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Context Angiopoietin-like protein 6 (ANGPTL6) is a hepatokine that improves insulin sensitivity in animals. However, serum ANGPTL6 concentration was found to be higher in human participants with diabetes or metabolic syndrome in cross-sectional studies, implying that ANGPTL6 may be induced to counteract hyperglycemia. Objective To investigate whether serum ANGPTL6 can predict incident diabetes and explore whether glucose or insulin can regulate ANGPTL6 expression and secretion. Design This cohort study included adults without diabetes at baseline who were followed every 2 years for incident diabetes. Serum ANGPTL6 concentrations were measured at baseline and during oral glucose tolerance tests (OGTTs). A hepatic cell line, HepG2, and diet-induced obesity mouse model were used to evaluate the response of ANGPTL6 expression and secretion to hyperglycemia and the metabolic syndrome. Results We recruited 1103 participants without diabetes at baseline. During the 4.22-year follow-up, 113 (10.2%) participants developed incident diabetes. Serum ANGPTL6 was negatively associated with the incidence of diabetes (adjusted hazard ratio, 0.77; P = 0.042). However, serum ANGPTL6 level was higher in participants with prediabetes (P = 0.018) and was elevated during OGTT. In HepG2 cells, treatment with glucose, but not insulin, induced ANGPTL6 expression. Hepatic ANGPTL6 expression and serum ANGPTL6 concentrations were significantly higher in mice fed with a high-fat diet than in those fed with a standard chow (both P < 0.05). Conclusion A high serum ANGPTL6 level is associated with a low incidence of diabetes in humans. ANGPTL6 is expressed and secreted in response to hyperglycemia to maintain glucose homeostasis.

Insulin resistance and obesity are pivotal features of type 2 diabetes mellitus. Peroxisome proliferator-activated receptor γ (PPARγ) is a master transcriptional regulator of systemic insulin sensitivity and energy balance. The anti-diabetic drug thiazolidinediones are potent synthetic PPARγ ligands and insulin sensitizers with undesirable side effects including increased adiposity, fluid retention, and osteoporosis, which limit their clinical use. We and others have proved that 15-keto-PGE2 is an endogenous natural PPARγ ligand. 15-keto-PGE2 is catalyzed by prostaglandin reductase 2 (PTGR2) to become inactive metabolites. We found that 15-keto-PGE2 level is increased in Ptgr2 knockout mice. Ptgr2 knockout mice were protected from diet-induced obesity, insulin resistance, and hepatic steatosis without fluid retention nor reduced bone mineral density. Diet-induced obese mice have drastically reduced 15-keto-PGE2 levels compared to lean mice. Administration of 15-keto-PGE2 markedly improved insulin sensitivity and prevented diet-induced obesity in mice. We demonstrated that 15-keto-PGE2 activates PPARγ through covalent binding to its cysteine 285 residue at helix 3, which restrained its binding pocket between helix 3 and β-sheets of the PPARγ ligand binding domain. This binding mode differs from the helix12-dependent binding mode of thiazolidinediones. We further identified a small-molecule PTGR2 inhibitor BPRPT245, which interferes the interaction between the substrate-binding sites of PTGR2 and 15-keto-PGE2. BPRPT245 increased 15-keto-PGE2 concentration, activated PPARγ, and promoted glucose uptake in adipocytes. BPRPT245 also prevented diet-induced obesity, improved insulin sensitivity and glucose tolerance, lowers fasting glucose without fluid retention and osteoporosis. In humans, reduced serum 15-keto-PGE2 levels were observed in patients with type 2 diabetes compared with controls. Furthermore, serum 15-keto-PGE2 levels correlate inversely with insulin resistance and fasting glucose in non-diabetic humans. In conclusion, we identified a new therapeutic approach to improve insulin sensitivity and protect diet-induced obesity through increasing endogenous natural PPARγ ligands without side effects of thiazolidinediones.

Obesity and type 2 diabetes have reached pandemic proportion. In particular, the population with diabetes is expected to rise rapidly in East and South Asia. ALDH2 (acetaldehyde dehydrogenase 2, mitochondrial) is the key metabolizing enzyme of acetaldehyde and other toxic aldehydes, such as 4-hydroxynonenal (4-HNE). A missense mutation, Glu504Lys of ALDH2 (denoted as the ALDH2*2 allele) is prevalent in 560 million East Asians, resulting in reduced ALDH2 enzymatic activity. We found that Aldh2*2/*2 homozygous knock-in (KI) mice mimicking human Glu504Lys mutation were prone to develop diet-induced obesity, glucose intolerance, insulin resistance, and fatty liver on a high-fat high-sucrose diet compared with controls. The Aldh2 KI mice demonstrated reduced energy expenditure and thermogenesis. Proteomic analyses of the brown adipose tissue (BAT) of the Aldh2 KI mice identified increased 4-HNE-adducted proteins involved in fatty acid oxidation and electron transport chain. Fatty acid oxidation rate and mitochondrial electron transport activity were reduced in the BAT of the Aldh2 KI mice, which explained the decrease in thermogenesis and energy expenditure. AD-9308 is a water-soluble prodrug of a potent and highly selective ALDH2 activator AD-5591. In vitro, AD-5591 enhanced both WT and mutant ALDH2 enzymatic activities. AD-9308 allosterically activates ALDH2 mainly by partially blocking the substrate exit tunnel, thereby accelerating the substrate-enzyme collision. In vivo, AD-9308 treatment reduced serum 4-HNE levels, ameliorated diet-induced obesity and fatty liver, and improved glucose homeostasis in both Aldh2 WT and KI mice dose-dependently. Our data highlight the therapeutic potential of reducing toxic aldehyde levels by activating ALDH2 for treating metabolic diseases.

Hemoglobin glycation index (HGI) is used to describe the difference between estimated and measured glycated hemoglobin (HbAThis retrospective cohort study enrolled 780 patients with type 2 diabetes and a low CKD risk according to the criteria of kidney disease: improving global outcomes. Participants were divided into two subgroups according to the baseline HGI calculated by fasting blood glucose and HbAThe participants were followed for a median of 7.3 years. A high HGI predicted rapid renal function decline without or with a resultant eGFR 60 ml/min/1.73 mHGI independently predicted renal function deterioration in patients with type 2 diabetes and a low CKD risk. Further investigations are warranted to elucidate its potential clinical impact.

Inflammation, oxidative stress, and formation of advanced glycated end products (AGEs) and advanced lipoxidation end products (ALEs) are important for atherosclerosis. Vascular adhesion protein-1 (VAP-1) participates in inflammation and has semicarbazide-sensitive amine oxidase (SSAO) activity, which catalyzes oxidative deamination to produce hydrogen peroxide and aldehydes, leading to generation of AGEs and ALEs. However, the effect of VAP-1/SSAO inhibition on atherosclerosis remains controversial, and no studies used coronary angiography to evaluate if plasma VAP-1/SSAO is a biomarker for coronary artery disease (CAD). Here, we examined if plasma VAP-1/SSAO is a biomarker for CAD diagnosed by coronary angiography in humans and investigated the effect of VAP-1/SSAO inhibition by a specific inhibitor PXS-4728A on atherosclerosis in cell and animal models. In the study, VAP-1/SSAO expression was increased in plaques in humans and in apolipoprotein E (ApoE)-deficient mice, and colocalized with vascular endothelial cells and smooth muscle cells (SMCs). Patients with CAD had higher plasma VAP-1/SSAO than those without CAD. Plasma VAP-1/SSAO was positively associated with the extent of CAD. In ApoE-deficient mice, VAP-1/SSAO inhibition reduced atheroma and decreased oxidative stress. VAP-1/SSAO inhibition attenuated the expression of adhesion molecules, chemoattractant proteins, and proinflammatory cytokines in the aorta, and suppressed monocyte adhesion and transmigration across human umbilical vein endothelial cells. Consequently, the expression of markers for macrophage recruitment and activation in plaques was decreased by VAP-1/SSAO inhibition. Besides, VAP-1/SSAO inhibition suppressed proliferation and migration of A7r5 SMC. Our data suggest that plasma VAP-1/SSAO is a novel biomarker for the presence and the extent of CAD in humans. VAP-1/SSAO inhibition by PXS-4728A is a potential treatment for atherosclerosis.

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.

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.

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.

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.

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.

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 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.

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

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.

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 (

Adipocyte differentiation is a multistep program under regulation by several factors. Peroxisome proliferator-activated receptor γ (PPARγ) serves as a master regulator of adipogenesis. However, the endogenous ligand for PPARγ remained elusive until 15-keto-PGE2 was identified recently as an endogenous PPARγ ligand. In this study, we demonstrate that zinc-containing alcohol dehydrogenase 2 (ZADH2; here termed prostaglandin reductase-3, PTGR-3) is a new member of prostaglandin reductase family that converts 15-keto-PGE2 to 13,14-dihydro-15-keto-PGE2. Adipogenesis is accelerated when endogenous PTGR-3 is silenced in 3T3-L1 preadipocytes, whereas forced expression of PTGR-3 significantly decreases adipogenesis. PTGR-3 expression decreased during adipocyte differentiation, accompanied by an increased level of 15-keto-PGE2. 15-keto-PGE2 exerts a potent proadipogenic effect by enhancing PPARγ activity, whereas overexpression of PTGR-3 in 3T3-L1 preadipocytes markedly suppressed the proadipogenic effect of 15-keto-PGE2 by repressing PPARγ activity. Taken together, these findings demonstrate for the first time that PTGR-3 is a novel 15-oxoprostaglandin-Δ(13)-reductase and plays a critical role in modulation of normal adipocyte differentiation via regulation of PPARγ activity. Thus, modulation of PTGR-3 might provide a novel avenue for treating obesity and related metabolic disorders.

Elevated oxidative stress is closely associated with obesity. Emerging evidence shows that instead of being a consequence of obesity, oxidative stress may also contribute to fat formation. Nonselenocysteine-containing phospholipid hydroperoxide glutathione peroxidase (NPGPx) is a conserved oxidative stress sensor/transducer and deficiency of NPGPx causes accumulation of reactive oxygen species (ROS). In this communication, we show that NPGPx was highly expressed in preadipocytes of adipose tissue. Deficiency of NPGPx promoted preadipocytes to differentiate to adipocytes via ROS-dependent dimerization of protein kinase A regulatory subunits and activation of CCAAT/enhancer-binding protein beta (C/EBPβ). This enhanced adipogenesis was alleviated by antioxidant N-acetylcysteine (NAC). Consistently, NPGPx-deficient mice exhibited markedly increased fat mass and adipocyte hypertrophy, while treatment with NAC ablated these phenotypes. Furthermore, single nucleotide polymorphisms (SNPs) in human NPGPx gene, which correlated with lower NPGPx expression level in adipose tissue, were associated with higher body mass index (BMI) in several independent human populations. These results indicate that NPGPx protects against fat accumulation in mice and human via modulating ROS, and highlight the importance of targeting redox homeostasis in obesity management. Deficiency of the glutathione peroxidase NPGPx increases ROS levels in preadipocytes and promotes adipocyte differentiation via increasing oxidative stress and consequent increased fat mass and adipocyte hypertrophy.

Semicarbazide-sensitive amine oxidase (SSAO)/vascular adhesion protein-1 (VAP-1) is involved in the pathogenesis of both atherosclerosis and cancer. Because chemical components and metabolites of cigarettes are deaminated by SSAO, the relationship between smoking and serum SSAO/VAP-1 was studied in humans.A total of 451 non-diabetic and normoalbuminuric Han Chinese subjects were recruited to participate in this study. Smoking history was obtained by using a questionnaire and those who smoked more than 100 cigarettes during a 6-month period were considered smokers. Serum VAP-1 concentration was measured by time-resolved immunofluorometric assay. Age, gender, waist circumference and estimated glomerular filtration rate (GFR) were adjusted in different statistical models.Smokers were mainly male (85.7% versus 26.3%) and were more obese than non-smokers (p 0.05). Subjects with higher serum VAP-1 concentrations were older (p 0.001) and tended to have larger waist circumferences and lower estimated GFR. Serum VAP-1 concentration was higher in smokers than in non-smokers (p 0.05) after adjusting for age, gender, waist circumference, estimated GFR, liver biochemistry and lipid profile.Cigarette smoking is associated with elevated serum VAP-1 concentration. Whether VAP-1 and its SSAO activity link the relationship between cigarette smoking, atherosclerosis and cancer requires further investigation.

Adiponectin is an important adipose-specific protein, which possesses insulin (INS)-sensitizing, antiinflammatory, and antiatherosclerotic functions. However, its regulation remains largely unknown. In this study, we identified that ryanodine receptor (RyR)3 plays an important role in the regulation of adiponectin expression. RyR3 was expressed in 3T3-L1 preadipocytes, and its level was decreased upon adipogenesis. Silencing of RyR3 expression in 3T3-L1 preadipocytes resulted in up-regulated adiponectin promoter activity, enhanced adiponectin mRNA expression, and more adiponectin protein secreted into the medium. An inverse relation between RyR3 and adiponectin mRNA levels was also observed in adipose tissues of db/db mice. In addition, knockdown of RyR3 with small interfering RNA (siRNA) in db/db mice and high-fat diet-fed obese mice increased serum adiponectin level, improved INS sensitivity, and lowered fasting glucose levels. These effects were in parallel with decreased mitochondrial Ca2+, increased mitochondrial mass, and reduced activating transcription factor 3 (atf3) expression. Overexpression of atf3 in 3T3-L1 preadipocytes blocked the effect of RyR3 silencing on adiponectin expression, indicating that an atf3-dependent pathway mediates the effect downstream of RyR3 silencing. Our data suggest that RyR3 may be a new therapeutic target for improving INS sensitivity and related metabolic disorders.

Diabet. Med. 30, 318–325 (2013) Abstract Aims To evaluate whether homeostasis model assessment and high-sensitivity C-reactive protein improve the prediction of isolated post-load hyperglycaemia. Methods The subjects were 1458 adults without self-reported diabetes recruited between 2006 and 2010. Isolated post-load hyperglycaemia was defined as fasting plasma glucose

OBJECTIVE To evaluate chronic kidney disease (CKD) and cardiovascular outcomes in TECOS (Clinical trial reg. no. NCT00790205, clinicaltrials.gov) participants with type 2 diabetes and cardiovascular disease treated with sitagliptin, a dipeptidyl peptidase 4 inhibitor, according to baseline estimated glomerular filtration rate (eGFR). RESEARCH DESIGN AND METHODS We used data from 14,671 TECOS participants assigned in a double-blind design to receive sitagliptin or placebo added to existing therapy, while aiming for glycemic equipoise between groups. Cardiovascular and CKD outcomes were evaluated over a median period of 3 years, with participants categorized at baseline into eGFR stages 1, 2, 3a, and 3b (≥90, 60–89, 45–59, or 30–44 mL/min/1.73 m2, respectively). RESULTS Participants with eGFR stage 3b were older, were more often female, and had a longer duration of diabetes. Four-point major adverse cardiovascular event rates increased with lower baseline eGFR (3.52, 3.55, 5.74, and 7.34 events/100 patient-years for stages 1–3b, respectively). Corresponding adjusted hazard ratios for stages 2, 3a, and 3b versus stage 1 were 0.93 (95% CI 0.82–1.06), 1.28 (1.10–1.49), and 1.39 (1.13–1.72), respectively. Sitagliptin therapy was not associated with cardiovascular outcomes for any eGFR stage (interaction P values were all >0.44). Kidney function declined at the same rate in both treatment groups, with a marginally lower but constant eGFR difference (−1.3 mL/min/1.73 m2) in those participants who were assigned to sitagliptin. Treatment differences in these eGFR values remained after adjustment for region, baseline eGFR, baseline HbA1c, time of assessment, and within-study HbA1c levels. CONCLUSIONS Impaired kidney function is associated with worse cardiovascular outcomes. Sitagliptin has no clinically significant impact on cardiovascular or CKD outcomes, irrespective of baseline eGFR.

Objective Using a specific cutoff of fasting plasma glucose (FPG) to screen gestational diabetes mellitus (GDM) can reduce the use of oral glucose tolerance tests (OGTT). Since the prevalence of GDM increases with age, this screening method may not be appropriate in healthcare systems where women become pregnant at older ages. Therefore, we aimed to develop a screening algorithm for GDM that takes maternal age into consideration. Methods We included 945 pregnant women without history of GDM who received 75g OGTT to diagnose GDM in 2011. Screening algorithms using FPG with or without age were developed. Another 362 pregnant women were recruited in 2013–2015 as the validation cohort. Results Using FPG criteria alone, more GDM diagnoses were missed in women ≥35 years than in women

We appreciate the comments on the discrepancy among the studies raised by Wu et al. However, the study designs and comparators for the acarbose treatment group in the three studies are obviously different. The first study by Chen et al. compared the risk of developing cardiovascular disease (CVD) among patients with Type 2 diabetes receiving various durations and doses of acarbose and those never receiving acarbose [1]. This study did not distinguish between acarbose monotherapy and combination therapy or between first-line acarbose therapy and second-line acarbose therapy. This article is protected by copyright. All rights reserved.

To determine the effectiveness of hemoglobin A1c (HbA1c) ≥ 6.5% in diagnosing diabetes compared to fasting plasma glucose (FPG) ≥ 126 mg/dL and 2-hour plasma glucose (2hPG) ≥ 200 mg/dL in a previously undiagnosed diabetic cohort, we included 5,764 adult subjects without established diabetes for whom HbA1c, FPG, 2hPG, and BMI measurements were collected. Compared to the FPG criterion, the sensitivity of HbA1c ≥ 6.5% was only 43.3% (106 subjects). Compared to the 2hPG criterion, the sensitivity of HbA1c ≥ 6.5% was only 28.1% (110 subjects). Patients who were diabetic using 2hPG criterion but had HbA1c < 6.5% were more likely to be older (64±15versus60±15years old,P=0.01, mean ± STD), female (53.2% versus 38.2%,P=0.008), leaner (29.7±6.1versus33.0±6.6 kg/m2,P=0.000005), and less likely to be current smokers (18.1% versus 29.1%,P=0.02) as compared to those with HbA1c ≥ 6.5%. The diagnostic agreement in the clinical setting revealed the current HbA1c ≥ 6.5% is less likely to detect diabetes than those defined by FPG and 2hPG. HbA1c ≥ 6.5% detects less than 50% of diabetic patients defined by FPG and less than 30% of diabetic patients defined by 2hPG. When the diagnosis of diabetes is in doubt by HbA1c, FPG and/or 2hPG should be obtained.

The ALDH2 gene encodes the mitochondrial aldehyde dehydrogenase 2 (ALDH2), a critical enzyme involved in ethanol clearance through acetaldehyde metabolism. ALDH2 also catalyzes the metabolism of other bioreactive aldehydes, including propionaldehyde, butyraldehyde, and 4-hydroxykenals (4-HNE). Increased levels of 4-HNE in adipose tissue positively correlate with obesity and insulin resistance. However, it remains unclear whether ALDH2 is involved in regulation of adipocyte differentiation. Here, we found that ALDH2 protein levels were lower in white adipose tissue of high-fat diet-fed mice and ob/ob mice relative to lean mice. Knockdown of ALDH2 expression in 3T3-L1 preadipocytes caused an increase in intracellular 4-HNE, thereby attenuated adipocyte differentiation. By contrast, an ALDH2 activator, Alda-1, significantly accelerated adipogenesis, which was accompanied by an increase in adipogenic gene expression. Consistently, adipogenesis was reduced when protein kinase C e (PKCe), an ALDH2 phosphorylating activator, was silenced in 3T3-L1 preadipocytes, whereas treatment with a PKCe agonist in 3T3-L1 preadipocytes enhanced adipogenesis. Whole-genome microarray profiling of Alda-1-treated cells demonstrated several upregulated transcripts encoding proteins involved in metabolism and the majority of these transcripts are for proteins involved in PPAR signaling pathways. Furthermore, PKCe-ALDH2 interaction alleviates 4-HNE induced aberrant PPARγ regulation on adipogenesis. Taken together, these results demonstrate that ALDH2 activation enhances adipogenesis and signaling pathways involving PPARγ. Thus, activation of PKCe-ALDH2 regulatory axis may be a therapeutic target for treating obesity and type 2 diabetes.

Accumulation of methylglyoxal (MG) contributes to glucotoxicity and mediates beta cell apoptosis. The molecular mechanism by which GLP-1 protects MG-induced beta cell apoptosis remains unclear. Metformin is a first-line drug for treating type 2 diabetes associated with AMPK activation. However, whether metformin prevents MG-induced beta cell apoptosis is controversial. Here, we explored the signaling pathway involved in the anti-apoptotic effect of GLP-1, and investigated whether metformin had an anti-apoptotic effect on beta cells. MG treatment induced apoptosis of beta cells, impaired mitochondrial function, and prolonged activation of AMP-dependent protein kinase (AMPK). The MG-induced pro-apoptotic effects were abolished by an AMPK inhibitor. Pretreatment of GLP-1 reversed MG-induced apoptosis, and mitochondrial dysfunction, and suppressed prolonged AMPK activation. Pretreatment of GLP-1 reversed AMPK activator 5-aminoimidazole-4-carboxamide riboside (AICAR)-induced apoptosis, and suppressed prolonged AMPK activation. However, metformin neither leads to beta cell apoptosis nor ameliorates MG-induced beta cell apoptosis. In parallel, GLP-1 also prevents MG-induced beta cell apoptosis through PKA and PI3K-dependent pathway. In conclusion, these data indicates GLP-1 but not metformin protects MG-induced beta cell apoptosis through improving mitochondrial function, and alleviating the prolonged AMPK activation. Whether adding GLP-1 to metformin provides better beta cell survival and delays disease progression remains to be validated.

Background Saxagliptin has been reported to be associated with an increased risk of hospitalization for heart failure (HF). The objective of this study was to test whether the increased risk is drug specific or a class effect for dipeptidyl peptidase-4 (DPP-4) inhibitors. Methods Diabetic patients prescribed sitagliptin, saxagliptin, and vildagliptin between 2011 and 2013 were identified from Taiwan's National Health Insurance (NHI) claims database. The outcome of interest was the first hospitalization for HF. The patients were followed for one year from drug initiation to outcome occurrence, death, or study termination (December 31, 2013). A Cox proportional hazards regression model was used to calculate the hazard ratios (HR) and their 95% confidence intervals, using sitagliptin as the reference group. Results A total of 239,669 patients, including 159,330 sitagliptin, 38,561 saxagliptin, and 41,778 vildagliptin initiators, were included in the analysis. With a follow-up period ranging from 269days (vildagliptin) to 313days (sitagliptin), the crude incidence rate of HF was 2.77, 2.63, and 1.91 per 100 person-years for sitagliptin, saxagliptin, and vildagliptin, respectively. Saxagliptin had a similar risk (HR: 0.98, 95% CI: 0.91–1.06) to sitagliptin, while vildagliptin was associated with a lower risk of HF (HR: 0.85, 95% CI: 0.78–0.93). Auxiliary analyses using acarbose (n=130,800) as a reference group consistently showed no increased risk of HF associated with DDP-4 inhibitors. Conclusion Three DPP-4 inhibitors studied seem to be safe regarding the risk of HF, while the reduced risk of vildagliptin might be a spurious association or a chance finding.

Supplemental Digital Content is available in the text, To analyze the association between use of DPP-4 inhibitors and acute pancreatitis in high-risk type 2 diabetic patients. A retrospective nationwide cohort study was conducted using the Taiwan National Health Insurance claim database. The risk associated with sitagliptin was compared to that with acarbose, a second-line antidiabetic drug prescribed for patients with similar diabetes severity and with a known neutral effect on pancreatitis. Between January 1, 2009 and December 31, 2010, a total of 8526 sitagliptin initiators and 8055 acarbose initiators who had hypertriglyceridemia or prior hospitalization history for acute pancreatitis were analyzed for the risk of hospitalization due to acute pancreatitis stratified for baseline propensity score. In the crude analysis, sitagliptin was associated with a decreased risk of acute pancreatitis (hazard ratio [HR] 0.74; 95% confidence interval [CI]: 0.62–0.88) compared to acarbose in diabetic patients with prior history of hospitalization for pancreatitis or hypertriglyceridemia. The association was abolished after stratification for propensity score quintiles (adjusted HR 0.95; 95% CI: 0.79–1.16). Similar results were found separately in both patients’ histories of prior hospitalization of acute pancreatitis (adjusted HR 0.97; 95% CI: 0.76–1.24) and those with hypertriglyceridemia (adjusted HR 0.86; 95% CI: 0.65–1.13). No significant association was found for different durations or accumulative doses of sitagliptin. In the stratified analysis, no significant effect modification was found in relation to patients’ characteristics. Use of sitagliptin was not associated with an increased risk of acute pancreatitis in high-risk diabetic patients with hypertriglyceridemia or with history of acute pancreatitis.

In the diagnosis of diabetes mellitus, hemoglobin A1c (HbA1c) is sometimes measured to determine the need of an oral glucose tolerance test (OGTT). However, HbA1c does not accurately reflect glycemic status in certain conditions. This study was performed to test the possibility that measurement of serum glycated albumin (GA) better assesses the need for OGTT. From 2006 to 2012, 1559 subjects not known to have diabetes or to use anti-diabetic medications were enrolled. Serum GA was measured, and a 75-g OGTT was then performed to diagnose diabetes. Serum GA correlated significantly to age (r = 0.27, p

Background Diabetes is the leading cause of end-stage renal disease (ESRD) worldwide. Vascular adhesion protein-1 (VAP-1) participates in inflammation and catalyzes the deamination of primary amines into aldehydes, hydrogen peroxide, and ammonia, both of which are involved in the pathogenesis of diabetic complications. We have shown that serum VAP-1 is higher in patients with diabetes and in patients with chronic kidney disease (CKD), and can predict cardiovascular mortality in subjects with diabetes. In this study, we investigated if serum VAP-1 can predict ESRD in diabetic subjects. Methods In this prospective cohort study, a total of 604 type 2 diabetic subjects were enrolled between 1996 to 2003 at National Taiwan University Hospital, Taiwan, and were followed for a median of 12.36 years. The development of ESRD was ascertained by linking our database with the nationally comprehensive Taiwan Society Nephrology registry. Serum VAP-1 concentrations at enrollment were measured by time-resolved immunofluorometric assay. Results Subjects with serum VAP-1 in the highest tertile had the highest incidence of ESRD (p

The deadenylase nocturnin (Noc, Ccrn4l) has been recently found to regulate lipid metabolism and to control preadipocyte differentiation. Here, we showed that among the five deadenylases tested, Noc and Pan2 exhibited a biphasic expression which is out of phase to each other during adipocyte differentiation of 3T3-L1 cells. The expression levels of other deadenylases, including Parn, Ccr4, and Caf1, were relatively unchanged or reduced. The immediate early expressed Noc during 3T3-L1 adipogenesis was involved in regulating mitotic clonal expansion (MCE) and cyclin D1 expression, as demonstrated in Noc-silenced 3T3-L1 cells and Noc(-/-) primary mouse embryonic fibroblasts (MEFs). Transcriptional profiling of Noc-depleted 3T3-L1 adipocytes revealed that most of the differentially expressed genes were related to cell growth and proliferation. In human adipose tissue, NOC mRNA level negatively associated with both fasting serum insulin and homeostasis model assessment of insulin resistance, and positively associated with both adiponectin mRNA levels and circulating adiponectin levels. Taken together, these results suggest the role of Noc in the modulation of early adipogenesis as well as systemic insulin sensitivity.

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.

Aims/Introduction: To evaluate if hemoglobin A1c (A1C) can replace the use of the oral glucose tolerance test (OGTT) to diagnose diabetes in Chinese patients. Materials and Methods: Subjects without pre-existing diabetes were included in this community-based study. Each participant received a 75-g OGTT and A1C tests. Results: A total of 1362 subjects, 512 men and 850 women, aged 18–88 years, were enrolled. The prevalence of diabetes was 7.4 and 7.3% by OGTT and by A1C ≥ 6.5% criteria, respectively. The optimal A1C cut-off for diabetes defined by OGTT was 6.1%. The performance of A1C ≥ 6.1% to find diabetes by OGTT was poor, with a kappa 0.50, sensitivity 80% and specificity 91%. Using current criteria of fasting plasma glucose (FPG)

Summary Background The association between haemoglobin A1c (HbA1c) levels and subclinical atherosclerosis in carotid arteries in Chinese populations is unknown. Aim, design and methods The objective of this study was to investigate this relationship and evaluate the ability of HbA1c levels to predict carotid atherosclerosis in a Chinese population. This was a cross-sectional study, which included 541 subjects without known diabetes (Taiwan Lifestyle Study). About 67 (9·2%) subjects were newly diagnosed with diabetes during the study. Carotid intima–media thickness (IMT) and the presence of carotid plaques were determined using ultrasonography. Results The HbA1c level in all subjects was positively correlated with carotid IMT (β = 0·018, P = 0·03) after being adjusted for age, gender, smoking, low-density lipoprotein cholesterol level, hypertension and body mass index. HbA1c level was higher in subjects with plaques in carotid arteries (P = 0·01). There was a positive and linear relationship between HbA1c levels and the probability of having plaques, thickened carotid IMT or both (P for all comparisons

Circulating adiponectin levels in cigarette smokers are lower than those in nonsmokers. We have previously shown that adiponectin is expressed in human monocytes. The aim of this study was to further investigate the effect of smoking on adiponectin expression in peripheral blood mononuclear cells (PBMCs).A group of 77 cigarette smokers and 51 nonsmokers were consecutively enrolled in this study. The participants' body weight, blood pressure, and metabolic parameters, including plasma glucose and plasma adiponectin levels, were recorded. The RNA from the PBMCs was assessed with real-time polymerase chain reaction (PCR) to determine the levels of adiponectin mRNA.Of the 77 smokers, 67 (87.0%) were male. Their mean (standard deviation) age was 43.17 (11.47) years, and they smoked 24.56 (12.53) cigarettes/day. The duration of smoking was 23.73 (11.69) years. Both circulating adiponectin levels (p=0.0262) and adiponectin mRNA levels in PBMCs (p0.0001) of smokers were significantly lower than those in nonsmokers. Both circulating adiponectin levels and adiponectin mRNA levels were negatively correlated with the number of cigarettes smoked per day (p0.01). In multiple linear regression analysis, smoking was an independent factor affecting adiponectin mRNA expression in PBMCs (p0.0001).Circulating adiponectin levels and adiponectin expression in PBMCs were lower in smokers; this finding suggested that attenuation of both systemic and local actions of adiponectin might contribute to the atherosclerotic process in cigarette smokers.

Most morbidly obese patients who undergo gastric bypass experience rapid remission of type 2 diabetes mellitus (T2DM) but the response in non-morbidly obese patients is not clear. This trial prospectively assessed the effect of diabetes remission, glucose metabolism, and the serial changes of insulin secretion after gastric bypass in inadequately controlled T2DM patients with a BMI of 23-35 kg/m(2).A total of 62 consecutive patients with T2DM and a BMI of 23-35 kg/m(2) underwent gastric bypass. Data were prospectively collected before surgery and 1, 4, 12, 26, and 52 weeks and 2 years after surgery. Insulin secretion was measured by insulinogenic index and area under the curve (AUC) during a standard oral glucose tolerance test (OGTT). Remission of type 2 diabetes was defined as fasting glucose level110 mg/dl and HbA1c6.0% without any glycemic therapy.Of the 62 patients, 24 were men and 38 were women (age 43.1 ± 10.8 years). Their preoperative characteristics were as follows: BMI 30.1 ± 3.3 kg/m(2), waist circumference 99.6 ± 9.6 cm, C-peptide 3.1 ± 1.4 ng/ml, and duration of T2DM 5.4 ± 5.1 years. The mean BMI decreased postoperatively to 22.6 ± 2.3 kg/m(2) in 1 year and 23.0 ± 2.7 kg/m(2) in 2 years. The mean HbA1c decreased from 9.7 ± 1.9% to 5.8 ± 0.5% in 1 year and 5.9 ± 0.5% in 2 years. Complete remission of T2DM was achieved in 57% in 1 year and 55% in 2 years after surgery. Before surgery, the OGTT test showed a blunted insulin secretion pattern with an insulinogenic index of 0.1 ± 0.2 and AUC of 2,324 ± 1,015 μIU min/ml. In 1 week after surgery, the insulinogenic index increased to 0.16 and AUC decreased to 1,366 μIU min/ml along with a rapid drop of insulin resistance. The insulinogenic index and AUC gradually increased to 0.27 and 3,220, respectively, 1 year after surgery and remained stable up to 2 years with a very low insulin resistance.Laparoscopic gastric bypass facilitates immediate improvement in the glucose metabolism of inadequately controlled non-severe obese T2DM patients, and the benefit is sustained up to 2 years after surgery. The benefit is regulated by the decrease in insulin resistance, increase in early insulin response, and total insulin secretion to glucose load.

OBJECTIVE Vascular adhesion protein-1 (VAP-1) participates in inflammation and catalyzes the breakdown of amines to produce aldehyde, hydrogen peroxide, and ammonia. Serum VAP-1 correlates positively with both acute hyperglycemia and diabetes. We conducted a cohort study to evaluate whether serum VAP-1 predicts 10-year survival in type 2 diabetic patients. RESEARCH DESIGN AND METHODS Between July 1996 and June 2003, we enrolled 661 type 2 diabetic subjects at National Taiwan University Hospital. Serum VAP-1 in the samples obtained at enrollment was measured by time-resolved immunofluorometric assay. The vital status of all subjects was ascertained by linking their data with computerized death certificates in Taiwan. RESULTS The medium follow-up period was 10.4 years. Subjects with serum VAP-1 in the highest tertile had a hazard ratio (HR) of 2.19 (95% CI 1.17–4.11) for all-cause mortality adjusted for age, sex, smoking, history of cardiovascular disease, obesity, hypertension, hemoglobin A1c, diabetes duration, total cholesterol, use of statins, abnormal ankle-brachial index, estimated glomerular filtration rate (eGFR), and proteinuria. The adjusted HRs for logarithmically transformed serum VAP-1 were 5.83 (95% CI 1.17–28.97) for cardiovascular mortality, 6.32 (95% CI 1.25–32.00) for mortality from cardiovascular and diabetic causes, and 17.24 (95% CI 4.57–65.07) for cancer mortality. There were four variables, including age, serum VAP-1, proteinuria, and eGFR, which could enhance mortality prediction significantly. CONCLUSIONS Serum VAP-1 can predict 10-year all-cause mortality, cardiovascular mortality, and cancer mortality independently in type 2 diabetic subjects. Serum VAP-1 is a novel biomarker that improves risk prediction over and above established risk factors.