Positive correlation of ANGPTL8 expression in human visceral adipose tissue with body mass index.

BACKGROUND: Angiopoietin-like protein 8 (ANGPTL8) is an important regulator of lipid metabolism. We aimed to investigate the difference of ANGPTL8 expression in different depots of adipose tissues between individuals with and without obesity, and its correlation with various metabolic parameters. METHODS: Subcutaneous (SAT) and visceral adipose tissue (VAT) samples were collected from patients who underwent bariatric or intra-abdominal surgery. Expression levels of ANGPTL8, monoglyceride lipase (MGL), monocyte chemoattractant protein-1 (MCP-1), leptin and adiponectin (APM1) were determined using real-time quantitative polymerase chain reaction. The correlation of ANGPTL8 expression with various metabolic parameters and other gene expression levels was analyzed using Person's correlation analysis. Logistic regression was used to establish a prediction model of obesity. RESULTS: Totally 330 subjects (obese: 281, non-obese: 49) were recruited. ANGPTL8 expression in VAT was significantly higher in the obesity group than in the non-obesity group (P = 0.0096). ANGPTL8 expression in VAT was positively correlated with body mass index (BMI) (r = 0.1169, P < 0.05) and was independently associated with obesity (O.R., 1.246; 95 % C.I. 1.013-21.533, P = 0.038). We also found the gene expression of ANGPTL8 in SAT and VAT was negatively correlated with APM1 expression in respective SAT and VAT. CONCLUSIONS: ANGPTL8 expression levels in VAT were higher in subjects with obesity, and positively correlated with BMI. This suggests a role of ANGPTL8 in the pathophysiology of obesity and may pave the way for novel treatment target of obesity.

Diabetes self-management education on the sustainability of metabolic control in type 2 diabetes patients: Diabetes share care program in Taiwan.

BACKGROUND: Diabetes self-management education (DSME) improves glycemic and metabolic control. However, the frequency, duration and sustainability of DSME for improving metabolic control have not been well studied. METHODS: The Diabetes Share Care Program (DSCP) stage 1 provided DSME every 3 months. If participants entering DSCP stage 1 ≥ 2 years and HbA1c < 7%, they can be transferred to stage 2 (DSME frequency: once a year). Three-to-one matching between DSCP stage 1 and stage 2 groups based on the propensity score method to match the two groups in terms of HbA1c and diabetes duration. We identified 311 people living with type 2 diabetes in DSCP stage 1 and 86 in stage 2 and evaluated their metabolic control and healthy behaviors annually for 5 years. RESULTS: In the first year, HbA1c in the DSCP stage 2 group was significantly lower than that in the stage 1 group. In the first and the fifth years, the percentage of patients achieving HbA1c < 7% was significantly higher in the DSCP stage 2 group than the stage 1 group. There was no significant difference in other metabolic parameters between the two groups during the 5-year follow-up. Self-monitoring of blood glucose (SMBG) frequency was associated with a reduced HbA1c after 5 years (95% CI: -0.0665 to -0.0004). CONCLUSION: We demonstrated sustainable effects of at least 2-year DSME on achieving better glycemic control for at least 1 year. SMBG contributed to improved glycemic control. The results may be applied to the reimbursement strategy in diabetes education.

Genome-Wide Association Studies for Albuminuria of Nondiabetic Taiwanese Population.

INTRODUCTION: Chronic kidney disease, which is defined by a reduced estimated glomerular filtration rate and albuminuria, imposes a large health burden worldwide. Ethnicity-specific associations are frequently observed in genome-wide association studies (GWAS). This study conducts a GWAS of albuminuria in the nondiabetic population of Taiwan. METHODS: Nondiabetic individuals aged 30-70 years without a history of cancer were enrolled from the Taiwan Biobank. A total of 6,768 subjects were subjected to a spot urine examination. After quality control using PLINK and imputation using SHAPEIT and IMPUTE2, a total of 3,638,350 single-nucleotide polymorphisms (SNPs) remained for testing. SNPs with a minor allele frequency of less than 0.1% were excluded. Linear regression was used to determine the relationship between SNPs and log urine albumin-to-creatinine ratio. RESULTS: Six suggestive loci are identified in or near the FCRL3 (p = 2.56 × 10-6), TMEM161 (p = 4.43 × 10-6), EFCAB1 (p = 2.03 × 10-6), ELMOD1 (p = 2.97 × 10-6), RYR3 (p = 1.34 × 10-6), and PIEZO2 (p = 2.19 × 10-7). Genetic variants in the FCRL3 gene that encode a secretory IgA receptor are found to be associated with IgA nephropathy, which can manifest as proteinuria. The PIEZO2 gene encodes a sensor for mechanical forces in mesangial cells and renin-producing cells. Five SNPs with a p-value between 5 × 10-6 and 5 × 10-5 are also identified in five genes that may have a biological role in the development of albuminuria. CONCLUSION: Five new loci and one known suggestive locus for albuminuria are identified in the nondiabetic Taiwanese population.

Application of deep learning image assessment software VeriSee™ for diabetic retinopathy screening.

PURPOSE: To develop a deep learning image assessment software VeriSee™ and to validate its accuracy in grading the severity of diabetic retinopathy (DR). METHODS: Diabetic patients who underwent single-field, nonmydriatic, 45-degree color retinal fundus photography at National Taiwan University Hospital between July 2007 and June 2017 were retrospectively recruited. A total of 7524 judgeable color fundus images were collected and were graded for the severity of DR by ophthalmologists. Among these pictures, 5649 along with another 31,612 color fundus images from the EyePACS dataset were used for model training of VeriSee™. The other 1875 images were used for validation and were graded for the severity of DR by VeriSee™, ophthalmologists, and internal physicians. Area under the receiver operating characteristic curve (AUC) for VeriSee™, and the sensitivities and specificities for VeriSee™, ophthalmologists, and internal physicians in diagnosing DR were calculated. RESULTS: The AUCs for VeriSee™ in diagnosing any DR, referable DR and proliferative diabetic retinopathy (PDR) were 0.955, 0.955 and 0.984, respectively. VeriSee™ had better sensitivities in diagnosing any DR and PDR (92.2% and 90.9%, respectively) than internal physicians (64.3% and 20.6%, respectively) (P < 0.001 for both). VeriSee™ also had better sensitivities in diagnosing any DR and referable DR (92.2% and 89.2%, respectively) than ophthalmologists (86.9% and 71.1%, respectively) (P < 0.001 for both), while ophthalmologists had better specificities. CONCLUSION: VeriSee™ had good sensitivity and specificity in grading the severity of DR from color fundus images. It may offer clinical assistance to non-ophthalmologists in DR screening with nonmydriatic retinal fundus photography.

Assessing the impact of diabetes on quality of life: validation of the Chinese version of the 19-item Audit of Diabetes-Dependent Quality of Life for Taiwan.

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

Age at onset of type 1 diabetes between puberty and 30 years old is associated with increased diabetic nephropathy risk.

Diabetic nephropathy is a critical complication of patients with type 1 diabetes, while epidemiological studies were scarce among Asian countries. We conducted a cross-sectional study to identify factors associated with diabetic nephropathy by questionnaires, using student's t-test, chi-square test, and multivariable logistic regression. Among 898 participants, 16.7% had diabetic nephropathy. Compared with non-diabetic nephropathy patients, the patients with diabetic nephropathy had significantly higher percentage with onset age of type 1 diabetes between puberty and under 30 years old (female ≥ 12 or male ≥ 13 years old to 29 years old), longer diabetes duration, having family history of diabetes and diabetic nephropathy, accompanied with hypertension, hyperlipidemia, or coronary artery disease (CAD). Compared with patients with onset age before puberty, the odds of diabetic nephropathy occurrence increased to 1.61 times in patients with onset age between puberty and under 30 years old (p = 0.012) after adjusting diabetes duration. Age of diabetes onset between puberty and under 30 years old, diabetes duration, HbA1c, hospital admission within 3 years, diabetic retinopathy, hypertension, systolic blood pressure (SBP), triglyceride levels, and use of angiotensin converting enzyme inhibitor (ACEI) and/or angiotensin receptor blockers (ARB) were independent factors associated with diabetic nephropathy Screening for proteinuria is important in daily clinical practice and should be part of diabetes self-management education for patients with type 1 diabetes.

Plasma YKL-40 predicts 10-year cardiovascular and all-cause mortality in individuals with type 2 diabetes.

OBJECTIVE: Elevated YKL-40 concentrations have been observed in both coronary heart disease (CHD) and diabetes. Thus, YKL-40 may play a role in pathogenesis of CHD in patients with diabetes. We evaluated whether plasma YKL-40 concentration can predict all-cause and cardiovascular mortality in individuals with type 2 diabetes. DESIGN: This is a prospective, observational study. PATIENTS: A total of 628 subjects with type 2 diabetes were recruited between July 1996 and June 2003. MEASUREMENTS: Plasma YKL-40 concentrations were measured via enzyme-linked immunosorbent assay (ELISA). The cohort was followed up until 31 December 2008, when vital status and causes of death were obtained. Survival analysis and concordance statistics were performed. All-cause and cardiovascular mortalities were documented. RESULTS: There were 153 (24·36%) mortalities, including 48 participants (7·64%) who died from cardiovascular diseases (CVDs). Participants with higher plasma YKL-40 (defined with a level above the median of 87·5 µg/l) had an increased risk of mortality. After adjusting for confounding variables, the hazard ratios (HR) for all-cause and cardiovascular mortality in participants with higher plasma YKL-40 were 1·97 (95% CI, 1·31-2·95, P < 0·01) and 2·45 (95% CI, 1·11-5·37, P < 0·05). The results remained similar after adjustment for age. Concordance statistics revealed that plasma YKL-40 concentration significantly increases the predictive power for both all-cause and cardiovascular mortality in different models. CONCLUSIONS: Plasma YKL-40 concentration is an independent predictor of 10-year all-cause and cardiovascular mortality in subjects with type 2 diabetes. Further investigations on the role of YKL-40 in the pathogenesis of CVD are required to elucidate the underlying mechanisms.

Thyrotropin-secreting pituitary tumor presenting with congestive heart failure and good response to dopaminergic agonist cabergoline.

Hyperthyroidism is an important inducing factor in patients with atrial fibrillation, and may trigger heart failure. Thyrotropin (thyroid stimulating hormone, TSH)-secreting pituitary tumors are rare causes of hyperthyroidism. Here, we report a 66-year-old man with a pituitary TSH-secreting tumor who presented with hyperthyroidism and congestive heart failure. Endonasal trans-sphenoidal pituitary adenomectomy was performed. After the operation, the symptoms of hyperthyroidism and congestive heart failure were relieved, associated with normalization of thyroid function tests. Unfortunately, hand tremor and progressively elevated free T4 and TSH concentrations recurred 5 months after surgery. A dopaminergic agonist, cabergoline was administered and euthyroidism was restored for at least 11 months.

Mechanisms and the strategy for remission of type 2 diabetes mellitus.

Type 2 diabetes is no longer seen as being an irreversible natural course, accompanied by progressive beta cell failure and various chronic diabetes related complications. In contrast, remission can be achieved through a personalized approach. It is a paradigm shift in our understanding of type 2 diabetes and it may be necessary to change the concept of type 2 diabetes as an urgent condition requiring rapid intervention rather than a chronic progressive disease.

A randomized trial on the effect of transcutaneous electrical nerve stimulator on glycemic control in patients with type 2 diabetes.

Transcutaneous electrical nerve stimulator (TENS) has been demonstrated to be beneficial in glycemic control in animal models, but its application in humans has not been well studied. We randomly assigned 160 patients with type 2 diabetes on oral antidiabetic drugs 1:1 to the TENS study device (n = 81) and placebo (n = 79). 147 (92%) randomized participants (mean [SD] age 59 [10] years, 92 men [58%], mean [SD] baseline HbA1c level 8.1% [0.6%]) completed the trial. At week 20, HbA1c decreased from 8.1% to 7.9% in the TENS group (- 0.2% [95% CI - 0.4% to - 0.1%]) and from 8.1% to 7.8% in the placebo group (- 0.3% [95% CI - 0.5% to - 0.2%]) (P = 0.821). Glycemic variability, measured as mean amplitude of glycemic excursion (MAGE) at week 20 were significantly different in the TENS group vs. the placebo group (66 mg/dL [95% CI 58, 73] vs. 79 mg/dL [95% CI 72, 87]) (P = 0.009). Our study provides the clinical evidence for the first time in humans that TENS does not demonstrate a statistically significant HbA1c reduction. However, it is a safe complementary therapy to improve MAGE in patients with type 2 diabetes.

Accountability, utilization and providers for diabetes management in Taiwan, 2000-2009: an analysis of the National Health Insurance database.

BACKGROUND/PURPOSE: The prevalence of diabetes has increased worldwide. To obtain nationwide data on accountability and utilization of health resources among diabetes patients in Taiwan, an analysis of the claims data for the National Health Insurance (NHI) from 2000 to 2009 was conducted. METHODS: One-third of the NHI claims database was randomly sampled from 2000 to 2009. Diabetes was defined by three or more outpatient visits with diagnostic codes [International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM): 250 or A code: A181] within 1 year, or one inpatient discharge diagnosis. Accountability items and NHI codes of various metabolic parameters and examinations were identified. Medical utilization was measured by the frequency and cost of care associated with ambulatory visits, hospitalizations, and emergency care within each year. RESULTS: The annual check-up frequency for various examinations significantly increased from 2000 to 2009. Both the average outpatient department (OPD) cost per diabetes patient/year and the average inpatient department (IPD) cost per time increased 1.34-fold in the past decade. The average OPD cost per diabetes patient and average IPD cost of each admission for diabetes patients was four times and 1.4 times compare with the general population, respectively. The annual average medical cost of each diabetes patient affected with both micro- and macrovascular complications was four times compared with those without vascular complications. There was an increasing trend for diabetes patients to visit regional hospital for OPD and IPD, whereas visits to the local hospital decreased in the past decade. CONCLUSION: Due to the increased frequency of annual check-ups after various examinations, the quality of diabetes management has improved in the past decade in Taiwan. As diabetes patients affected with both micro- and macrovascular complications incurred costs four times compared with those without complications, it is worth screening high-risk individuals to ensure earlier intervention and thus reduce diabetic complications and healthcare expenditure.

Use of expert consensus to improve the diagnosis and management of type 1 diabetes mellitus.

BACKGROUND: Although type 1 diabetes mellitus (T1DM) is recognized as a catastrophic disease among the different types of diabetes, it is often confusedly diagnosed in clinical practice and difficult in care. The objective of this study is to reach a multidisciplinary consensus for the establishment of clinical recommendations on T1DM to optimize its undoubtedly diagnostic evaluation and transitional care. METHODS: Scientific evidence was reviewed by a committee of researchers, based on which recommendations related to T1DM diagnosis were formulated. A two-round method was conducted to compare the opinions of a panel of 32 specialists (adult endocrinologists [53.1%], pediatric endocrinologists [43.8%], a diabetes educator for child and adolescent [3.1%]) on these issues. RESULTS: The panel reached consensus on two of the six items discussed. The four items on which no consensus was reached were related to autoantibody detection and age of onset. Up to 80% of the panelists favored items related to the glucagon test and diabetic ketoacidosis history for T1DM diagnosis. Consensus regarding transitional care through diabetes educators was established. CONCLUSION: The assessment conducted by experts on T1DM showed a high level of professional agreement regarding the proposed diagnostic and transitional care recommendations. A comprehensive analysis of the latest evidence is warranted for the items on which consensus was not established.

Visit-to-visit variability in albuminuria predicts renal function deterioration in patients with type 2 diabetes.

AIMS/INTRODUCTION: We aimed to study the predictive ability of visit-to-visit variability in albuminuria for changes in renal function in patients with type 2 diabetes mellitus. MATERIALS AND METHODS: The cohort study was carried out in a single medical center. In the model development cohort of 1008 subjects, we developed the albuminuria variability score (AVS) to evaluate the visit-to-visit variability in albuminuria, which was the percentage of the number of changes in the urine albumin : creatinine ratio ≥3.39 mg/mmol among all visit-to-visit urine albumin : creatinine ratio differences within an individual. Multivariate logistic regression was applied to predict the influence of AVS levels on the occurrence of study end-points. In another independent validation cohort of 310 participants, survival analysis was carried out to evaluate the ability of AVS in predicting the study end-point. RESULTS: In the model development cohort, a higher AVS was associated with higher adjusted odds of having a declined or rapidly declined estimated glomerular filtration rate (eGFR) trajectory (1.84, 95% confidence interval 1.23-2.76 and 5.70, 95% confidence interval 2.28-14.25, respectively), a resultant eGFR <60 mL/min/1.73 m2 (2.61, 95% confidence interval 1.63-4.16) and a >40% decline in eGFR from baseline (6.44, 95% confidence interval 2.15-19.26). In the validation cohort, a higher AVS independently predicted a 5-year decrease of >40% in eGFR to <60 mL/min/1.73 m2 (adjusted hazard ratio 3.33, 95% confidence interval 1.10-10.05). Integrated discrimination index and concordance statistics showed that AVS significantly improved the predictive ability of the models. CONCLUSIONS: Visit-to-visit variability in albuminuria can independently predict long-term renal function deterioration in patients with type 2 diabetes mellitus. Further investigations are warranted to elucidate the potential clinical applications.

Hemoglobin glycation index predicts renal function deterioration in patients with type 2 diabetes and a low risk of chronic kidney disease.

AIMS: Hemoglobin glycation index (HGI) is used to describe the difference between estimated and measured glycated hemoglobin (HbA1c). We aimed to study whether HGI can predict renal function deterioration in patients with type 2 diabetes and a low risk of chronic kidney disease (CKD). METHODS: This 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 HbA1c. Multivariate Cox proportional hazard models were used to evaluate the hazard ratios of the study endpoints. Longitudinal data was analyzed using generalized estimating equation (GEE). RESULTS: The 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 m2, but not onset of macroalbuminuria. The longitudinal GEE model demonstrated a negative association between HGI and the predicted eGFR changes in both the 1-year and 3-year intervals. CONCLUSIONS: HGI 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.

Genetic predisposition and nongenetic risk factors of thiazolidinedione-related edema in patients with type 2 diabetes.

OBJECTIVE: This study aimed to analyze the association of thiazolidinedione (TZD)-related edema with genetic and clinical variables and develop a simple points system to predict the risk of developing TZD-related edema. METHODS: Fifty-eight (21.6%) of 268 individuals who received TZD for type 2 diabetes developed peripheral edema. Twenty-eight tag single nucleotide polymorphisms (SNPs) from candidate genes involved in sodium and water reabsorption were genotyped. Cox regression and logistic regression models were used to analyze the associations of different genotypes and weighted genotypic scores with TZD-related edema risk. RESULTS: Individuals with edema were older, predominantly female, and had greater weight gain. The AQP2 rs296766 T allele was associated with TZD-related edema [allelic P=0.0059; odds ratio (OR), 2.89; 95% confidence interval (CI), 1.61-5.17]. The SLC12A rs12904216 G allele had borderline significance (allelic P=0.049), which disappeared after correction for multiple testing. Patients with two SNP-based (AQP2 rs296766 and SLC12A1 rs12904216), who weighted genotypic scores within the top quartile, had a higher risk of developing TZD-related edema (OR, 16.45; 95% CI, 3.05-88.76). Combining the weighted genetic scores of two SNPs or all SNPs with age and sex information significantly improved the predictive power for TZD-related edema. We also developed a simple risk factor-based points system to predict an individual's risk of developing TZD-related edema. CONCLUSION: A clinically applicable prediction model including age, sex, and genetic information from AQP2 rs296766 and/or SLC12A rs12904216 SNPs can be developed to estimate the risk of TZD-related edema in type 2 diabetes patients.

Update in the epidemiology, risk factors, screening, and treatment of diabetic retinopathy.

Despite progress in the treatment of diabetic macular edema and diabetic retinopathy, the rate of lower fundus examination due to limitations of medical resources delays the diagnosis and treatment of diabetic retinopathy. Therefore, implementation of automated diabetic retinopathy screening program and the identification of more specific and sensitive biomarkers are important for facilitating the earlier detection of diabetic macular edema and diabetic retinopathy to decrease the prevalence of poor vision and blindness.

Decreased glomerular filtration rate and increased albuminuria for identification of cardiovascular autonomic neuropathy in subjects with and without diabetes.

OBJECTIVE: The purpose of this study was to determine the relationship between chronic kidney disease (CKD) and cardiovascular autonomic neuropathy (CAN). RESEARCH DESIGN AND METHODS: From October 2008 to May 2011, we enrolled 218 patients with diabetes and 62 nondiabetic subjects. Heart rate variability was represented as the maximal heart rate minus the minimal heart rate (HRmax-min) during a one-minute deep breathing test. Normal, impaired cardiovascular autonomic function and CAN were defined as s HRmax-min > 15 beats/min, HRmax-min of 10-15 beats/min and HRmax-min < 10 beats/min, respectively. CKD was diagnosed if the estimated glomerular filtration rate (eGFR) was <60/min/1.73 m2 or albuminuria. RESULTS: In our sample, 19.4% of nondiabetic subjects and 49.5% of diabetic subjects had CKD. The prevalence of CAN was higher among patients with diabetes than among nondiabetic subjects (26.4 vs. 4.9%). A significant association was observed between eGFR and HRmax-min. CAN was independently associated with CKD with an adjusted odds ratio of 2.77 (95% CI, 1.15-6.68) in diabetic patients. A positive linear trend was observed for the odds of CAN with increasing CKD severity in diabetes. The areas under the curve (AUCs) for the predictive ability of eGFR for the risk of impaired cardiovascular autonomic function for nondiabetic group and CAN for the diabetic group were 0.734 and 0.703, respectively. Adding age, sex, body mass index, and albuminuria to the prediction model increased the AUCs to 0.852 and 0.791, respectively. CONCLUSION: CKD is associated with the risk of CAN in both nondiabetic and diabetic subjects. eGFR and albuminuria improve the prediction of CAN.

Activation of Aldehyde Dehydrogenase 2 Ameliorates Glucolipotoxicity of Pancreatic Beta Cells.

Chronic hyperglycemia and hyperlipidemia hamper beta cell function, leading to glucolipotoxicity. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) detoxifies reactive aldehydes, such as methylglyoxal (MG) and 4-hydroxynonenal (4-HNE), derived from glucose and lipids, respectively. We aimed to investigate whether ALDH2 activators ameliorated beta cell dysfunction and apoptosis induced by glucolipotoxicity, and its potential mechanisms of action. Glucose-stimulated insulin secretion (GSIS) in MIN6 cells and insulin secretion from isolated islets in perifusion experiments were measured. The intracellular ATP concentrations and oxygen consumption rates of MIN6 cells were assessed. Furthermore, the cell viability, apoptosis, and mitochondrial and intracellular reactive oxygen species (ROS) levels were determined. Additionally, the pro-apoptotic, apoptotic, and anti-apoptotic signaling pathways were investigated. We found that Alda-1 enhanced GSIS by improving the mitochondrial function of pancreatic beta cells. Alda-1 rescued MIN6 cells from MG- and 4-HNE-induced beta cell death, apoptosis, mitochondrial dysfunction, and ROS production. However, the above effects of Alda-1 were abolished in Aldh2 knockdown MIN6 cells. In conclusion, we reported that the activator of ALDH2 not only enhanced GSIS, but also ameliorated the glucolipotoxicity of beta cells by reducing both the mitochondrial and intracellular ROS levels, thereby improving mitochondrial function, restoring beta cell function, and protecting beta cells from apoptosis and death.

SLC2A10 genetic polymorphism predicts development of peripheral arterial disease in patients with type 2 diabetes. SLC2A10 and PAD in type 2 diabetes.

BACKGROUND: Recent data indicate that loss-of-function mutation in the gene encoding the facilitative glucose transporter GLUT10 (SLC2A10) causes arterial tortuosity syndrome via upregulation of the TGF-ß pathway in the arterial wall, a mechanism possibly causing vascular changes in diabetes. METHODS: We genotyped 10 single nucleotide polymorphisms and one microsatellite spanning 34 kb across the SLC2A10 gene in a prospective cohort of 372 diabetic patients. Their association with the development of peripheral arterial disease (PAD) in type 2 diabetic patients was analyzed. RESULTS: At baseline, several common SNPs of SLC2A10 gene were associated with PAD in type 2 diabetic patients. A common haplotype was associated with higher risk of PAD in type 2 diabetic patients (haplotype frequency: 6.3%, P = 0.03; odds ratio [OR]: 14.5; 95% confidence interval [CI]: 1.3- 160.7) at baseline. Over an average follow-up period of 5.7 years, carriers with the risk-conferring haplotype were more likely to develop PAD (P = 0.007; hazard ratio: 6.78; 95% CI: 1.66- 27.6) than were non-carriers. These associations remained significant after adjustment for other risk factors of PAD. CONCLUSION: Our data demonstrate that genetic polymorphism of the SLC2A10 gene is an independent risk factor for PAD in type 2 diabetes.

Serum Angiopoietin-like Protein 6, Risk of Type 2 Diabetes, and Response to Hyperglycemia: A Prospective Cohort Study.

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.