Association of lipid composition and unsaturated fatty acids of VLDL with atrial remodeling in metabolic syndrome.

Subjects with metabolic syndrome (MetS) commonly have atrial remodeling, which indicates a risk for atrial fibrillation. This study determined MetS-related changes in lipid components in very-low-density lipoprotein (VLDL), which has been shown to cause atrial remodeling, the effect of statins on these changes, and the correlation between atrial remodeling and VLDL lipid compositions. Blood samples were collected from 12 non-MetS and 27 sex- and age-matched MetS subjects. Fourteen patients with MetS (MetS-off statin) discontinued statin therapy 14 days before the study, while the remaining 13 remained on it (MetS-on statin). The VLDLs were isolated and processed for mass-based lipid profiling. Lipidomic analyses were performed and associated with atrial remodeling markers measured using standard echocardiography and electrocardiography. Compared with the VLDL components of the non-MetS group, glucosyl/galactosyl ceramide, lyso-phosphatidylcholine, lyso-phosphatidylethanolamine, and triglycerides were enriched in the MetS-off statin group. Statin therapy attenuated all abnormally abundant lipid classes in MetS, except for triglycerides. In addition, lyso-phosphatidylcholine, lyso-phosphatidylethanolamine, and triglycerides were significantly correlated with atrial dilatation, and the latter two were also correlated with the PR interval. Enrichment of double bonds, which indicate unsaturated fatty acids, was also significantly correlated with atrial remodeling and P-wave duration. This study suggests that the pathological lipid payload of MetS-VLDL may contribute to atrial remodeling in patients.

Interaction among dietary n-3 and n-6 polyunsaturated fatty acid intake, fatty acid desaturase 2 genetic variants, and low-density lipoprotein cholesterol levels in type 2 diabetes patients.

AIMS/INTRODUCTION: Fatty acid desaturase (FADS) genetic polymorphisms are strongly correlated with the risk of dyslipidemia and cardiovascular disease. In this study, we examined the impact of FADS1 and FADS2 genetic variants on plasma lipid status, and assessed interactions between FADS genetic polymorphisms and plasma n-3/n-6 fatty acids regarding lipid status within a population of 816 Taiwanese patients with type 2 diabetes. MATERIALS AND METHODS: Selected tag single-nucleotide polymorphisms (FADS1 rs174546 [T/C]; FADS2 rs174602 [A/G] and rs2072114 [A/G]) were genotyped (n = 816). RESULTS: The distribution of genotypes were compared with reports publicly available in the Genome Aggregation Database for East Asian populations (https://gnomad.broadinstitute.org). In the subgroup of patients not taking lipid-lowering medications (n = 192), we observed that the G allele of FADS2 rs174602 was statistically significantly correlated with lower low-density lipoprotein cholesterol (LDL-C) concentrations (P = 0.001), whereas the G allele of rs2072114 was marginally associated with LDL-C concentrations (P = 0.091). Using a general linear model adjusted for confounding factors, statistically significant interactions (P = 0.016) between single-nucleotide polymorphisms in rs2072114 and a low alpha-linolenic acid (18:3n-3)/linoleic acid (18:2n-6) ratio; the G allele correlated with lower LDL-C levels among individuals with a low alpha-linolenic acid/linoleic acid ratio. Interaction between rs174602 single-nucleotide polymorphisms and low alpha-linolenic acid/linoleic acid values on LDL-C was only marginally significant (P = 0.063). CONCLUSIONS: Our results show the role of n-3/n-6 dietary polyunsaturated fatty acids in modifying the effects of genetic susceptibility on lipoprotein concentrations in patients with type 2 diabetes. Our findings highlight the potential of interventions with dietary polyunsaturated fatty acids regarding developing individualized prevention strategies for type 2 diabetes presenting with co-occurring dyslipidemia and cardiovascular diseases.

Metformin use and cirrhotic decompensation in patients with type 2 diabetes and liver cirrhosis.

AIMS: To compare the risks of all-cause mortality, hepatic outcomes, major adverse cardiovascular events between metformin users and nonusers for patients with diabetes and cirrhosis. METHODS: From the Taiwan's National Health Insurance Research Database, we selected propensity-score matched metformin users and nonusers from the cohorts of type 2 diabetes mellitus with compensated (n = 26 164) or decompensated liver cirrhosis (n = 15 056) between 1 January 2000 and 31 December 2009, and followed them until 31 December 2010. Cox proportional hazards models with robust sandwich standard error estimates were used to assess risk of investigated outcomes for metformin users. RESULTS: The incidence rates of mortality during follow-up were 3.8 and 3.3 per 100 patient-years (adjusted hazard ratio [aHR] 1.13, 95% confidence interval 1.01-1.25) for metformin users and nonusers, respectively. The incidence rates of cirrhotic decompensation during follow-up were 5.9 and 4.9 per 100 patient-years (aHR 1.15, 95% confidence interval 1.04-1.27) for metformin users and nonusers. The risk of death (P for trend <.01) and cirrhotic decompensation (P for trend <.0001) associated with metformin use was significant for those taking metformin for >40 defined daily doses in 90 days or >1000 mg/d. The outcomes of metformin use vs nonuse for type 2 diabetes mellitus with decompensated liver cirrhosis were not statistically different, except that metformin users had higher risk of mortality (aHR 1.15). CONCLUSION: Metformin use was associated with higher risks of mortality and cirrhotic decompensation in patients with compensated liver cirrhosis. Prospective studies are required to confirm our results.

Epidemiological characteristics of diabetic kidney disease in Taiwan.

Diabetic kidney disease (DKD) is a critical microvascular complication of diabetes. With the continuous increase in the prevalence of diabetes since 2000, the prevalence of DKD has also been increasing in past years. The prevalence of DKD among individuals with type 2 diabetes in Taiwan increased from 13.32% in 2000 to 17.92% in 2014. The cumulative incidence of DKD among individuals with type 1 diabetes in Taiwan was higher than 30% during 1999-2012. DKD is the leading cause of end-stage renal disease (ESRD), with a prevalence of approximately 45% in a population on chronic dialysis in Taiwan. Among individuals with type 2 diabetes, the prevalence of ESRD in the receipt of dialysis also increased from 1.32% in 2005 to 1.47% in 2014. Risk factors for DKD development are age, race, family history, hyperglycemia, hypertension, dyslipidemia, dietary patterns, and lifestyles. Prognostic factors that aggravate DKD progression include age, family history, sex, glycemic control, blood pressure (BP), microvascular complications, and atherosclerosis. This review summarizes updated information on the onset and progression of DKD, particularly in the Taiwanese population. Translating these epidemiological features is essential to optimizing the kidney care and improving the prognosis of DKD in Asian populations.

Disruption of retinoid homeostasis induces RBP4 overproduction in diabetes: O-GlcNAcylation involved.

BACKGROUND: Retinol-binding protein 4 (RBP4) is elevated and associated with inflammation in metabolic diseases. Disruption of the retinol cascade and O-GlcNAcylation of the RBP4 receptor (STRA6) are found in diabetic kidneys. OBJECTIVES: We investigated whether the disruption of the retinol cascade induces RBP4 overproduction and if O-linked GlcNAc modification targets RBPR2 and contributes to the disruption of retinol cascades in diabetic livers. METHODS: Western blot or immunohistochemistry for RBPR2, CRBP1, LRAT, RALDH, RARα, RARγ, RXRα, RBP4, GFAT, OGT, OGA and inflammatory markers, as well as ELISA for RBP4, were performed in livers of db/db and ob/ob mice and high glucose-cultured hepatocytes. Immunoprecipitation and dual fluorescence staining were used to explore O-GlcNAc-modified RBPR2 and RBP4 binding activity on RBPR2. Transfection of the CRBP1 gene was done to verify whether a disrupted retinol cascade induces RBP4 overproduction. OGT silencing was done to investigate the association of O-GlcNAcylation with the disruption of retinol cascade. RESULTS: Disruption of retinol cascade, RBP4 overproduction, O-GlcNAcylation of RBPR2, decreased RBP4 binding activity on RBPR2 and inflammation were found in livers of db/db and ob/ob mice and high glucose-cultured hepatocytes. CRBP1 gene transfection reversed the suppression of the cellular retinol cascade and simultaneously attenuated the RBP4 overproduction and inflammation in high glucose-treated hepatocytes. The silencing of OGT reversed the disruption of the cellular retinol cascade, RBP4 overproduction and inflammation induced by high glucose in hepatocytes. CONCLUSIONS: This study indicates that the disruption of cellular retinol cascade is strongly associated with RBP4 overproduction and inflammation in diabetic livers. RBPR2 is one target for high glucose-mediated O-linked GlcNAc modification, which causes liver retinol dyshomeostasis.

The role of postprandial very-low-density lipoprotein in the development of atrial remodeling in metabolic syndrome.

BACKGROUND: Negatively charged very-low-density lipoprotein (VLDL-χ) in metabolic syndrome (MetS) patients exerts cytotoxic effects on endothelial cells and atrial myocytes. Atrial cardiomyopathy, manifested by atrial remodeling with a dilated diameter, contributes to atrial fibrillation pathogenesis and predicts atrial fibrillation development. The correlation of VLDL-χ with atrial remodeling is unknown. This study investigated the association between VLDL-χ and remodeling of left atrium. METHODS: Consecutively, 87 MetS and 80 non-MetS individuals between 23 and 74 years old (50.6% men) without overt cardiovascular diseases were included in the prospective cohort study. Blood samples were collected while fasting and postprandially (at 0.5, 1, 2, and 4 h after a unified meal). VLDL was isolated by ultracentrifugation; the percentile concentration of VLDL-χ (%) was determined by ultra-performance liquid chromatography. The correlations of left atrium diameter (LAD) with variables including VLDL-χ, LDL-C, HDL-C, triglycerides, glucose, and blood pressure, were analyzed by multiple linear regression models. A hierarchical linear model was conducted to test the independencies of each variable's correlation with LAD. RESULTS: The mean LAD was 3.4 ± 0.5 cm in non-MetS subjects and 3.9 ± 0.5 cm in MetS patients (P < 0.01). None of the fasting lipid profiles were associated with LAD. VLDL-χ, BMI, waist circumference, hip circumference, and blood pressure were positively correlated with LAD (all P < 0.05) after adjustment for age and sex. Significant interactions between VLDL-χ and blood pressure, waist circumference, and hip circumference were observed. When adjusted for obesity- and blood pressure-related variables, 2-h postprandial VLDL-χ (mean 1.30 ± 0.61%) showed a positive correlation with LAD in MetS patients. Each 1% VLDL-χ increase was estimated to increase LAD by 0.23 cm. CONCLUSIONS: Postprandial VLDL-χ is associated with atrial remodeling particularly in the MetS group. VLDL-χ is a novel biomarker and may be a therapeutic target for atrial cardiomyopathy in MetS patients. TRIAL REGISTRATION: ISRCTN 69295295 . Retrospectively registered 9 June 2020.

Increased APOE glycosylation plays a key role in the atherogenicity of L5 low-density lipoprotein.

Low-density lipoprotein (LDL) is heterogeneous, composed of particles with variable atherogenicity. Electronegative L5 LDL exhibits atherogenic properties in vitro and in vivo, and its levels are elevated in patients with increased cardiovascular risk. Apolipoprotein E (APOE) content is increased in L5, but what role APOE plays in L5 function remains unclear. Here, we characterized the contributions of APOE posttranslational modification to L5's atherogenicity. Using two-dimensional electrophoresis and liquid chromatography-mass spectrometry, we studied APOE's posttranslational modification in L5 from human plasma. APOE structures with various glycan residues were predicted. Molecular docking and molecular dynamics simulation were performed to examine the functional changes of APOE resulting from glycosylation. We also examined the effects of L5 deglycosylation on endothelial cell apoptosis. The glycan sequence N-acetylgalactosamine, galactose, and sialic acid was consistently expressed on serine 94, threonine 194, and threonine 289 of APOE in L5 and was predicted to contribute to L5's negative surface charge and hydrophilicity. The electrostatic force between the negatively charged sialic acid-containing glycan residue of APOE and positively charged amino acids at the receptor-binding area suggested that glycosylation interferes with APOE's attraction to receptors, lipid-binding ability, and lipid transportation and metabolism functions. Importantly, L5 containing glycosylated APOE induced apoptosis in cultured endothelial cells through lectin-like oxidized LDL receptor-1 (LOX-1) signaling, and glycosylation removal from L5 attenuated L5-induced apoptosis. APOE glycosylation may contribute to the atherogenicity of L5 and be a useful biomarker for rapidly quantifying L5.

Electronegative low-density lipoprotein of patients with metabolic syndrome induces pathogenesis of aorta through disruption of the stimulated by retinoic acid 6 cascade.

AIMS/INTRODUCTION: Electronegative low-density lipoprotein (L5) is the most atherogenic fraction of low-density lipoprotein and is elevated in people with metabolic syndrome (MetS), whereas the retinol-binding protein 4 receptor (stimulated by retinoic acid 6 [STRA6]) cascade is disrupted in various organs of patients with obesity-related diseases. Our objective was to investigate whether L5 from MetS patients capably induces pathogenesis of aorta through disrupting the STRA6 cascade. MATERIAL AND METHODS: We examined the in vivo and in vitro effects of L5 on the STRA6 cascade and aortic atherogenic markers. To investigate the role of this cascade on atherosclerotic formation, crbp1 transfection was carried out in vitro. RESULTS: This study shows that L5 activates atherogenic markers (p38 mitogen-activated protein kinases, pSmad2 and matrix metallopeptidase 9) and simultaneously suppresses STRA6 signals (STRA6, cellular retinol-binding protein 1, lecithin-retinol acyltransferase, retinoic acid receptor-α and retinoid X receptor-α) in aortas of L5-injected mice and L5-treated human aortic endothelial cell lines and human aortic smooth muscle cell lines. These L5-induced changes of the STRA6 cascade and atherogenic markers were reversed in aortas of LOX1-/- mice and in LOX1 ribonucleic acid-silenced human aortic endothelial cell lines and human aortic smooth muscle cell lines. Furthermore, crbp1 gene transfection reversed the disruption of the STRA6 cascade, the phosphorylation of p38 mitogen-activated protein kinases and Smad2, and the elevation of matrix metallopeptidase 9 in L5-treated human aortic endothelial cell lines. CONCLUSIONS: This study shows that L5 from MetS patients induces atherogenic markers by disrupting STRA6 signaling. Suppression of STRA6 might be one novel pathogenesis of aorta in patients with MetS.

Blood biomarkers of various dietary patterns correlated with metabolic indicators in Taiwanese type 2 diabetes.

BACKGROUND: Metabolic alterations correlate with adverse outcomes in type 2 diabetes. Dietary modification serves as an integral part in its treatment. OBJECTIVE: We examined the relationships among dietary patterns, dietary biomarkers, and metabolic indicators in type 2 diabetes (n = 871). DESIGN: Diabetic patients (n = 871) who provided complete clinical and dietary data in both 2008 and 2009 were selected from a cohort participating in a diabetic control study in Taiwan. Dietary data were obtained using a short, semiquantitative food frequency questionnaires, and dietary pattern identified by factor analysis. Multiple linear regressions were used to analyze the association between dietary biomarkers (ferritin, folate, and erythrocyte n-3 polyunsaturated fatty acids [n-3 PUFAs]) and metabolic control upon adjusting for confounders. RESULTS: Three dietary patterns (high-fat meat, traditional Chinese food-snack, and fish-vegetable) were identified. Ferritin correlated positively with high-fat meat factor scores (P for trend <0.001). Erythrocyte n-3 PUFAs (eicosapentaenoic acid [EPA] + docosahexaenoic acid [DHA], n-3/n-6 PUFA ratio) correlated positively with fish-vegetable factor scores (all P for trends <0.001). Multiple linear regressions revealed a positive relationship between ferritin concentrations and fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), and triglycerides, but a negative relationship with high-density lipoprotein cholesterol (HDL-C). Erythrocyte n-3 PUFA, EPA+DHA, and n-3/n-6 PUFA ratio were negatively linked to FPG, HbA1c, and triglycerides (all P < 0.05) and positively with HDL-C (though n-3/n-6 ratio marginally correlated). CONCLUSIONS: Ferritin and n-3 PUFA can serve as valid biomarkers for high-fat meat and fish-vegetable dietary patterns. Unlike ferritin, erythrocyte n-3 PUFA status was related to better glycemic and blood lipid profiles. Our results suggest that habitual consumption of diet pattern rich in fish and vegetables may contribute in part to a healthier metabolic profile in type 2 diabetes.

Diabetes-related kidney, eye, and foot disease in Taiwan: An analysis of nationwide data from 2005 to 2014.

BACKGROUND/PURPOSE: Patients with diabetes have a higher risk of developing chronic complications and cause a huge burden to the public health care system as well as on patients and their families. We studied these diabetic complications about kidney, eye and peripheral vascular diseases to understand their prevalence and distributions in a national survey. METHODS: We analyzed diabetic complications using National-Health-Insurance claims filed from 2005 to 2014. We used this database to evaluate their developments of kidney, eye, and peripheral vascular diseases according to the International-Classification-of-Diseases, Ninth Revision using clinical modification diagnosis codes. RESULTS: The prevalence of diabetic kidney disease (DKD) significantly increased from 10.49% to 17.92% from 2005 to 2014. The prevalence rate of diabetic foot significantly decreased from 1.34% to 1.05% from 2005 to 2014, and the rate of severe infection also significantly decreased from 50.69% to 45.85%. The amputation rate significantly decreased from 24.91% to 17.47% among all patients with diabetic foot. CONCLUSION: In this study, the trends in DKD and dialysis prevalence were similar to those of the 2012 report. The rate of increase in dialysis prevalence is lower in this study than in the 2012 report. The prevalence of diabetic foot, severe infection, and amputation in this report exhibited significantly decreasing trends. This improvement may be attributable to care from multidisciplinary teams. We should dedicate more resources to our prevention program of DKD and retinopathy to further improve outcomes in the future.

Hospitalization in patients with type 2 diabetes mellitus in Taiwan: A nationwide population-based observational study.

BACKGROUND/PURPOSE: We investigated hospitalization rates of patients with type 2 diabetes mellitus (T2DM) and individuals without diabetes mellitus (non-DM) in a disease-specific manner from 2005 to 2014 in Taiwan. METHODS: This population-based study was conducted using data from the National Health Insurance Research Database. We analyzed the hospitalization rates of patients with and without T2DM. We collected up to five diagnostic codes given at discharge for each hospitalization, and the first one was considered the main diagnosis. Odds ratios were determined to assess the risk of hospitalization according to disease-specific classifications in patients with T2DM compared with those without T2DM. RESULTS: The hospitalization rates of non-DM patients was stable from 2005 to 2014. By contrast, the rate of hospitalization among patients with T2DM decreased from 395.4 (per 1000 person-years) in 2005 to 336.9 (per 1000 person-years) in 2014. An increase in hospitalization rates for malignancies and sepsis/infection (other than pneumonia) was observed from 2005 to 2014 in both patients with and without T2DM. Although patients with T2DM had a higher hospitalization risk for all the disease-specific classifications than non-DM patients, this difference in risk decreased from 2005 to 2014 for all diseases except pneumonia. CONCLUSION: Hospitalization rates for malignancies and sepsis/infection (other than pneumonia) continually increased from 2005 to 2014 in Taiwan. Although patients with T2DM had a greater risk of disease-specific hospitalization than those without, this difference in risk decreased from 2005 to 2014 for all diseases except for pneumonia.

Very Low-Density Lipoproteins of Metabolic Syndrome Modulates STIM1, Suppresses Store-Operated Calcium Entry, and Deranges Myofilament Proteins in Atrial Myocytes.

Individuals with metabolic syndrome (MetS) are at high risk for atrial myopathy and atrial fibrillation. Very low-density lipoproteins (VLDLs) of MetS (MetS-VLDLs) are cytotoxic to atrial myocytes in vivo and in vitro. The calcineurin-nuclear factor of activated T-cells (NFAT) pathway, which is regulated by stromal interaction molecule 1 (STIM1)/ calcium release-activated calcium channel protein 1 (Orai1)-mediated store-operated Ca2+ entry (SOCE), is a pivotal mediator of adaptive cardiac hypertrophy. We hypothesized that MetS-VLDLs could affect SOCE and the calcineurin-NFAT pathway. Normal-VLDL and MetS-VLDL samples were isolated from the peripheral blood of healthy volunteers and individuals with MetS. VLDLs were applied to HL-1 atrial myocytes for 18 h and were also injected into wild-type C57BL/6 male mouse tails three times per week for six weeks. After the sarcoplasmic reticulum (SR) Ca2+ store was depleted, SOCE was triggered upon reperfusion with 1.8 mM of Ca2+. SOCE was attenuated by MetS-VLDLs, along with reduced transcriptional and membranous expression of STIM1 (P = 0.025), and enhanced modification of O-GlcNAcylation on STIM1 protein, while Orai1 was unaltered. The nuclear translocation and activity of calcineurin were both reduced (P < 0.05), along with the alteration of myofilament proteins in atrial tissues. These changes were absent in normal-VLDL-treated cells. Our results demonstrated that MetS-VLDLs suppressed SOCE by modulating STIM1 at the transcriptional, translational, and post-translational levels, resulting in the inhibition of the calcineurin-NFAT pathway, which resulted in the alteration of myofilament protein expression and sarcomere derangement in atrial tissues. These findings may help explain atrial myopathy in MetS. We suggest a therapeutic target on VLDLs to prevent atrial fibrillation, especially for individuals with MetS.

GREATER LOW-DENSITY LIPOPROTEIN CHOLESTEROL VARIABILITY INCREASES THE RISK OF CARDIOVASCULAR EVENTS IN PATIENTS WITH TYPE 2 DIABETES MELLITUS.

Objective: Variability in lipid levels has been associated with poor cardiovascular outcomes in patients with coronary artery disease. The aim of this study was to investigate whether low-density lipoprotein cholesterol (LDLC) variability can be used to predict cardiovascular events in patients with type 2 diabetes mellitus (DM). Methods: A total of 5,354 patients with type 2 DM were enrolled in this study. Cardiovascular events including peripheral arterial disease, coronary artery disease, stroke, and cardiovascular death were defined as the study endpoints, and standard deviations of lipid levels were used to define intra-individual lipid variability. Results: Univariate Cox proportional hazards analysis showed that LDL-C standard deviation (hazard ratio [HR] = 1.016; 95% confidence interval [CI] = 1.006 to 1.022; P<.001) was associated with a higher risk of cardiovascular events. Multivariate Cox proportional hazards analysis showed that an increase in LDL-C standard deviation significantly increased the risk of cardiovascular events (HR = 1.063; 95% CI = 1.025 to 1.102; P = .01). Kaplan-Meier analysis of cardiovascular event-free survival showed that the patients in tertiles 2 and 3 of the standard deviation of LDL-C had worse cardiovascular event-free survival compared to those in tertile 1. Conclusion: Variability in LDL-C could predict cardiovascular events in the patients with type 2 DM in this study. Abbreviations: CAD = coronary artery disease; CI = confidence interval; CVD = cardiovascular disease; DM = diabetes mellitus; eGFR = estimated glomerular filtration rate; HbA1c = glycosylated hemoglobin; HDL-C = high-density lipoprotein cholesterol; HR = hazard ratio; KMUHRD = Kaohsiung Medical University Hospital Research Database; LDL-C = low-density lipoprotein cholesterol; SD = standard deviation; UACR = urine albumin to creatinine ratio.

O-GlcNAcylation disrupts STRA6-retinol signals in kidneys of diabetes.

BACKGROUND: O-GlcNAcylation is an important mechanism of diabetic complication. Retinoid homeostasis regulates cell-physiological functions through STRA6-retinol signaling. Therefore, we investigated whether O-GlcNAcylation disrupted STRA6-retinol signals in diabetes. METHODS: Immunoprecipitation and proximity ligation assay were used to investigate O-GlcNAcylation of STRA6-retinol signals in kidneys of db/db and ob/ob mice. Western blot and immunohistochemistry were done for STRA6/CRBP1/LRAT/RALDH1/RARs pathway, GFAT, OGT, TGFß1 and collagen 1 level. HPLC and ELISA for retinol, retinal, and retinoic acid concentrations were performed in vivo and vitro. RBP4 binding with STRA6 was measured in vitro. To verify whether O-GlcNAcylation disrupted STRA6-retinol signals, treatment of TMG and OSMI-1, transfection of OGA and OGT, and OGT siRNA were performed in HK-2 cells. RESULTS: STRA6 and RALDH1 were highly O-GlcNAc-modified in glomeruli and tubules of db/db and ob/ob mice. RBP4, p-Try, p-JAK2, and p-STAT5 on STRA6 immunoprecipitate were reduced. Cellular retinol signals (CRBP1, LRAT, ADH, retinol, retinal, RA, RARα, RARγ and RXRα) remarkably decreased in kidneys of db/db, ob/ob mice and HG-cultured cells. TMG and OGT transfection induced O-GlcNAcylation of STRA6 and RALDH1, repressed RBP4-bound STRA6, and retinol signals in NG-cultured cells. OSMI-1, OGA transfection, and OGT silence reversed O-GlcNAc-modification of STRA6 and RALDH1, and rescued the decrease of retinol signals, and reversed the increase of TGFß1 and collagen 1 in HG-treated cells. CONCLUSIONS: O-GlcNAcylation significantly modified STRA6 and RALDH1, suppressed RBP4 binding activity, and disrupted retinol signals in the kidney of diabetes. GENERAL SIGNIFICANCE: This study first indicates that STRA6-retinol signals were directly disrupted by O-GlcNAcylation in diabetic kidney.

Severe Hypoglycemia as a Predictor of End-Stage Renal Disease in Type 2 Diabetes: A National Cohort Study.

Aims: This study investigated whether there is a link between severe hypoglycemia and progression into end-stage renal disease (ESRD) in patients with type 2 diabetes. Methods: Tapping into Taiwan's Health Insurance Research Database, we identified all type 2 diabetes patients between 1996 and 2013 and identified those diagnosed with a severe hypoglycemia episode during an emergency department visit and those who were not. Controls were then matched 1:1 for age, sex, index year, and medication. Results: We identified 468,421 type 2 diabetes patients diagnosed as having severe hypoglycemia in an emergency department visit. Compared with controls, these patients with SH had a higher risk of all-cause mortality (Hazard Ratio (HR), 1.76; 95% confidence interval, 1.61⁻1.94) and progressed into ESRD within a shorter period of time. Results were similar after controlling for competing risk. Conclusion: Severe hypoglycemia is significantly associated with worsening renal dysfunction in patients with type 2 diabetes and hastened progression into ESRD.

Successful management of type IV hypersensitivity reactions to human insulin analogue with injecting mixtures of biphasic insulin aspart and dexamethasone.

Although hypersensitivity reaction to insulin was supposed to be less-frequent with current insulin analogue, case reports with different types of allergic reactions to insulin analogue were still reported. The most common form is type I hypersensitivity reaction with IgE-mediated. Besides, type III (IgG and IgM-mediated) and type IV (T-cell mediated delayed reaction) hypersensitivity reactions were also reported. Here we presented a long-standing type 2 diabetes with insulin requirements with hypersensitivity reactions to insulin actrapid, insulin aspart, insulin glargine, insulin detemir, and biphasic insulin aspart 30. Insulin desensitization was performed as initial management but failed as skin biopsy with immunohistochemical staining proved type IV hypersensitivity reaction. We continued with the next treatment approach using subcutaneous injection with the mixture of biphasic insulin aspart 30 and dexamethasone to alleviate allergy, and the result was successful with steroid-free biphasic insulin aspart 30 injection eight months later. Besides, the treatment effect had lasted after ten years even with switched type of insulin analogue from biphasic insulin aspart 30 to insulin glargine and insulin aspart. The case report demonstrated a good example of how clinicians deal with the rare but important questions of hypersensitivity reactions to insulin analogue.

Determinants for quality of life trajectory patterns in patients with type 2 diabetes.

PURPOSE: The purpose of the study was to identify quality of life (QoL) trajectory patterns and the determinants in patients with Type 2 diabetes (T2DM). METHODS: A longitudinal design was employed. Totally, 466 patients with T2DM recruited from five diabetic clinics in Taiwan were participants of this study. Demographic and disease characteristics, biomedical factors (HbA1c levels and body mass index), psychosocial factors (self-care behaviors, social support, resilience, diabetes distress), and QoL were collected at baseline. QoL was further measured every 6 months for four waves after baseline. Latent class growth analysis was used to identify QoL trajectory patterns. The multinomial logistic regression was further applied to explore the important determinants of different QoL trajectory patterns. RESULTS: The "steadily poor" (n = 27, 5.8%), "consistently moderate" (n = 174, 37.3%), and "consistently good" (n = 265, 56.9%) trajectory patterns were identified. The HbA1c levels (OR 2.16) and diabetes distress (OR 1.18) were important for determining participants in the "steadily poor" QoL trajectory pattern. HbA1c levels (OR 1.25) and diabetes distress (OR 1.14) were important for determining participants in the "consistently moderate" QoL trajectory pattern. CONCLUSIONS: To prevent development of relatively worse QoL trajectory patterns in patients with T2DM in a timelier manner, healthcare providers could regularly assess the QoL and provide intervention, especially for those with high HbA1c levels and high diabetes distress. Meanwhile, early intervention for decreasing HbA1c levels and diabetes distress may improve the trajectory development of QoL in patients with T2DM.

Range of L5 LDL levels in healthy adults and L5's predictive power in patients with hyperlipidemia or coronary artery disease.

Electronegative L5 low-density lipoprotein (LDL) level may be a useful biomarker for predicting cardiovascular disease. We determined the range of plasma L5 levels in healthy adults (n = 35) and examined the power of L5 levels to differentiate patients with coronary artery disease (CAD; n = 40) or patients with hyperlipidemia (HLP) without evidence of CAD (n = 35) from healthy adults. The percent L5 in total LDL (L5%) was quantified by using fast-protein liquid chromatography with an anion-exchange column. Receiver operating characteristic curve analysis was performed to determine cut-off values for L5 levels. The mean L5% and plasma concentration of L5 (ie, [L5]) were significantly higher in patients with HLP or CAD than in healthy adults (P < 0.001). The ranges of L5% and [L5] in healthy adults were determined to be <1.6% and <1.7 mg/dL, respectively. In individuals with L5% >1.6%, the odds ratio was 9.636 for HLP or CAD. In individuals with [L5] >1.7 mg/dL, the odds ratio was 17.684 for HLP or CAD. The power of L5% or [L5] to differentiate patients with HLP or CAD from healthy adults was superior to that of the LDL/high-density lipoprotein ratio. The ranges of L5% and [L5] in healthy adults determined here may be clinically useful in preventing and treating cardiovascular disease.

Cardiovascular Benefits of Acarbose vs Sulfonylureas in Patients With Type 2 Diabetes Treated With Metformin.

Context: Although α-glucosidase inhibitors (AGIs) have been shown to reduce the risk of myocardial infarction in patients with impaired glucose tolerance, the cardiovascular benefits of AGIs in those with type 2 diabetes (T2D) remains unclear. Objective: We compared the clinical outcomes of adding acarbose vs sulfonylureas to metformin therapy in patients with T2D. Design, Setting, and Participants: The study population was drawn from the database of the Diabetes Pay-for-Performance program in Taiwan. Sulfonylureas and acarbose were prescribed to 196,143 and 14,306 patients with T2D, respectively, from 2004 to 2015, who had been treated with metformin. A propensity score-matched cohort study was conducted. The patients were followed up for clinical adverse events of all-cause mortality and hospitalizations of major atherosclerotic events (i.e., myocardial infarction and ischemic stroke), heart failure, or hypoglycemia. Results: A total of 14,306 propensity score-matched pairs (age, 55.8 ± 13.1 years; 47.8% men) were enrolled in the present analysis. Compared with sulfonylureas as the add-on therapy to metformin, the use of acarbose was associated with significantly lower risks of hospitalizations for major atherosclerotic events [hazard ratio (HR), 0.69; 95% CI, 0.52 to 0.91], ischemic stroke (HR, 0.68; 95% CI, 0.49 to 0.94), and hypoglycemia (HR, 0.23; 95% CI, 0.08 to 0.71), after accounting for major confounding factors. Conclusions: In T2D treatment, the use of acarbose as an add-on remedy to metformin was associated with lower risks of major atherosclerotic events, ischemic stroke, and hypoglycemia compared with the use of sulfonylurea as an add-on remedy.

ASSOCIATIONS BETWEEN TRIGLYCERIDE/HIGH-DENSITY LIPOPROTEIN CHOLESTEROL RATIO AND MICRO- AND MACROANGIOPATHIES IN TYPE 2 DIABETES MELLITUS.

OBJECTIVE: The triglyceride (TG) to high-density lipoprotein cholesterol (HDL-C) ratio has been reported to be a marker of insulin resistance. The aim of this study was to investigate associations between the TG/HDL-C ratio and micro- and macroangiopathies in patients with type 2 diabetes mellitus (DM). METHODS: A total of 1,981 (851 male and 1,130 female) patients with type 2 DM were enrolled from our outpatient clinic. These patients were stratified into 4 groups according to TG/HDL-C ratio quartiles. RESULTS: There were significant trends for stepwise increases in albuminuria ≥30 mg/g ( P<.001), coronary artery disease (CAD, P = .040), cerebrovascular disease (CVA, P = .002) and ankle-brachial index (ABI) <0.9 ( P = .001) corresponding to TG/HDL-C ratio quartiles, but not diabetic retinopathy ( P = .105). Furthermore, quartile 4 of the TG/HDL-C ratio was significantly associated with albuminuria, CAD, CVA, and ABI <0.9 after multivariate analysis compared to quartile 1. CONCLUSION: A high TG/HDL-C ratio was significantly associated with albuminuria, CAD, CVA, and peripheral artery occlusive disease (PAOD) in patients with DM, which translated into an increased risk of cardiovascular disease. ABBREVIATIONS: ABI = ankle-brachial index; ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker; BMI = body mass index; CAD = coronary artery disease; CI = confidence interval; CVA = cerebrovascular disease; DM = diabetes mellitus, DR = diabetic retinopathy; eGFR = estimated glomerular filtration rate; HbA1c = glycated hemoglobin A1c; HDL-C = high-density lipoprotein cholesterol; OR = odds ratio; PAOD = peripheral artery occlusive disease; TGs = triglycerides.