voting. Based on the available evidence, we conclude that SGLT‐2 inhibitors represent an evidence‐based therapeutic option for the primary prevention of heart failure hospitalization and secondary prevention of CVD in patients with T2DM, and should be considered early on in the treatment algorithm for patients with multiple risk factors, or those with established CVD.

Background: We investigated the association between glucose excursions and the dawn phenomenon, and the effects of oral-glucose lowering drugs on the dawn phenomenon in patients with type 2 diabetes (T2D). Methods: We conducted a post hoc analysis using data from a previous randomized trial. Patients with T2D on metformin monotherapy were randomized to receive add-on acarbose or glibenclamide for 16 weeks. Ambulatory continuous glucose monitoring (CGM) was conducted before randomization and at the end of the study. Using the CGM data, we assessed glucose excursions as indicated by mean amplitude of glycemic excursions (MAGE). The magnitude of the dawn phenomenon was calculated as the difference between the nocturnal nadir (0:00 to 6:00 a.m.) and prebreakfast glucose level. Results: A total of 50 patients with T2D [mean age 53.5 ± 8.2 years, mean glycated hemoglobin (HbA1c) 8.4 ± 1.2%] were analyzed. There was an independent association between MAGE and the dawn phenomenon [β coefficient 0.199, 95% confidence interval (CI) 0.074–0.325, p = 0.003]. HbA1c improved significantly after treatment with acarbose or glibenclamide. However, only treatment with acarbose significantly improved glucose excursions. The dawn phenomenon decreased significantly only in patients treated with acarbose (from 35.9 ± 15.7–28.3 ± 16.5 mg/dl, p = 0.037), but not in those treated with glibenclamide (from 35.9 ± 20.6–34.6 ± 17.0 mg/dl, p = 0.776). Conclusion: Glucose excursions were independently associated with the dawn phenomenon in patients with T2D on metformin monotherapy. Both glucose excursions and the dawn phenomenon improved after treatment with acarbose, but not after treatment with glibenclamide.

We investigated the association between postchallenge glucose increment and hemoglobin glycation index (HGI), the difference between observed and predicted glycated hemoglobin (HbA1c), in subjects with no history of diabetes. We enrolled 1381 subjects who attended our outpatient clinic for an oral glucose tolerance test (OGTT) to screen for diabetes. HGI was defined as observed HbA1c minus predicted HbA1c. The predicted HbA1c was calculated by entering fasting plasma glucose (FPG) level into an equation [HbA1c(%)=FPG(mg/dL)*0.029+2.9686] determined from an HbA1c versus FPG regression analysis using data from an independent cohort of 2734 subjects with no history of diabetes. The association between 2-hour glucose increment and HGI was analyzed using linear regression analyses with adjustment of relevant parameters. Overall, the proportions of subjects with normal glucose tolerance, pre-diabetes, and newly diagnosed diabetes were 42.3%, 41.3%, and 16.4%, respectively. Compared with subjects who had an HGI≤0, subjects with an HGI>0 had a lower FPG (95.0±13.3 vs 98.5±15.3 mg/dL, p

Aims: To assess the cardiovascular (CV) safety of oral semaglutide, the first tablet formulation of a glucagon-like peptide-1 receptor agonist. Materials and methods: PIONEER 6 is a multinational, randomized, placebo-controlled, double-blind trial in patients with type 2 diabetes at high risk of CV events (defined as being aged ≥50 years and having established CV disease [CVD] or moderate [stage 3] chronic kidney disease [CKD], or being aged ≥60 years with ≥1 other CV risk factor). Patients were randomized to once-daily oral semaglutide (up to 14 mg) or placebo added to standard of care. The primary composite endpoint is time to first occurrence of CV death or non-fatal myocardial infarction or non-fatal stroke. The primary hypothesis was to exclude an excess in CV risk with oral semaglutide by assessing non-inferiority versus placebo for the primary endpoint (non-inferiority margin of 1.8 for the upper boundary of the 95% confidence interval of the hazard ratio). PIONEER 6 is event-driven, with follow-up continuing until accrual of at least 122 primary outcome events. There is no pre-defined minimal duration. Results: Overall, 3183 patients have been enrolled (mean age 66.1 years, 31.6% females) in 214 sites across 21 countries. At baseline, the mean duration of diabetes was 14.9 years, mean glycated haemoglobin concentration was 66 mmol/mol (8.2%), and 84.6% of patients had established CVD/moderate CKD. Conclusions: PIONEER 6 will provide evidence regarding the CV safety of oral semaglutide in patients with type 2 diabetes and high CV risk.

We aimed to investigate the association of difference between observed and predicted glycated hemoglobin (dopHbA1c) and HbA1c reduction after vildagliptin-based oral therapy in patients with type 2 diabetes (T2D).This was a prospective observational study. Adults ≥ 20 years old with T2D and HbA1c ≧7% treated with oral anti-diabetic drugs (OADs) were eligible if their OADs were shifted to vildagliptin-based dual oral therapy. Fasting plasma glucose (FPG) and HbA1c were recorded at baseline, week 12, and week 24. To determine baseline dopHbA1c, a predicted HbA1c was calculated by inserting baseline FPG into a regression equation (HbA1c = FPG ∗ 0.0225 + 4.3806) developed from linear relationship between HbA1c and FPG in an independent cohort of 3239 outpatients with T2D (dopHbA1c = observed HbA1c - predicted HbA1c). Patients were assigned to low (≦0) or high (0) dopHbA1c group according to their baseline dopHbA1c levels. The study endpoint was changes from baseline to week 24 in HbA1c levels.A total of 1224 patients were enrolled. Patients with a dopHbA1c0 had a greater HbA1c reduction after vildagliptin-based dual oral therapy than those with a dopHbA1c ≦0 (-1.5 ± 2.0 vs. -0.4 ± 1.0%, p 0.001). Baseline dopHbA1c was positively associated with HbA1c reduction from baseline to week 24 (β coefficient 0.883, 95% CI 0.811 to 0.955, p 0.001), and the association remained significant after adjustment for confounders.In T2D patients with an HbA1c ≧7%, a higher baseline dopHbA1c was associated with a greater HbA1c reduction after shifting to vildagliptin-based dual oral therapy.

Aim To investigate the effect of changes in fasting plasma glucose (FPG) variability, as assessed by 2-year trajectories of FPG variability, on mortality risk in patients with type 2 diabetes (T2D). Methods From 2009 to 2012, outpatients with T2D, aged>18 years, were enrolled from a medical centre. FPG was measured every 3 months for 2 years in 3569 people. For each of the eight 3-month intervals, FPG variability and means were calculated, with variability defined as the coefficient of variation of FPG. Also, trajectories of FPG variability and means were determined separately, using group-based trajectory analysis with latent class growth models. These models were fitted using the SAS Proc Traj procedure. The primary outcome was all-cause mortality, which was followed-up to the end of 2014. Results Five distinct trajectories of FPG variability (low, increasing, fluctuating, decreasing and high) and means (well controlled, stable control, worsening control, improving control and poor control) were established. The five trajectories of mean FPG were all associated with the same mortality risk. In contrast, in comparison to the low FPG variability trajectory, the fluctuating, decreasing and high variability trajectories all had significantly higher risks of mortality, with respective hazards ratios of 2.63 (95% CI: 1.40–4.93; P = 0.003), 2.78 (95% CI: 1.33–5.80; P = 0.007) and 4.44 (95% CI: 1.78–11.06; P = 0.001) after multivariable adjustment. Conclusion Changes in FPG variability were independently associated with increased mortality risk in patients with T2D.

We investigated the associations of fibroblast growth factor 21 (FGF-21) with cardiovascular risk and β-cell function in patients who had no history of diabetes.We enrolled 269 outpatients who had been referred for an oral glucose tolerance test (OGTT). Plasma glucose, insulin, and FGF-21 were measured before and at 2h after the OGTT. β-cell function was assessed using the insulinogenic index, corrected for insulin resistance. Patients' 10-year coronary heart disease (CHD) risk was assessed using the Chinese Multi-provincial Cohort Study functions.Overall, there was a 10% decrease in FGF-21 after OGTT (p0.001). The decrease of FGF-21 after OGTT in patients with normal glucose tolerance, prediabetes, and diabetes was 8%, 10%, and 21%, respectively (all p0.05). Patients with a history of admission for coronary angiography had a higher 10-year CHD risk and fasting FGF-21 (both p0.001). In multivariate regression analysis, fasting FGF-21 was positively associated with 10-year CHD risk, while FGF-21 relative change 2h after OGTT was positively associated with β-cell function.In patients who had no history of diabetes, fasting FGF-21 was positively associated with 10-year CHD risk, while FGF-21 relative change 2h after OGTT was positively associated with β-cell function.

The aim was to determine the effects of dulaglutide, a synthetic once-weekly, injectable human glucagon-like peptide 1 analogue that lowers blood glucose, body weight, appetite and blood pressure, on cardiovascular outcomes. People with type 2 diabetes, aged ≥50 years, with glycated haemoglobin (HbA1c) ≤9.5%, and either a previous cardiovascular event, evidence of cardiovascular disease or ≥2 cardiovascular risk factors were randomly allocated to a weekly subcutaneous injection of either dulaglutide (1.5 mg) or placebo and followed within the ongoing Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial every 3 to 6 months. The primary cardiovascular outcome is the first occurrence of the composite of cardiovascular death or non-fatal myocardial infarction or non-fatal stroke. Secondary outcomes include each component of the primary composite cardiovascular outcome, a composite clinical microvascular outcome comprising retinal or renal disease, hospitalization for unstable angina, heart failure requiring hospitalization or an urgent heart failure visit, and all-cause mortality. Follow-up will continue until the accrual of 1200 confirmed primary outcomes. Recruitment of 9901 participants (mean age 66 years, 46% women) occurred in 370 sites located in 24 countries over a period of 2 years. The mean duration of diabetes was 10 years, mean baseline HbA1c was 7.3%, and 31% had prior cardiovascular disease. The REWIND trial's international scope, high proportion of women, high proportion of people without prior cardiovascular disease and inclusion of participants whose mean baseline HbA1c was 7.3% suggests that its cardiovascular and safety findings will be directly relevant to the typical middle-aged patient seen in general practice throughout the world.

In June 2020, the Taskforce of the Guideline Workshop 2019 convened via teleconferencing to initiate a pilot project that demonstrates the various processes and considerations involved in developing high-quality, evidence-based clinical practice guidelines for the medical management of individuals with type 2 diabetes (T2D) and its associated comorbidities, including cardiovascular disease (CVD) and chronic kidney disease (CKD). The goal of the pilot project was to create evidence-based guidelines for use of sodium-glucose transport protein 2 inhibitors (SGLT2-I) when managing very high risk T2D patients, evidenced by the presence of both CVD and CKD. For this purpose the Taskforce represented a guideline panel and made use of synthesized evidence from an ongoing BMJ Rapid Recommendations project on SGLT2-I and GLP-1 receptor agonists. Results from the Taskforce pilot project demonstrated the value, feasibility and utility of using a step-wise approach to identifying and grading evidence and then developing actionable recommendations for utilizing SGLT2-I in this at-risk T2D population. This report describes the various steps involved in the process and explains how it can be utilized to rapidly develop recommendations in a format that is easy to use and can be quickly updated as new evidence becomes available, also within the emerging concept of living guidelines.

In addition to increased risks of macrovascular and microvascular complications, patients with type 2 diabetes mellitus (T2DM) usually also are at increased risk for cognitive impairment and dementia. Hypoglycemia, a common consequence of diabetes treatment, is considered an independent risk factor for dementia in patients with T2DM. Hypoglycemia and dementia are clinically underestimated and are related to poor outcomes; thus, they may compromise the life expectancy of patients with T2DM. Epidemiological evidence of hypoglycemia-associated cognitive decline and dementia is highly varied. Acute, severe hypoglycemic episodes induce chronic subclinical brain damage, cognitive decline, and subsequent dementia. However, the effects of recurrent moderate hypoglycemia on cognitive decline and dementia remain largely uninvestigated. Poor glycemic control (including fluctuation of hemoglobin A1C [HbA1c] and glucose values) and the viscous circle of bidirectional associations between dementia and hypoglycemia may be clinically relevant. The possible pathophysiological hypotheses include post-hypoglycemic neuronal damage, inflammatory processes, coagulation defects, endothelial abnormalities, and synaptic dysfunction of hippocampal neurons during hypoglycemia episodes. This article reviews previous findings, provides insight into the detection of groups at high risk of hypoglycemia-associated dementia, and proposes specific strategies to minimize the potential burdens associated with hypoglycemia-related neurocognitive disorders in patients with T2DM.

Background The aim of the present study was to examine the association between glycemic excursions before treatment and HbA1c reduction after treatment intensification with acarbose or glibenclamide in patients with type 2 diabetes (T2D). Methods Patients receiving single or dual oral antidiabetic drug treatment with an HbA1c of 7.0–11.0 % (53–97 mmol/mol) were switched to metformin monotherapy (500 mg, t.i.d.) for 8 weeks, followed by randomization to either acarbose (100 mg, t.i.d.) or glibenclamide (5 mg, t.i.d.) as add-on treatment for 16 weeks. Glycemic excursions were assessed as mean amplitude of glycemic excursions (MAGE) with 72-h ambulatory continuous glucose monitoring. Treatment efficacy was evaluated as relative HbA1c reduction (%), calculated as (baseline HbA1c – post-treatment HbA1c)/baseline HbA1c × 100. Results Fifty patients (mean [±SD] age 53.5 ± 8.2 years, 48 % men, mean baseline HbA1c 8.4 ± 1.2 %) were analyzed. Baseline MAGE was positively correlated with relative HbA1c reduction from baseline in patients treated with acarbose (r = 0.421, P = 0.029) but not glibenclamide (r = 0.052, P = 0.813). Linear regression analysis revealed that the association between baseline MAGE and relative HbA1c reduction from baseline (β = 0.125, P = 0.029) in patients treated with acarbose remained significant after adjustment for several confounders (P

AimsThe efficacy and safety of exenatide twice daily (BID) and once weekly (QW) were assessed in Asian versus White patients with type 2 diabetes mellitus (T2DM).MethodsThis post-hoc pooled analysis evaluated patients receiving 10μg exenatide BID for 12–30 weeks or 2mg exenatide QW for 24–30 weeks in exenatide clinical development program trials. Race was self-identified.ResultsA total of 4625 patients were included (exenatide BID: Asian, n=787; White, n=2223; exenatide QW: Asian, n=511; White, n=1104). At study end, glycated hemoglobin (HbA1c), fasting glucose (FG), body weight, post-prandial glucose (PPG), and PPG excursions were significantly reduced (all P

Aim The aim of this study was to examine the association between glycemic excursions and duration of hypoglycemia after treatment intensification in patients with type 2 diabetes (T2D). Methods Patients with T2D on oral anti-diabetes drug (OAD) with glycated hemoglobin (HbA1c) of 7.0–11.0% were switched to metformin monotherapy (500mg thrice daily) for 8 weeks, followed by randomization to either glibenclamide or acarbose as add-on treatment for 16 weeks. Glycemic excursions were assessed as mean amplitude of glycemic excursions (MAGE) with 72-h ambulatory continuous glucose monitoring (CGM) before randomization and at the end of study. Hypoglycemia was defined as sensor glucose level of less than 60mg/dl in two or more consecutive readings from CGM. Results A total of 50 patients (mean age 53.5±8.2 years, male 48%, mean baseline HbA1c 8.4±1.2%) were analyzed. Duration of hypoglycemia significantly increased after treatment with glibenclamide (from 5.5±13.8 to 18.8±35.8min/day, p =0.041), but not with acarbose (from 2.9±10.9 to 14.7±41.9min/day, p =0.114). Post treatment MAGE was positively associated with change from baseline in duration of hypoglycemia after treatment with either glibenclamide ( β coefficient 0.345, p =0.036) or acarbose ( β coefficient 0.674, p =0.046). The association remained significant after multivariate adjustment ( p Conclusions Post treatment glycemic excursions are associated with changes in duration of hypoglycemia after treatment intensification with OAD in patients with T2D. Glycemic excursions should be an important treatment target for T2D to reduce the risk of hypoglycemia.

Aims: Activation of glomerular mesangial cells (MCs) and functional changes of renal tubular cells are due to metabolic abnormalities, oxidative stress, and matrix accumulation in the diabetic nephropathy (DN). Aryl hydrocarbon receptor (AhR) activation has been implicated in DN. In this study, we investigated the role of AhR in the pathophysiological processes of DN using AhR knockout (AhRKO) and pharmacological inhibitor α-naphthoflavone mouse models. Results: The increased blood glucose, glucose intolerance, MC activation, macrophage infiltration, and extracellular matrix (ECM) accumulation were significantly attenuated in AhRKO mice with diabetic inducer streptozotocin (STZ) treatment. AhR deficiency by genetic knockout or pharmacological inhibition also decreased the induction of cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2), lipid peroxidation, oxidative stress, NADPH oxidase activity, and N-ɛ-carboxymethyllysine (CML, a major advanced glycation end product) in STZ-induced diabetic mice....

Context The association between adipsin and glucose metabolism in human subjects remains unclear. Objective We investigated the associations between adipsin and insulin resistance/β-cell function in subjects with various degrees of glucose intolerance. Design Fasting blood samples were collected for measurements of fasting plasma glucose (FPG), insulin, and adipsin. An oral glucose tolerance test was conducted in subjects with no history of diabetes. Setting This study was conducted at a medical center. Patients We enrolled 240 subjects with no history of diabetes and 80 patients with known type 2 diabetes (T2D) on diet control or metformin monotherapy. Main Outcome Measure β-cell function and insulin resistance were assessed using the homeostasis model assessment (HOMA-β and HOMA-IR, respectively). Results Levels of serum adipsin were higher in subjects with normal glucose tolerance (4.0 ± 1.1 µg/mL) or prediabetes (4.0 ± 1.5 µg/mL) compared with subjects with newly diagnosed diabetes (3.8 ± 1.1 µg/mL) or with known T2D on diet control (3.4 ± 1.0 µg/mL) or metformin monotherapy (3.0 ± 1.0 µg/mL, P < 0.001). There was no significant association between adipsin and HOMA-β. In contrast, there was an independent negative association between adipsin and HOMA-IR (β coefficient −0.414, 95% CI −0.720 to −0.109, P = 0.008). The association was more prominent in subjects with a body mass index (BMI) ≥25 kg/m2 or an FPG ≥100 mg/dL (P interaction < 0.001 and 0.014, respectively). Conclusions Serum adipsin levels were negatively associated with insulin resistance, especially in subjects with a BMI ≥25 kg/m2 or an FPG ≥100 mg/dL.

Daily glucose variability, such as fasting plasma glucose fluctuation or postprandial hyperglycemia, has been proposed as contributors to diabetes-related macrovascular complications. However, its impacts on microvascular complications, such as diabetes retinopathy remain controversial. We reviewed the current evidence of the relationship between glycemic variability and diabetes retinopathy in patients with type 1 or type 2 diabetes. In general, the short-term glycemic fluctuation, either expressed as standard deviation of fasting glucose or mean glucose levels, may contribute to the development or progression of diabetic retinopathy in patients with type 2 diabetes, whereas long-term glycemic fluctuation, reflected by variation of levels of HbA1c, appeared to show a stronger association with diabetes retinopathy both in patients with type 1 and type 2 diabetes. These findings emphasize the need to reduce glycemic variability by various measures in order to reduce development and progression of diabetes retinopathy both in type 1 and type 2 diabetes patients.

Background Arterial stiffening blunts postprandial vasodilatation. We hypothesized that brain-derived neurotrophic factor (BDNF) may modulate postprandial central pulse pressure, a surrogate marker for arterial stiffening. Methods A total of 82 non-diabetic subjects received a 75-g oral glucose tolerance test (OGTT) after overnight fasting. Serum BDNF concentrations were determined at 0, 30, and 120 min to calculate the area under the curve (AUC). Brachial and central blood pressures were measured using a noninvasive central blood pressure monitor before blood withdrawals at 0 and 120 min. Results With the median AUC of BDNF of 45 (ng/ml) ∗ h as the cutoff value, the central pulse pressure after glucose intake was significantly higher in the subjects with a low BDNF than in those with a high BDNF (63 ± 16 vs. 53 ± 11 mm Hg, P = 0.003), while the brachial pulse pressure was not significantly different between the 2 groups (P = 0.099). In a multivariate linear regression model, a lower AUC of BDNF was an independent predictor of a higher central pulse pressure after oral glucose intake (linear regression coefficient − 0.202, 95% confidence interval − 0.340 to − 0.065, P = 0.004). Conclusion After oral glucose challenge, a lower serum BDNF response is significantly associated with a higher central pulse pressure.

Background There is a high hospitalization rate for diabetic patients. Since retinopathy and albuminuria are both important manifestations of microvascular disease in diabetes, our aim was to investigate the effect of retinopathy and albuminuria on long-term mortality in type 2 diabetic inpatients through this observational cohort study. Methods Type 2 diabetic inpatients given a primary diagnosis of poor glucose control were consecutively enrolled during their hospitalization periods. Clinical information was collected through review of each patient’s medical records, and mortality data were obtained from the national registry in Taiwan. Results A total of 761 type 2 diabetic inpatients were enrolled in the study with a median follow-up period of 6.6 years (interquartile range, 4.0–9.6 years). Patients in the Albuminuria(−)/Retinopathy(+), Albuminuria(+)/Retinopathy(−) and Albuminuria(+)/Retinopathy(+) groups had significantly higher risks of all-cause mortality and cardiovascular mortality than those in the Albuminuria(−)/Retinopathy(−) group. However, among patients with albuminuria, there was no significant difference in cumulative mortality between those with and without retinopathy (P = 0.821). A decrease in the estimated glomerular filtration rate (eGFR), but not retinopathy, was an independent predictor of all-cause mortality (95% CI 0.647‒0.893; P

Rationale: Diabetic retinopathy is characterized by vasopermeability, vascular leakage, inflammation, blood–retinal barrier breakdown, capillary degeneration, and neovascularization. However, the mechanisms underlying the association between diabetes mellitus and progression retinopathy remain unclear. Objective: TPL2 (tumor progression locus 2), a serine-threonine protein kinase, exerts a pathological effect on vascular angiogenesis. This study investigated the role of N ε -(carboxymethyl)lysine, a major advanced glycation end products, and the involved TPL2-related molecular signals in diabetic retinopathy using models of in vitro and in vivo and human samples. Methods and Results: Serum N ε -(carboxymethyl)lysine levels and TPL2 kinase activity were significantly increased in clinical patients and experimental animals with diabetic retinopathy. Intravitreal administration of pharmacological blocker or neutralizing antibody inhibited TPL2 and effectively suppressed the pathological characteristics of retinopathy in streptozotocin-induced diabetic animal models. Intravitreal VEGF (vascular endothelial growth factor) neutralization also suppressed the diabetic retinopathy in diabetic animal models. Mechanistic studies in primary human umbilical vein endothelial cells and primary retinal microvascular endothelial cells from streptozotocin-diabetic rats, db/db mice, and samples from patients with diabetic retinopathy revealed a positive parallel correlation between N ε -(carboxymethyl)lysine and the TPL2/chemokine SDF1α (stromal cell–derived factor-α) axis that is dependent on endoplasmic reticulum stress-related molecules, especially ATF4 (activating transcription factor-4). Conclusions: This study demonstrates that inhibiting the N ε -(carboxymethyl)lysine-induced TPL2/ATF4/SDF1α axis can effectively prevent diabetes mellitus–mediated retinal microvascular dysfunction. This signaling axis may include the therapeutic potential for other diseases involving pathological neovascularization or macular edema.

C-reactive protein (CRP) encoded by CRP gene is a reflection of systemic inflammation. Many studies associated CRP level with diabetes and glucose levels, but the association of CRP gene with these traits is unclear. We conducted a cross-sectional study consisting of 945 siblings from 330 families collected by the Stanford Asian Pacific Program in Hypertension and Insulin Resistance (SAPPHIRe) to investigate associations between CRP polymorphisms, circulating CRP, diabetes, and glucose levels. Five single-nucleotide polymorphisms were analyzed: rs3093059, rs2794521, rs1417938, rs1800947, and rs1205. The generalized estimating equation approach was used to deal with correlated data within families. CRP level was positively correlated with diabetes prevalence and levels of fasting and 2-hour glucose (each P C at rs3093059 and G at rs1205 were associated with elevated CRP level (each P −6). Allele C at rs3093059 was associated with fasting glucose (β = 0.20, P = 0.045) and G at rs1205 was associated with 2-hour glucose (β = 0.46, P = 0.00090) post oral glucose tolerance test, but only the latter passed Bonferroni correction. No polymorphism was associated with diabetes. Since 2-hour glucose is an indicator of glucose tolerance, this study indicated CRP gene is associated with glucose intolerance.

Type 2 diabetes mellitus (T2DM) is a global health-care and national policy issue. As fluctuating glycemic control in diabetes often results in serious complications, we must encourage the diabetes educators' efforts at long-term follow-up among patients with T2DM. Therefore, certified diabetes educators (CDEs) play the most pivotal roles as life-long protectors for patients with T2DM. In the past 15 years, more than 4,000 CDEs have been trained and qualified, including health professionals such as physicians, nurses, dieticians, and pharmacists. The most important initiation of diabetes share care in Taiwan was originated in I-Lan County. Initiated to provide regional diabetes care, the name of this program is the Lan-Yang Diabetes Shared Care System. In 2006, the Taiwanese Association of Diabetes Educators (TADE) carried out a nationwide survey to evaluate the status of diabetes control in Taiwan, focusing on the "ABC" goal (A: HbA1c7.0%, B: blood pressure130/80 mmHg, C: LDL-cholesterol100 mg/dl/total cholesterol160 mg/dl). The results revealed that the percentage of patients with diabetes who fulfilled all ABC goals was only 4.1%. Five years later, in 2011, TADE compared two nationwide surveys and found total ABC attainment rates of 4.1% and 8.6%, respectively. The team-care approach to T2DM has been underway for over 20 years in Taiwan. Future interventions and treatment algorithms with team-based education should aim at preventing acute and chronic complications, which remains a long-term challenge in Taiwan.

Objective: Fasting hypoglycemia may occur in subjects with systemic lupus erythematosus (SLE) when accompanied with insulin-binding antibodies or insulin-receptor antibodies. However, insulinoma has not been reported in SLE subjects with hypoglycemia.Methods: We present a case report and review the relevant literature.Results: A 26-year-old female with underlying SLE experienced several episodes of neuropsychiatric symptoms in a fasting state. The steroid dosage was titrated up, but in vain. Timely imaging studies showed a pancreatic tumor, and insulinoma was proven by pathology. Hypoglycemia did not recur after surgery.Conclusion: Physicians should distinguish insulinoma from autoimmunity-mediated hypoglycemia in SLE patients with fasting hypoglycemia.

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.

Aim: Prescription refill might be effective in saving health expenditures, but whether arefilled prescription that reduces physician consultation affects quality of diabetes care isunknown. This study sought to examine the effect of prescription refill on the outcomequality of diabetes care.Methods: A quasi-experiment design with repeated HbA1c measures for the pretest andposttest periods for a total of 2 years was used. HbA1c functions as an outcome qualityindicator. Prescription refill was measured dichotomously and also in times. Retrospectivedata of 1005 patients with type 2 diabetes were analyzed mainly by repeated measureGeneral Linear Modeling at the multivariate level with difference-in-difference (DID) statis-tics.Results: Patients using prescription refills (n = 779) experienced a significant decrease inHbA1c (from 8.4% to 7.8%, P < 0.001), compared with those without refill (n = 226, from 8.5%to 8.3%, P = 0.171), with 0.3% of DID (P = 0.043). Compared with non-refill peers, a greaterpercentage of patients refilling their prescriptions met the American Diabetes Associationstandards goal of (

Patients who experience acute ischemic stroke may develop hyperglycemia, even in the absence of diabetes. In the current study we determined the effects of acute stroke on hepatic insulin signaling, TNF-α expression, endoplasmic reticulum (ER) stress, the activities of c-Jun N-terminal kinase (JNK), inhibitor κB kinase β (IKK-β), and nuclear factor-κB (NF-κB) pathways. Rats with cerebral ischemia developed higher blood glucose, and insulin levels, and insulin resistance index, as well as hepatic gluconeogenic enzyme expression compared with the sham-treated group. The hepatic TNF-α mRNA and protein levels were elevated in stroke rats in association with increased ER stress, phosphorylation of JNK1/2 and IKK-β proteins, IκB/NF-κB signaling, and phosphorylation of insulin receptor-1 (IRS-1) at serine residue. The basal and insulin-stimulated tyrosine phosphorylation of IRS-1 and AKT proteins was reduced. In addition, acute stroke increased circulating catecholamines in association with hepatic adrenergic signaling activation. After administration of a nonselective β-adrenergic receptor blocker (propranolol) before induction of cerebral ischemic injury, hepatic adrenergic transduction, TNF-α expression, ER stress, and the activation of the JNK1/2, IKK-β, and NF-κB pathways, and serine phosphorylation of IRS-1 were all attenuated. In contrast, the phosphorylated IRS-1 at tyrosine site and AKT levels were partially restored with improved poststroke hyperglycemia and insulin resistance index. These results suggest that acute ischemic stroke can activate proinflammatory pathways in the liver by the catecholamines and is associated with the development of hepatic insulin resistance.

Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10 -8 for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD. © 2013 Nature America, Inc. All rights reserved.

Blood levels of adiponectin, an adipocyte-secreted protein correlated with metabolic and cardiovascular risks, are highly heritable. Genome-wide association (GWA) studies for adiponectin levels have identified 14 loci harboring variants associated with blood levels of adiponectin. To identify novel adiponectin-associated loci, particularly those of importance in East Asians, we conducted a meta-analysis of GWA studies for adiponectin in 7827 individuals, followed by two stages of replications in 4298 and 5954 additional individuals. We identified a novel adiponectin-associated locus on chromosome 10 near WDR11-FGFR2 (P = 3.0 × 10(-14)) and provided suggestive evidence for a locus on chromosome 12 near OR8S1-LALBA (P = 1.2 × 10(-7)). Of the adiponectin-associated loci previously described, we confirmed the association at CDH13 (P = 6.8 × 10(-165)), ADIPOQ (P = 1.8 × 10(-22)), PEPD (P = 3.6 × 10(-12)), CMIP (P = 2.1 × 10(-10)), ZNF664 (P = 2.3 × 10(-7)) and GPR109A (P = 7.4 × 10(-6)). Conditional analysis at ADIPOQ revealed a second signal with suggestive evidence of association only after conditioning on the lead SNP (Pinitial = 0.020; Pconditional = 7.0 × 10(-7)). We further confirmed the independence of two pairs of closely located loci (

ObjectivePatients with diabetes mellitus have an increased risk of coronary heart disease; however, many patients with diabetes remain untreated or undertreated for coronary heart disease risk factors. The incidence of type 2 diabetes is rapidly increasing in Taiwan. The aim of this study was to assess the lipid-lowering effects of atorvastatin in Taiwanese diabetic patients with hyperlipidemia.Materials and MethodsThis 12-week open-label study, conducted at six hospitals in Taiwan, included 157 outpatients (aged 18–80 years old) with type 2 diabetes and concomitant hyperlipidemia. Individuals were randomized (1:1:1) to three dosage groups, as follows: 52 patients received 10 mg of atorvastatin per day; 52 patients received 20 mg of atorvastatin per day; and the remaining 53 patients received 40 mg of atorvastatin per day. Treatment targets were established according to the recommendations of the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP) III. The response was evaluated by Cochran-Mantel-Haenszel tests. The change from the baseline level of all lipid parameters and high-sensitivity C-reactive protein (hs-CRP) was determined through analysis of covariance and was assessed at each time point.ResultsThe primary endpoint—a low-density lipoprotein-cholesterol (LDL-C) response of >100 mg/dL at Week 12—was achieved in a dose-dependent manner. The percentage of patients improving to this level was higher in the 20 mg/day group (82%) and 40 mg/day group (82%) than in the 10 mg/day group (56%; p = 0.002). The percentage of patients achieving the more aggressive LDL-C goal of >70 mg/dL was 9.6%, 31.4%, and 47.1% in the 10 mg/day, 20 mg/day, and 40 mg/day groups, respectively (p

Background Epicardial adipose tissue (EAT) induces activated inflammatory cells secreting cytokines, including soluble CD40 ligand (sCD40L). In turn, the serum sCD40L can trigger inflammatory responses. We examined the reduction of EAT in response to weight loss (WL) and its relationship with alterations in sCD40L in obese men. Methods We prospectively provided dietary education and exercise intervention for 3 months for 32 non-diabetic obese men with metabolic syndrome. Twenty-five age-matched healthy men served as controls. Circulating sCD40L was measured, and EAT thickness (EATt) was determined by magnetic resonance imaging before and after WL. Results EATt was increased in the obese individuals, but there were no significant differences in baseline serum sCD40L levels between the 2 groups. Serum concentrations of sCD40L were higher in individuals with high right atrioventricular groove (RAVG)–EATt. EATt was reduced significantly in individuals who completed the weight-loss program. In addition, a positive correlation was shown between changes in sCD40L and RAVG–EATt. Multiple linear regression analysis showed the change in sCD40L to be independently associated with the change in RAVG–EATt. Conclusion WL can significantly reduce epicardial fat thickness, and the reduced EATt after WL may provide a beneficial reduction in circulating levels of sCD40L in obese males.

Aims To understand the trends of ABC control in 5 years interval in Taiwan. Methods We compared two waves of nationwide surveys (n = 7541 and n = 5599, mainly type 2 diabetes) to examine the trends of ABC control across 5 years in accredited Diabetes Health Promotion Institutes in Taiwan. Results The percentages of subjects who had HbA1c lower than 7% (A), both SBP and DBP lower than 130/80 mmHg (B), and total cholesterol lower than 160 mg/dl or LDL cholesterol lower than 100 mg/dl (C) increased by 6.5% (from 32.4% to 34.5%), 22.0% (from 30.9% to 37.7%), and 57.8% (from 35.3% to 55.7%), respectively, with a resulting total ABC attainment rate from 4.1% to 8.6%. A subgroup of 720 diabetic subjects who participated in both surveys showed the same pattern of changes in B and C but had a slight deterioration of glycemic control. Logistic regression analysis revealed that diagnosis of type 1 diabetes, lower BMI and individuals not requiring insulin were independently associated with attainment of ABC goals in 2006 and 2011. An accountabilities examination revealed that annular tests of HbA1c, BP and lipids were all above 90% in both surveys. Conclusions We observed an improvement of individual and overall attainments of ABC goals across 5 years in Taiwan owing to recent implementation of several diabetes care models and initiatives. We anticipate that these improvements will translate into reductions of both macrovascular and microvascular complications.

Background Brain-derived neurotrophic factor (BDNF) is important for neural protection and energy homeostasis. In this study, we examined the effects of vascular cell adhesion molecule-1 (VCAM-1) and coronary artery disease (CAD) on BDNF. Methods Subjects who had undergone diagnostic angiography for angina were recruited, and a total of 240 subjects (144 with CAD and 96 without CAD) were enrolled. Serum BDNF was determined at 0, 30, and 120 min during an oral glucose tolerance test (OGTT) to calculate the area under the curve (AUC) for BDNF. Serum VCAM-1 was determined at fasting. Results Significantly lower AUC of BDNF (42.8 ± 10.7 vs. 47.4 ± 11.7 ng-h/ml, P = 0.002) and higher serum VCAM-1 (583 ± 383 vs. 482 ± 171 ng/ml, P = 0.017) were noted in subjects with CAD compared to those without CAD. High VCAM-1 level was an independent predictor of low AUC of BDNF in subjects with and without CAD (95%CI between − 0.011 and − 0.002, P = 0.008; − 0.033 and − 0.002, P = 0.029, respectively). Serum BDNF was lowest in the CAD subjects with high VCAM-1 levels at all time points during OGTT. Conclusion Our results showed that CAD was associated with low serum BDNF in response to OGTT, and VCAM-1 had a synergistic effect with CAD on the BDNF.

Background Excessive visceral fat with unbalanced adipokines is a critical pathogenic factor of metabolic syndrome (MetS), which is associated with disorders of the central nervous system and cardiovascular disease. Because brain-derived neurotrophic factor (BDNF) plays an important role in neurons, we examined the relationship of BDNF to MetS, adipose tissue and biomarkers in men. Methods Thirty-four non-diabetic men with MetS and another 24 age-matched men without MetS were enrolled. In addition to fasting blood samples, the area of adipose tissue at the waist was assessed by magnetic resonance imaging (MRI). Results There was no significant difference in serum BDNF concentrations between men with or without MetS (40.9 ± 8.0 vs. 43.2 ± 6.1 ng/ml, P = 0.235). However, the serum concentration of soluble vascular cell adhesion molecule-1 (VCAM-1) was higher in the subjects with a lower BDNF level (737 ± 230 vs. 628 ± 115 ng/ml, P = 0.025). An inverse correlation between VCAM-1 and BDNF was observed ( r = − 0.391, P = 0.002). After adjusting for visceral adipose tissue, VCAM-1 was found to be independently associated with BDNF [95% confidence interval (− 0.025, − 0.005), P = 0.004]. Conclusion These data show no difference in serum BDNF levels between the men with MetS and controls. However, serum BDNF was inversely correlated with serum VCAM-1 in men without diabetes.

Summary Background A recent genome-wide association study for type 2 diabetes in Han Chinese identified several novel genetic variants. We investigated their associations with quantitative measures to explore the mechanism by which these variants influence glucose homoeostasis. We also examined whether these variants predict progression to diabetes in a large prospective family based Chinese cohort. Methods Five single nucleotide polymorphisms (SNPs) near the protein tyrosine phosphatase, receptor type, D (PTPRD), SRR, MAF/WWOX, and KCNQ1 genes were genotyped in 1138 subjects of Chinese origin from the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance study. Results At baseline, the risk-conferring rs7192960 C allele near the MAF/WWOX genes was associated with lower homoeostasis model assessment of β-cell (HOMA-β) (P = 0·01) and second-phase insulin response in oral glucose tolerance test (OGTT) (P = 0·04). The risk-conferring rs2237897 C alleles in the KCNQ1 gene were associated with higher fasting glucose (P = 0·009), lower HOMA-β (P = 0·03), and lower first-phase insulin response in OGTT (P = 0·03). Over an average follow-up period of 5·43 years, participants with the risk-conferring rs17584499 TT genotype in the PTPRD gene were more likely to progress from nondiabetes to diabetes than were noncarriers (hazard ratio: 8·82, P = 4 × 10−5). The risk-conferring T allele in the PTPRD gene was associated with greater increase in homoeostasis model assessment of insulin resistance (HOMA-IR) (P = 0·04) over time. PTPRD gene expression in human adipose tissues was negatively associated with fasting insulin levels and HOMA-IR. Conclusion Genetic variants near the KCNQ1 and MAF/WWOX genes are associated with reduced insulin secretion. The PTPRD genetic variant appears to be associated with progression to diabetes in Han Chinese, most likely through increased insulin resistance.

Asia bears the world's greatest burden of type 2 diabetes (T2DM) and prevalence is increasing rapidly. Compared to other races, Asians develop T2DM younger, at a lower degree of obesity, suffer longer from its complications and die earlier. Curbing this epidemic requires an integrated, risk-based, and multidisciplinary approach. Inadequately managed T2DM has macrovascular and microvascular sequelae, Asians with T2DM being particularly susceptible to diabetic nephropathy. Earlier and more intensive monitoring and management of risk factors are required, especially for patients with, or at risk of, renal impairment. Particular challenges of T2DM management in Asia include: lack of access to specialist healthcare, insufficient clinical evaluation and delayed diagnosis. As in Caucasians, conventional treatment modalities are limited by deteriorating glycaemic control with disease progression and there is an unmet need for efficacious, safe, cost-effective and convenient pharmacotherapies for treating different stages of T2DM and preventing its complications, particularly in high-risk patients. There is a trend towards increasing use of DPP-IV inhibitors, which are no less efficacious and safe in Asians than Caucasians and may have some advantages over existing oral antidiabetic agents, particularly for certain high-risk groups. Such agents may play a significant future role in the management of T2DM.

Paraoxonase-1 (PON1) is an esterase associated with the high-density lipoprotein (HDL) in serum. To date, there have been few reports about circulating PON1 protein concentration and specific activity in subjects with metabolic syndrome (MetS). More importantly, it is unknown whether weight loss could alter PON1 protein expression or specific activity in obese non-diabetic men with MetS.We prospectively enrolled a total of 40 obese non-diabetic men with MetS. Among them, 22 subjects finished the 3-month course of weight loss program and complied for longer follow-ups post-weight loss at the 3rd, 12th, and 18th month from the beginning of the program. Twenty-six healthy volunteers served as controls. Serum circulating PON1 concentration was measured by an enzyme linked immunosorbent kit (ELISA) and PON1 activity was measured by an automated PON1 activity assay.Obese non-diabetic men with MetS (n=40) had a higher PON1 protein concentration (31.0 ± 11.3 vs. 24.8 ± 9.7 μg/ml, p=0.025) but lower specific enzyme activity (7.5 ± 4.0 vs. 11.2 ± 7.2 mU/μg, p=0.023) than those of the controls. Multivariate regression analysis of baseline PON1 specific activity revealed that adiponectin was a significant positive predictor (p=0.044) while monocyte chemotactic protein-1 (MCP-1) was a negative predictor (p=0.031). After a 3-month weight loss program, obese MetS men (n=22) had a significant weight reduction (95.8 ± 9.0 to 86.3 ± 10.4 kg, with a 9.9 ± 5.4% decrease, p0.001). PON1 protein decreased significantly after weight loss and kept declining through the 3rd month till the 18th month follow-up. PON1 specific enzyme activity (baseline 7.5 ± 2.6 mU/μg) increased significantly after weight loss and kept increasing through the 12th month till the 18th month follow-ups (11.8 ± 6.4 mU/μg, p=0.001 vs. baseline).Weight loss by a 3-month diet and exercise program time-sequentially increased PON1 specific enzyme activity in obese non-diabetic men with MetS.

The world is facing an epidemic of cardiovascular disease (CVD) and type 2 diabetes, with populations in low- to middle-income countries, including many in the Asia Pacific (AP) region, being disproportionately affected. Emerging data identify postprandial hyperglycaemia (PPHG) as an important predictor of CVD, and several professional bodies, including the International Diabetes Federation, have issued guidelines on the management of PPHG in type 2 diabetes. Guidance on how international recommendations could be implemented in Asian populations is currently lacking. Therefore, a panel of experts from the AP region convened to consider the current status of PPHG and CVD in the region, and to develop recommendations for clinical practice. The group concluded that improved awareness of the impact of PPHG on CVD risk, among clinicians and the general public, and more widespread use of routine screening for PPHG, using oral glucose tolerance testing in those without recognised diabetes, are required. Additionally, frequent meal-based testing and effective PPHG management are essential to the management of IGT and type 2 diabetes.

Both metabolic syndrome (MetS) and chronic kidney disease (CKD) are major global health issues. Current clinical markers used to reflect renal injury include albuminuria and estimated glomerular filtration rate (eGFR). Given the same eGFR level, urine albumin might be a better risk marker to predict progression of CKD and future development of cardiovascular diseases (CVDs). Serum Cystatin C is emerging as a new biomarker for early detection of renal injury associated with MetS and cardiovascular risk. In addition to each component, MetS per se influences the incidence and prognosis of renal injury and the odds ratios increased with the increase in the number of metabolic abnormalities. Hyperinsulinemia, activation of rennin-angiotensin-aldosterone system, increase of oxidative stress, and inflammatory cytokines are proposed to be the plausible biological link between MetS and CKD. Weight control, stick control of blood pressure, glucose, and lipids disorders may lead to lessening renal injury and even the subsequent CVD.

Patients who experience acute ischemic stroke may develop hyperglycemia, even in the absence of diabetes, but the exact mechanisms are still unclear. Adipose tissue secretes numerous proinflammatory cytokines and is involved in the regulation of glucose metabolism. This study aimed to determine the effects of acute stroke on adipose inflammatory cytokine expression. In addition, because sympathetic activity is activated after acute stroke and catecholamines can regulate the expression of several adipocytokines, this study also evaluated whether alterations in adipose proinflammatory cytokines following acute stroke, if any, were medicated by sympathetic system. Acute ischemic brain injury was induced by ligating the right middle cerebral artery and bilateral common carotid arteries in male adult Sprague-Dawley rats. Adipose tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) mRNA and protein levels were determined by RT-PCR and enzyme-linked immunoassay, respectively. The stroke rats developed glucose intolerance on days 1 and 2 after cerebral ischemic injury. The fasting blood insulin levels and insulin resistance index measured by homeostasis model assessment were higher in the stroke rats compared with the sham group. Epididymal adipose TNF-α and MCP-1 mRNA and protein levels were elevated one- to twofold, in association with increased macrophage infiltration into the adipose tissue. When the rats were treated with a nonselective β-adrenergic receptor blocker, propranolol, before induction of cerebral ischemic injury, the acute stroke-induced increase in TNF-α and MCP-1 was blocked, and fasting blood insulin concentration and homeostasis model assessment-insulin resistance were decreased. These results suggest a potential role of adipose proinflammatory cytokines induced by the sympathetic nervous system in the pathogenesis of glucose metabolic disorder in rats with acute ischemic stroke.

Background A previous study has reported that the Ile227 and Ala357 genetic variants of human urea transporter-2 (HUT2) were associated with blood pressure in males in Asian population. In this study, we aimed to investigate five known HUT2 genetic variants with metabolic syndrome (MetS) and its related traits in the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) study cohort. Methods Five HUT2 single nucleotide polymorphisms (SNPs) were selected and genotyped among 1791 subjects in the SAPPHIRe study cohort. We first computed allele frequency and performed Hardy–Weinberg equilibrium (HWE) test in controls for each SNP. Next, we tested genotype associations with metabolic syndrome using multiple generalized estimating equations (GEE) models with covariate adjustment. Furthermore, multi-marker and multi-trait association tests were carried out using FBAT program. To account for multiple testing, Bonferroni correction was applied in this study. Results Among those 5 HUT2 SNPs, SNPs 1, 2 and 3 were significantly associated with MetS in the total sample and females, separately (9 × 10−4 ≤ p ≤ 0.04), but only the association between SNP 1 and MetS in females remained statistically significant after Bonferroni correction. When testing 5 SNPs simultaneously, significant associations were found with triglycerides (TG) (p = 0.04). Likewise, significant multi-trait association (combining the data of waist circumference, TG, high density lipoprotein (HDL) cholesterol and fasting glucose together) was found with SNP 2 (p = 0.04), but both results of multi-maker and multi-trait associations did not remain significant after multiple testing correction. Conclusion The results have provided evidence that the HUT2 gene may play a certain role in developing MetS and its related traits in Asian population. Further investigation of the HUT2 gene influencing MetS and its related traits will be warranted.

Prohormone convertase subtilisin/kexin type 1 (PCSK1) genetic polymorphisms have recently been associated with obesity in European populations. This study aimed to examine whether common PCSK1 genetic variation is associated with obesity and related metabolic phenotypes in the Chinese population. We genotyped nine common tag single-nucleotide polymorphisms (tagSNP) of the PCSK1 gene in 1,094 subjects of Chinese origin from the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) family study. One SNP in the PCSK1 gene (rs155971) were nominally associated with risk of obesity in the SAPPHIRe cohort (P = 0.01). A common protective haplotype was associated with reduced risk of obesity (23.79% vs. 32.89%, P = 0.01) and smaller waist circumference (81.71 +/- 10.22 vs. 84.75 +/- 10.48 cm, P = 0.02). Another common haplotype was significantly associated with increased risk of obesity (37.07% vs. 23.84%, P = 0.005). The global P value for haplotype association with obesity was 0.02. We also identified a suggestive association of another PCSK1 SNP (rs3811951) with fasting glucose, fasting insulin, homeostasis model assessment of insulin resistance (HOMA(IR)), triglycerides, and high-density lipoprotein cholesterol (P = 0.05, 0.003, 0.001, 0.04, and 0.04, respectively). These data indicate common PCSK1 genetic variants are associated with obesity in the Chinese population.

Cirrhosis is characterized by skeletal muscle wasting. In this study, the effects of nitric oxide production on skeletal muscle protein nitration and degradation in cirrhosis were investigated. Cirrhosis was induced by bile duct ligation (BDL) in Sprague-Dawley rats for 4 weeks. The BDL-induced cirrhotic rats and sham-operated rats were then injected daily with either saline or NG- l -nitro-arginine methyl ester ( l -NAME) for 7 days from week 4 to week 5, after which nitrite/nitrate, glutathione reduction, as well as protein nitration, ubiquitination, and degradation were assessed in skeletal muscle. Elevated muscular nitrite/nitrate concentrations, protein nitration, total ubiquitin conjugates, and degradation fragments of myosin heavy chain as well as diminished glutathione reduction levels were observed in BDL-induced cirrhotic rats as compared with controls. Administration of l -NAME for 1 week led to reduction of nitrite/nitrate levels; protein nitration was also decreased in the skeletal muscle. In addition, ubiquitination of muscular proteins and degradation of myosin heavy chain were significantly diminished after treatment of l -NAME. In conclusion, nitrosative stress occurred in the skeletal muscle of BDL-induced cirrhotic rats and may lead to increased proteolysis of muscle-specific structural proteins.

Results of studies regarding the association between the MS and osteoporosis have been largely controversial. The objectives of this study were to measure bone mineral density (BMD) with and without the MS and evaluate the associations between bone mineral loss and the components of the MS. In all, 352 men (mean age 70.6+/-11.9 years) and 468 women (mean age 67.8+/-12.0 years) in Puli township, Taiwan, were enrolled. Height (cm), weight (kg), waist circumference (cm), and blood pressure (mmHg) were measured. Fasting plasma glucose (FPG) and blood lipids were determined. Calcaneal BMD was measured using the ultrasound pulse transmission method. The prevalence of MS was 33.0% in men and 44.2% in women. In subjects with the MS, lower diastolic blood pressure (DBP) in both sexes (p < 0.001), lower triglycerides (p = 0.016) and more central obesity in men (p = 0.011) predicted bone mineral loss. The MS was not associated with bone mineral loss in either of sexes (p = 0.550 in men; p = 0.628 in women).