The receptor-interacting protein 1 (RIPK1)/RIPK3 kinases play important roles in necroptosis that is closely linked to inflammatory response. Although the activation of necroptosis is well characterized, how necroptosis is tuned down is largely unknown. Here, we found that Parkin (also known as PARK2 ), an E3 ubiquitin ligase implicated in Parkinson’s disease and a tumor suppressor, regulates necroptosis and inflammation by regulating necrosome formation. Parkin prevents the formation of the RIPK1-RIPK3 complex by promoting polyubiquitination of RIPK3. Parkin is phosphorylated and activated by the cellular energy sensor AMP-activated protein kinase (AMPK). Parkin-deficiency potentiates the RIPK1-RIPK3 interaction, RIPK3 phosphorylation, and necroptosis. Importantly, Parkin deficiency enhances inflammation and inflammation-associated tumorigenesis. These findings demonstrate that the AMPK-Parkin axis negatively regulates necroptosis via inhibiting the RIPK1-RIPK3 complex formation and this regulation may serve as an important mechanism to fine-tune necroptosis and inflammation.
BackgroundRepresentative data on the secular trends in cardiovascular disease (CVD) are limited in Asian populations with diabetes. We aimed to estimate the temporal trends in cardiovascular complications using Korean nationwide whole population-based claims data in subjects with and without diabetes.MethodsType 2 diabetes was defined as a current medication history of anti-diabetic drugs and the presence of International Classification of Diseases (ICD)-10 codes (E11–E14) as diagnosis. We compared the 8-year rates of six cardiovascular complications [i.e., ischemic heart disease, acute myocardial infarction (AMI), ischemic stroke, hemorrhagic stroke, percutaneous coronary intervention (PCI), and coronary artery bypass graft (CABG)] in Korean adults aged 30 years and older using data from four consecutive nationwide databases (2006–2007, 2008–2009, 2010–2011, and 2012–2013) of Korean national health insurance service.ResultsA total of 1,645,348, 1,971,559, 2,291,247, and 2,562,612 subjects with type 2 diabetes were found in the year of 2006–2007, 2008–2009, 2010–2011, and 2012–2013, respectively. Age and gender standardized rates of the six predefined cardiovascular complications decreased in Korean adults with type 2 diabetes during the study period. The greatest relative reductions were observed for hospitalization due to AMI (−37.28%), followed by hospitalizations due to ischemic stroke (−36.98%). In the overall population without type 2 diabetes, the greatest relative reductions were observed for hospitalization for hemorrhagic stroke (−29.47%), followed by hospitalization due to ischemic stroke (−28.92%). Relative decreases in all six predefined cardiovascular complications were generally more profound in adults with diabetes than in those without diabetes, which led to significant decrease in the relative risks of all six cardiovascular complications in subjects with diabetes over the past 8 years. However, people with diabetes still had a two- to sixfold higher risk of hospitalization for major CVD events and interventions than people without diabetes.ConclusionsOur findings suggest a significant reduction in the rate of people affected by CVD within the diabetic population. However, as the number of people with diabetes rises, the absolute burden of CVD will still be high in Korea.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0482-6) contains supplementary material, which is available to authorized users.
Objective This study assessed factors associated with the quality of life (QoL) and investigated the influence of age in 401 Korean type 2 diabetic patients. Methods The QoL was assessed using the latest version of the Audit of Diabetes-Dependent Quality of Life (ADDQoL) instrument in order to evaluate the perceived impact of diabetes on 19 life domains. The Beck Depression Inventory (BDI) was used to measure depressive symptoms. Logistic regression analyses were performed to assess the associations between the factors and the ADDQoL scores in the lower quartile. The interaction terms of these factors with age strata were included to evaluate the distinctive associations across age, followed by a stratified analysis. Results According to a multivariate analysis, a positive association between depressive symptoms (BDI ! 16) and lower ADDQoL scores was consistently found across all ages. In the younger group (<60 years), insulin use (odds ratio: 4.45, 95% confidence interval: 1.29-15.33, p=0.018) and the presence of a family history of diabetes (OR: 0.23, 95% CI: 0.08-0.68, p=0.008) were independently associated with lower ADDQoL scores. However, in the older group (! 60 years), insulin use and a family history of diabetes were not significantly associated with lower ADDQoL scores. Conclusion The findings suggest that insulin use, depressive symptoms and a family history of diabetes can be associated with the QoL in Korean type 2 diabetic patients; however, the associations show different patterns of age dependency.
We investigated the relationship between insulin resistance markers and subsarcolemmal (SS) and intramyofibrillar (IMF) ceramide concentrations, as well as the contribution of plasma palmitate (6.5-h infusion of [U-13C]palmitate) to intramyocellular ceramides. Seventy-six postabsorptive men and women had muscle biopsies 1.5, 6.5, and 24 h after starting the tracer infusion. Concentrations and enrichment of muscle ceramides were measured by liquid chromatography-tandem mass spectrometry. We found that HOMA of insulin resistance, plasma insulin, and triglyceride concentrations were positively correlated with SS C16:0 and C18:1 ceramide, but not SS C14:0-Cer, C20:0-Cer, C24:0-Cer, and C24:1-Cer concentrations; IMF ceramide concentrations were not correlated with any metabolic parameters. The fractional contribution of plasma palmitate to 16:0 ceramide was greater in SS than IMF (SS, 18.2% vs. IMF, 8.7%; P = 0.0006). Plasma insulin concentrations correlated positively with the fractional contribution of plasma palmitate to SS 16:0 ceramide. The fractional contribution of plasma palmitate to intramyocellular SS 16:0 ceramide was positively correlated with SS C16:0 ceramide concentrations (γ = 0.435; P = 0.002). We conclude that skeletal muscle SS ceramides, especially C16 to C18 chain lengths and the de novo synthesis of intramyocellular ceramide from plasma palmitate are associated with markers of insulin resistance.
Background/AimsWe investigated the associations among body mass index (BMI), insulin resistance, and β-cell function in Korean patients newly presenting with type 2 diabetes.MethodsIn total, 132 patients with new-onset type 2 diabetes mellitus were investigated. A standard 75-g oral glucose tolerance test was performed, and the indices of insulin secretion and insulin resistance were calculated.ResultsA higher BMI was associated with higher homeostasis model assessment values for insulin resistance (HOMA-IR), homeostasis model assessment of β-cell function (HOMA-β), and insulinogenic index as well as lower levels of insulin sensitivity index composite (ISIcomp) and disposition index (DI). In multiple regression models, BMI had independent positive associations with HOMA-IR, ISIcomp, and HOMA-β and inverse associations with the DI.ConclusionsOur results showed that BMI had independent positive associations with indices of insulin resistance and an inverse association with β-cell function adjusted for insulin resistance in Korean patients newly presenting with type 2 diabetes.
BackgroundThe aim of this study was to investigate the prevalence of obesity in Korean men with Klinefelter syndrome (KS) and the associated risk factors for obesity and hyperglycemia.MethodsData were collected retrospectively from medical records from 11 university hospitals in Korea between 1994 and 2014. Subjects aged ≥18 years with newly diagnosed KS were enrolled. The following parameters were recorded at baseline before treatment: chief complaint, height, weight, fasting glucose level, lipid panel, blood pressure, testosterone, luteinizing hormone, follicle-stimulating hormone, karyotyping patterns, and history of hypertension, diabetes, and dyslipidemia.ResultsData were analyzed from 376 of 544 initially enrolled patients. The rate of the 47 XXY chromosomal pattern was 94.1%. The prevalence of obesity (body mass index ≥25 kg/m2) in Korean men with KS was 42.6%. The testosterone level was an independent risk factor for obesity and hyperglycemia.ConclusionObesity is common in Korean men with KS. Hypogonadism in patients with KS was associated with obesity and hyperglycemia.
Serum total bilirubin concentrations within the physiologic range are inversely associated with the prevalence of cardiovascular autonomic neuropathy in patients with Type 2 diabetes.
Younger age at type 2 diabetes diagnosis is significantly associated with a poor diabetes-related QoL.
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