Income variability and incident cardiovascular disease in diabetes: a population-based cohort study.

BACKGROUND AND AIMS: Longitudinal change in income is crucial in explaining cardiovascular health inequalities. However, there is limited evidence for cardiovascular disease (CVD) risk associated with income dynamics over time among individuals with type 2 diabetes (T2D). METHODS: Using a nationally representative sample from the Korean National Health Insurance Service database, 1 528 108 adults aged 30-64 with T2D and no history of CVD were included from 2009 to 2012 (mean follow-up of 7.3 years). Using monthly health insurance premium information, income levels were assessed annually for the baseline year and the four preceding years. Income variability was defined as the intraindividual standard deviation of the percent change in income over 5 years. The primary outcome was a composite event of incident fatal and nonfatal CVD (myocardial infarction, heart failure, and stroke) using insurance claims. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated after adjusting for potential confounders. RESULTS: High-income variability was associated with increased CVD risk (HRhighest vs. lowest quartile 1.25, 95% CI 1.22-1.27; Ptrend < .001). Individuals who experienced an income decline (4 years ago vs. baseline) had increased CVD risk, which was particularly notable when the income decreased to the lowest level (i.e. Medical Aid beneficiaries), regardless of their initial income status. Sustained low income (i.e. lowest income quartile) over 5 years was associated with increased CVD risk (HRn = 5 years vs. n = 0 years 1.38, 95% CI 1.35-1.41; Ptrend < .0001), whereas sustained high income (i.e. highest income quartile) was associated with decreased CVD risk (HRn = 5 years vs. n = 0 years 0.71, 95% CI 0.70-0.72; Ptrend < .0001). Sensitivity analyses, exploring potential mediators, such as lifestyle-related factors and obesity, supported the main results. CONCLUSIONS: Higher income variability, income declines, and sustained low income were associated with increased CVD risk. Our findings highlight the need to better understand the mechanisms by which income dynamics impact CVD risk among individuals with T2D.

Chronic disease management program applied to type 2 diabetes patients and prevention of diabetic complications: a retrospective cohort study using nationwide data.

BACKGROUND: The outcomes of education and counseling by medical professionals for patients with type 2 diabetes mellitus (T2DM) are unclear. This study examined the effects of the Chronic Disease Management Program (CDMP), a health insurance fee-for-service benefit, on the incidence of diabetic complications in patients newly diagnosed with T2DM using the National Health Insurance data. METHODS: Patients newly diagnosed with T2DM aged ≥ 20 years from 2010 to 2014 were followed up until 2015. Selection bias was minimized using propensity score matching. A stratified Cox proportional hazards model was used to analyze the association between the CDMP and the risk of incident diabetic complications. Subgroup analysis was performed for patients with high medication adherence, which was indicated by a medication possession ratio (MPR) ≥ 80. RESULTS: Among the 11,915 patients with T2DM in the cohort, 4,617 were assigned to the CDMP and non-CDMP group each. The CDMP helped reduce the overall and microvascular risks of complications compared to the non-CDMP group; however, the protective effect against macrovascular complications was only observed in those aged ≥ 40 years. Subgroup analysis of the group aged ≥ 40 years with high adherence (an MPR ≥ 80) showed that the CDMP effectively reduced the incidence of micro- and macrovascular complications. CONCLUSIONS: Effective management of T2DM is crucial in preventing complications in patients with the condition, and includes regular monitoring and adjustment of treatment by qualified physicians. Nevertheless, long-term prospective studies on the effects of CDMP are required to confirm this finding.

AB569, a nontoxic chemical tandem that kills major human pathogenic bacteria.

Antibiotic-resistant superbug bacteria represent a global health problem with no imminent solutions. Here we demonstrate that the combination (termed AB569) of acidified nitrite (A-NO2-) and Na2-EDTA (disodium ethylenediaminetetraacetic acid) inhibited all Gram-negative and Gram-positive bacteria tested. AB569 was also efficacious at killing the model organism Pseudomonas aeruginosa in biofilms and in a murine chronic lung infection model. AB569 was not toxic to human cell lines at bactericidal concentrations using a basic viability assay. RNA-Seq analyses upon treatment of P. aeruginosa with AB569 revealed a catastrophic loss of the ability to support core pathways encompassing DNA, RNA, protein, ATP biosynthesis, and iron metabolism. Electrochemical analyses elucidated that AB569 produced more stable SNO proteins, potentially explaining one mechanism of bacterial killing. Our data implicate that AB569 is a safe and effective means to kill pathogenic bacteria, suggesting that simple strategies could be applied with highly advantageous therapeutic/toxicity index ratios to pathogens associated with a myriad of periepithelial infections and related disease scenarios.

Mutant Huntingtin Is Cleared from the Brain via Active Mechanisms in Huntington Disease.

Huntington disease (HD) is a neurodegenerative disease caused by a CAG trinucleotide repeat expansion in the huntingtin (HTT) gene. Therapeutics that lower HTT have shown preclinical promise and are being evaluated in clinical trials. However, clinical assessment of brain HTT lowering presents challenges. We have reported that mutant HTT (mHTT) in the CSF of HD patients correlates with clinical measures, including disease burden as well as motor and cognitive performance. We have also shown that lowering HTT in the brains of HD mice results in correlative reduction of mHTT in the CSF, prompting the use of this measure as an exploratory marker of target engagement in clinical trials. In this study, we investigate the mechanisms of mHTT clearance from the brain in adult mice of both sexes to elucidate the significance of therapy-induced CSF mHTT changes. We demonstrate that, although neurodegeneration increases CSF mHTT concentrations, mHTT is also present in the CSF of mice in the absence of neurodegeneration. Importantly, we show that secretion of mHTT from cells in the CNS followed by glymphatic clearance from the extracellular space contributes to mHTT in the CSF. Furthermore, we observe secretion of wild type HTT from healthy control neurons, suggesting that HTT secretion is a normal process occurring in the absence of pathogenesis. Overall, our data support both passive release and active clearance of mHTT into CSF, suggesting that its treatment-induced changes may represent a combination of target engagement and preservation of neurons.SIGNIFICANCE STATEMENT: Changes in CSF mutant huntingtin (mHTT) are being used as an exploratory endpoint in HTT lowering clinical trials for the treatment of Huntington disease (HD). Recently, it was demonstrated that intrathecal administration of a HTT lowering agent leads to dose-dependent reduction of CSF mHTT in HD patients. However, little is known about how HTT, an intracellular protein, reaches the extracellular space and ultimately the CSF. Our findings that HTT enters CSF by both passive release and active secretion followed by glymphatic clearance may have significant implications for interpretation of treatment-induced changes of CSF mHTT in clinical trials for HD.

Cerebrospinal fluid mutant huntingtin is a biomarker for huntingtin lowering in the striatum of Huntington disease mice.

Huntington disease (HD) is a neurodegenerative disease caused by a trinucleotide repeat expansion in the HTT gene encoding an elongated polyglutamine tract in the huntingtin (HTT) protein. Expanded mutant HTT (mHTT) is toxic and leads to regional atrophy and neuronal cell loss in the brain, which occurs earliest in the striatum. Therapeutic lowering of mHTT in the central nervous system (CNS) has shown promise in preclinical studies, with multiple approaches currently in clinical development for HD. Quantitation of mHTT in the cerebrospinal fluid (CSF) is being used as a clinical pharmacodynamic biomarker of target engagement in the CNS. We have previously shown that the CNS is a major source of mHTT in the CSF. However, little is known about the specific brain regions and cell types that contribute to CSF mHTT. Therefore, a better understanding of the origins of CSF mHTT and whether therapies targeting mHTT in the striatum would be expected to be associated with significant lowering of mHTT in the CSF is needed. Here, we use complementary pharmacological and genetic-based approaches to either restrict expression of mHTT to the striatum or selectively deplete mHTT in the striatum to evaluate the contribution of this brain region to mHTT in the CSF. We show that viral expression of a mHTT fragment restricted to the striatum leads to detectable mHTT in the CSF. We demonstrate that targeted lowering of mHTT selectively in the striatum using an antisense oligonucleotide leads to a significant reduction of mHTT in the CSF of HD mice. Furthermore, using a transgenic mouse model of HD that expresses full length human mHTT and wild type HTT, we show that genetic inactivation of mHTT selectively in the striatum results in a significant reduction of mHTT in the CSF. Taken together, our data supports the conclusion that the striatum contributes sufficiently to the pool of mHTT in the CSF that therapeutic levels of mHTT lowering in the striatum can be detected by this measure in HD mice. This suggests that CSF mHTT may represent a pharmacodynamic biomarker for therapies that lower mHTT in the striatum.

Synergistic association between underweight and type 2 diabetes on the development of laryngeal cancer: a national population-based retrospective cohort study.

BACKGROUND: Although cigarette smoking is the most significant risk factor for laryngeal cancer, other risk factors might also be associated with the development of laryngeal cancer. We investigated whether underweight and type 2 diabetes are associated with laryngeal cancer in a Korean population. METHODS: A total of 9,957,059 participants (≥20 years) without prior history of cancer who underwent a National Health Insurance Service health checkup in 2009 were followed up until December 31, 2018. Newly diagnosed laryngeal cancer was identified using claim data, and underweight was defined as body mass index (BMI) < 18.5 kg/m2. A Cox proportional-hazards models with multivariable adjustment were used to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (95% CIs). RESULTS: During the median follow-up period of 8.3 years, 3504 cases of laryngeal cancer occurred. Underweight was associated with increased risk of laryngeal cancer after adjusting for potential confounders (HR: 1.43, 95% CI: 1.22-1.69) compared to those who were not underweight. Underweight and type 2 diabetes were synergistically associated with higher risk of laryngeal cancer (HR: 2.33, 95% CI: 1.54-3.51), compared to those without either condition. This relationship was stronger in those with an age < 65 years (HR: 3.33, 95% CI: 1.88-5.87) and alcohol consumption (HR: 2.72, 95% CI: 1.64-4.53). CONCLUSIONS: These results suggest that underweight may be a significant risk factor for laryngeal cancer and that underweight and type 2 diabetes might synergistically increase the risk of laryngeal cancer.

A deep learning model for screening type 2 diabetes from retinal photographs.

BACKGROUND AND AIMS: We aimed to develop and evaluate a non-invasive deep learning algorithm for screening type 2 diabetes in UK Biobank participants using retinal images. METHODS AND RESULTS: The deep learning model for prediction of type 2 diabetes was trained on retinal images from 50,077 UK Biobank participants and tested on 12,185 participants. We evaluated its performance in terms of predicting traditional risk factors (TRFs) and genetic risk for diabetes. Next, we compared the performance of three models in predicting type 2 diabetes using 1) an image-only deep learning algorithm, 2) TRFs, 3) the combination of the algorithm and TRFs. Assessing net reclassification improvement (NRI) allowed quantification of the improvement afforded by adding the algorithm to the TRF model. When predicting TRFs with the deep learning algorithm, the areas under the curve (AUCs) obtained with the validation set for age, sex, and HbA1c status were 0.931 (0.928-0.934), 0.933 (0.929-0.936), and 0.734 (0.715-0.752), respectively. When predicting type 2 diabetes, the AUC of the composite logistic model using non-invasive TRFs was 0.810 (0.790-0.830), and that for the deep learning model using only fundus images was 0.731 (0.707-0.756). Upon addition of TRFs to the deep learning algorithm, discriminative performance was improved to 0.844 (0.826-0.861). The addition of the algorithm to the TRFs model improved risk stratification with an overall NRI of 50.8%. CONCLUSION: Our results demonstrate that this deep learning algorithm can be a useful tool for stratifying individuals at high risk of type 2 diabetes in the general population.

Potent and sustained huntingtin lowering via AAV5 encoding miRNA preserves striatal volume and cognitive function in a humanized mouse model of Huntington disease.

Huntington disease (HD) is a fatal neurodegenerative disease caused by a pathogenic expansion of a CAG repeat in the huntingtin (HTT) gene. There are no disease-modifying therapies for HD. Artificial microRNAs targeting HTT transcripts for degradation have shown preclinical promise and will soon enter human clinical trials. Here, we examine the tolerability and efficacy of non-selective HTT lowering with an AAV5 encoded miRNA targeting human HTT (AAV5-miHTT) in the humanized Hu128/21 mouse model of HD. We show that intrastriatal administration of AAV5-miHTT results in potent and sustained HTT suppression for at least 7 months post-injection. Importantly, non-selective suppression of huntingtin was generally tolerated, however high dose AAV5-miHTT did induce astrogliosis. We observed an improvement of select behavioural and modest neuropathological HD-like phenotypes in Hu128/21 mice, suggesting a potential therapeutic benefit of miRNA-mediated non-selective HTT lowering. Finally, we also observed that potent reduction of wild type HTT (wtHTT) in Hu21 control mice was tolerated up to 7 months post-injection but may induce impairment of motor coordination and striatal atrophy. Taken together, our data suggests that in the context of HD, the therapeutic benefits of mHTT reduction may outweigh the potentially detrimental effects of wtHTT loss following non-selective HTT lowering.

Efficacy of Personalized Diabetes Self-care Using an Electronic Medical Record-Integrated Mobile App in Patients With Type 2 Diabetes: 6-Month Randomized Controlled Trial.

BACKGROUND: A system that combines technology and web-based coaching can help treat chronic conditions such as diabetes. However, the effectiveness of apps in mobile health (mHealth) interventions is inconclusive and unclear due to heterogeneous interventions and varying follow-up durations. In addition, randomized controlled trial data are limited, and long-term follow-up is lacking, especially for apps integrated into electronic medical records. OBJECTIVE: We aimed to assess the effect of an electronic medical record-integrated mobile app for personalized diabetes self-care, focusing on the self-monitoring of blood glucose and lifestyle modifications, on glycemic control in patients with type 2 diabetes mellitus. METHODS: In a 26-week, 3-arm, randomized, controlled, open-label, parallel group trial, patients with type 2 diabetes mellitus and a hemoglobin A1c (HbA1c) level of ≥7.5% were recruited. The mHealth intervention consisted of self-monitoring of blood glucose with the automatic transfer of glucose, diet, and physical activity counseling data (iCareD system). Participants were randomly assigned to the following three groups: usual care (UC), mobile diabetes self-care (MC), and MC with personalized, bidirectional feedback from physicians (MPC). The primary outcome was the change in HbA1c levels at 26 weeks. In addition, diabetes-related self-efficacy, self-care activities, and satisfaction with the iCareD system were assessed after the intervention. RESULTS: A total of 269 participants were enrolled, and 234 patients (86.9%) remained in the study at 26 weeks. At 12 weeks after the intervention, the mean decline in HbA1c levels was significantly different among the 3 groups (UC vs MC vs MPC: -0.49% vs -0.86% vs -1.04%; P=.02). The HbA1c level decreased in all groups; however, it did not differ among groups after 26 weeks. In a subgroup analysis, HbA1c levels showed a statistically significant decrease after the intervention in the MPC group compared with the change in the UC or MC group, especially in patients aged <65 years (P=.02), patients with a diabetes duration of ≥10 years (P=.02), patients with a BMI of ≥25.0 kg/m2 (P=.004), patients with a C-peptide level of ≥0.6 ng/mL (P=.008), and patients who did not undergo treatment with insulin (P=.004) at 12 weeks. A total of 87.2% (137/157) of the participants were satisfied with the iCareD system. CONCLUSIONS: The mHealth intervention for diabetes self-care showed short-term efficacy in glycemic control, and the effect decreased over time. The participants were comfortable with using the iCareD system and exhibited high adherence. TRIAL REGISTRATION: Clinical Research Information Service, Republic of Korea KCT0004128; https://tinyurl.com/bdd6pa9m.

Rescue of aberrant huntingtin palmitoylation ameliorates mutant huntingtin-induced toxicity.

Huntington disease (HD) is a neurodegenerative disorder caused by a CAG expansion in the HTT gene that codes for an elongated polyglutamine tract in the huntingtin (HTT) protein. HTT is subject to multiple post-translational modifications (PTMs) that regulate its cellular function. Mutating specific PTM sites within mutant HTT (mHTT) in HD mouse models can modulate disease phenotypes, highlighting the key role of HTT PTMs in the pathogenesis of HD. These findings have led to increased interest in developing small molecules to modulate HTT PTMs in order to decrease mHTT toxicity. However, the therapeutic efficacy of pharmacological modulation of HTT PTMs in preclinical HD models remains largely unknown. HTT is palmitoylated at cysteine 214 by the huntingtin-interacting protein 14 (HIP14 or ZDHHC17) and 14-like (HIP14L or ZDHHC13) acyltransferases. Here, we assessed if HTT palmitoylation should be regarded as a therapeutic target to treat HD by (1) investigating palmitoylation dysregulation in rodent and human HD model systems, (2) measuring the impact of mHTT-lowering therapy on brain palmitoylation, and (3) evaluating if HTT palmitoylation can be pharmacologically modulated. We show that palmitoylation of mHTT and some HIP14/HIP14L-substrates is decreased early in multiple HD mouse models, and that mHTT palmitoylation decreases further with aging. Lowering mHTT in the brain of YAC128 mice is not sufficient to rescue aberrant palmitoylation. However, we demonstrate that mHTT palmitoylation can be normalized in COS-7 cells, in YAC128 cortico-striatal primary neurons and HD patient-derived lymphoblasts using an acyl-protein thioesterase (APT) inhibitor. Moreover, we show that modulating palmitoylation reduces mHTT aggregation and mHTT-induced cytotoxicity in COS-7 cells and YAC128 neurons.

Associations of general obesity and central obesity with the risk of hepatocellular carcinoma in a Korean population: A national population-based cohort study.

Numerous previous studies have shown an association between general obesity and hepatocellular carcinoma (HCC). However, relatively few reports on the association of central obesity and HCC are available in Asian populations. Therefore, we investigated the association between WC representing central obesity and the risk of HCC in addition to BMI representing general obesity and the risk of HCC in Korea. A total of 10 505 818 participants who received the National Health Insurance Service (NHIS) health checkups in 2009 were screened for study eligibility, and 26 979 cases of HCC occurred during the 7.3 years of mean follow-up. General obesity increased the risk of HCC with hazard ratios (HRs) of 1.14 (95% CI, 1.11-1.18) for BMI 25.0-<30.0 kg/m2 and 1.52 (95% CI, 1.43-1.61) for BMI ≥30 kg/m2 compared to those whose BMI is within the normal range. Central obesity was also associated with a higher risk of HCC. For the participants with a WC ≥105 cm in men and WC ≥100 cm in women, the risk of HCC was higher than that of the reference group (HR = 1.69, 95% CI, 1.54-1.85). The HRs were 1.13 (95% CI, 1.07-1.19) for nonobese participants with central obesity, and 1.34 (95% CI, 1.30-1.38) for obese participants with central obesity compared to those without both conditions. Our findings suggest that the risk of HCC increases even more when general obesity is combined with central obesity. Moreover, central obesity is associated with the risk of HCC, regardless of general obesity.

The Anti-Inflammatory Effects of Glucagon-Like Peptide Receptor Agonist Lixisenatide on the Retinal Nuclear and Nerve Fiber Layers in an Animal Model of Early Type 2 Diabetes.

This study explored the anti-inflammatory effects of a glucagon-like peptide-1 receptor agonist (GLP-1RA), known as lixisenatide, on the eyes of early type 2 diabetic mice. Diabetic (db/db) mice were divided into three groups: GLP-1RA [lixisenatide (LIX)], insulin (INS) with controlled hyperglycemia based on the glucose concentration of lixisenatide, and diabetic control (D-CON). Nondiabetic control mice (db/dm) were also characterized for comparison. After 8 weeks of treatment, mRNA levels of inflammatory markers, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, immunohistochemical staining; Western blot of glial fibrillary acidic protein (GFAP) and thioredoxin-interacting protein; and retinal thickness were assessed in the central and peripheral neurosensory retina. LIX showed decreased immunohistochemical staining for both thioredoxin-interacting protein and GFAP in the central and peripheral neurosensory retina compared with D-CON and INS, and decreased expression of these proteins in the neurosensory retina and immunohistochemical staining in the optic nerve head for GFAP compared with D-CON. The inner nuclear layer in the peripheral retina in LIX was only thinner than those of D-CON and INS. In an early type 2 diabetic mouse model, lixisenatide treatment showed superior anti-inflammatory effects on the retina and optic nerve head independent of hyperglycemia. Thus, the neuroprotective effects of lixisenatide treatment in the peripheral inner nuclear layer should be evaluated in early type 2 diabetic retinopathy.

Waist circumference, body mass index, and colorectal cancer risk according to diabetes status: A Korean nationwide population-based cohort study.

BACKGROUND AND AIM: We investigated the relationship of BMI and waist circumference with the risk of colorectal cancer (CRC) using a population-based cohort database and to explore the relationship of CRC with diabetes status. METHODS: Retrospective data (age >20 years) on anthropometric variables, blood parameters of fasting sugar, lipid levels, and blood pressure were collected from the National Health Insurance Corporation database between 2009 and 2012. Cox regression models were used to estimate hazard ratio (HR) and corresponding 95% confidence intervals (95% CI). RESULTS: Of the 23 121 360 people studied, 120 579 were diagnosed with CRC after a median follow-up period of 5.4 years. Both waist circumference and body mass index were positively associated with increased risk of CRC, regardless of age or sex. After mutual adjustment, only waist circumference was significantly associated with increased risk of CRC (HR = 1.275, 95% CI: 1.205-1.349). When the risk of CRC was compared according to diabetes status among people with the same waist circumference range, risk of CRC was higher for those with worse diabetes status. CONCLUSION: When waist circumference and body mass index were mutually adjusted, only waist circumference was associated with CRC risk. In addition, the risk of CRC is gradually higher in those with worsening diabetes, even if their waist circumferences are within the same range.

Lactiplantibacillusplantarum ATG-K2 Exerts an Anti-Obesity Effect in High-Fat Diet-Induced Obese Mice by Modulating the Gut Microbiome.

Obesity is a major health problem. Compelling evidence supports the beneficial effects of probiotics on obesity. However, the anti-obesity effect of probiotics remains unknown. In this study, we investigated the anti-obesity effects and potential mechanisms of Lactiplantibacillus plantarum ATG-K2 using 3T3-L1 adipocytes and high-fat diet (HFD)-induced obese mice. 3T3-L1 cells were incubated to determine the effect of lipid accumulation with lysate of L. plantarum ATG-K2. Mice were fed a normal fat diet or HFD with L. plantarum ATG-K2 and Orlistat for 8 weeks. L. plantarum ATG-K2 inhibited lipid accumulation in 3T3-L1 adipocytes, and reduced body weight gain, WAT weight, and adipocyte size in HFD-induced obese mice, concurrently with the downregulation of PPARγ, SREBP1c, and FAS and upregulation of PPARα, CTP1, UCP1, Prdm16, and ND5. Moreover, L. plantarum ATG-K2 decreased TG, T-CHO, leptin, and TNF-α levels in the serum, with corresponding gene expression levels in the intestine. L. plantarum ATG-K2 modulated the gut microbiome by increasing the abundance of the Lactobacillaceae family, which increased SCFA levels and branched SCFAs in the feces. L. plantarum ATG-K2 exhibited an anti-obesity effect and anti-hyperlipidemic effect in 3T3-L1 adipocytes and HFD-induced obese mice by alleviating the inflammatory response and regulating lipid metabolism, which may be influenced by modulation of the gut microbiome and its metabolites. Therefore, L. plantarum ATG-K2 can be a preventive and therapeutic agent for obesity.

Optimal fasting plasma glucose and haemoglobin A1c levels for screening of prediabetes and diabetes according to 2-hour plasma glucose in a high-risk population: The Korean Diabetes Prevention Study.

BACKGROUND: The primary aim of this study was to assess the utility of fasting plasma glucose (FPG) and HbA1c to identify diabetes by the 2-hour plasma glucose (PG) criterion in the Korean population at high risk for diabetes. METHODS: A total of 1646 participants with a body mass index of ≥23 kg/m2 without having a history of diabetes were recruited in this study. The cut-off values of FPG and HbA1c for detecting diabetes were identified using the Youden index using receiver operating characteristic (ROC) analysis. The gold standard for diabetes prediction was defined by the 2-hour PG level of ≥200 mg/dL. RESULTS: The participants comprised 54.0% women, and the mean age of all participants was 55.0 ± 8.1 years. At baseline, FPG was 104.1 ± 14.2 mg/dL, the 2-hour PG value was 162.9 ± 55.3 mg/dL, and HbA1c was 5.9% ± 0.5%. Four hundred and forty-six subjects (27.1%) were diagnosed with diabetes and 976 subjects (59.3%) were determined to be at prediabetes. The area under the ROC curve (AUC) of FPG and HbA1c for diabetes were 0.776 and 0.802, while the AUC of FPG and HbA1c for prediabetes were 0.515 and 0.477. The optimal cut-off value for diagnosing diabetes of FPG and HbA1c were 104.5 mg/dL (sensitivity 75.8%, specificity 67.5%) and 5.9% (sensitivity 80.6%, specificity 63.8%), respectively. CONCLUSIONS: FPG of 104.5 mg/dL and HbA1c value of 5.9% (41 mmol/mol) can be used as an optimal screening value for diabetes by 2-hour PG criterion in the Korean population at high risk for diabetes.

Effect of sodium-glucose cotransporter 2 inhibitor, empagliflozin, and α-glucosidase inhibitor, voglibose, on hepatic steatosis in an animal model of type 2 diabetes.

OBJECTIVE: We investigated the effects of sodium-glucose cotransporter 2 inhibitor, empagliflozin, and α-glucosidase inhibitor, voglibose, on hepatic steatosis in an animal model of type 2 diabetes (T2DM). METHODS: Empagliflozin (OLETF-EMPA) or voglibose (OLETF-VOG) was administered to Otsuka Long-Evans Tokushima fatty (OLETF) rats once daily for 12 weeks. Control Long-Evans Tokushima Otsuka (LETO) and OLETF (OLETF-C) rats received saline. RESULTS: Blood glucose levels were significantly suppressed in OLETF-EMPA and OLETF-VOG compared with the OLETF-C group. The liver fat content was significantly higher in the OLETF-C group than in the OLETF-EMPA and OLETF-VOG. Hepatic gene expressions involved in gluconeogenesis (glucose 6-phosphatase [G6Pase], fructose-1,6-bisphosphatase [FBP1], and phosphoenolpyruvate carboxykinase [PEPCK]) and lipogenesis (acetyl-CoA carboxylase [ACC], fatty acid synthase [FAS], and sterol regulatory element-binding transcription factor 1c [SREBP-1c]) were significantly decreased in the OLETF-EMPA group compared with other OLETF groups (OLETF-C and OLETF-VOG). Sirtuin 1 (SIRT1) expression level and SIRT1 activity were markedly reduced in OLETF-C rats; however, its expression increased in the OLETF-EMPA and OLETF-VOG. AMP-activated protein kinase (AMPK) phosphorylation level was remarkably increased by empagliflozin treatment in OLETF rats compared with other OLETF groups. Long-term empagliflozin and voglibose treatment reduced hepatic steatosis with suppression of gluconeogenesis and lipogenesis pathway in OLETF rats. CONCLUSION: We suggest that this metabolic improvement might be related to SIRT1 and AMPK pathway in T2DM. But empagliflozin is thought to have more advantage to prevent hepatic steatosis than voglibose in T2DM.

Severe hypoglycemia and the risk of cardiovascular disease and mortality in type 2 diabetes: a nationwide population-based cohort study.

BACKGROUND: We investigated the association regarding severe hypoglycemia episodes with cardiovascular disease risk and all-cause mortality in patients with type 2 diabetes. METHODS: Baseline and follow-up data (n = 1,568,097) from patients with type 2 diabetes were retrieved from the National Health Insurance System database (covering the entire Korean population). Type 2 diabetes, severe hypoglycemia, and major comorbidities were identified using International Classification of Diseases 10 codes and medication information. Individuals who were classified as type 2 diabetes in the year of 2009 were screened, and we counted severe hypoglycemia episodes from 2007 to 2009. The primary outcome was newly developed myocardial infarction (MI), stroke, heart failure, or all-cause mortality. Participants were followed from the baseline index date to the date of death or until December 31, 2015. RESULTS: In total, 19,660 (1.2%) patients developed at least one severe hypoglycemia event during the period from 2007 to 2009. Mean follow-up was 5.7 years. After adjustment for confounding factors, the hazard ratio (HR) of MI significantly and sequentially increased: 0 vs. 1 episode, HR 1.56, 95% CI 1.46-1.64; 0 vs. 2 episodes, HR 1.86, 95% CI 1.61-2.15; 0 vs. 3 or more episodes, HR 1.86, 95% CI 1.48-2.35, P for trend < 0.001. Similar findings were noted regarding the relationship of severe hypoglycemia episodes with stroke, heart failure, and all-cause mortality. Risks for all outcomes were highest within 1 year from the index date and showed decreasing trends with follow-up. Sensitivity analyses of the data from the subgroup population and 797,544 subjects who received a national health examination did not change the significance of the main findings. CONCLUSION: Among adult Korean patients with type 2 diabetes, a severe hypoglycemia episode is associated with increased risk for cardiovascular outcomes and all-cause mortality. Significant results from dose-response, temporal, and sensitivity analyses may suggest the possibility of direct causality between severe hypoglycemia and cardiovascular outcomes and mortality.

The association of diabetes duration and glycemic control with depression in elderly men with type 2 diabetes mellitus.

BACKGROUND: The prevalence of depression and type 2 diabetes mellitus (T2DM) are increasing in the elderly and are reportedly related to each other. We evaluated the relationship between T2DM-related factors and the degree of depression in elderly patients with T2DM based on gender. MATERIALS AND METHODS: A total of 155 patients with T2DM (56 males and 99 females aged ≥ 65 years) from seven hospitals were included in the study. To assess the status of depressive symptoms, the short form of the Geriatric Depression Scale-Korean version (SGDS-K) was used. We evaluated DM-related factors, such as T2DM duration, hemoglobin A1c (HbA1c) levels, and T2DM complications, as well as other possible factors that could affect depression, such as cognitive function, physical function, education level, and other personal factors. RESULTS: Mean age of the participants was 71.3 years with a mean HbA1c level of 7.6%. Males in the good glycemic control group (HbA1c <7%) showed lower SGDS-K scores compared to those in the poor glycemic control group, and the mean SGDS-K score was higher in the group with a longer duration of DM (M10 years); however, no difference was observed in females. Males and females with microvascular and macrovascular complications tended to have higher SGDS-K scores than participants with no microvascular or macrovascular complications. A multiple linear regression analysis revealed that DM duration and HbA1c level were independently associated with SGDS-K scores in males. CONCLUSION: Greater depression was associated with poorer glycemic control and a longer duration of DM in elderly males with T2DM.

An enhanced Q175 knock-in mouse model of Huntington disease with higher mutant huntingtin levels and accelerated disease phenotypes.

Huntington disease (HD) model mice with heterozygous knock-in (KI) of an expanded CAG tract in exon 1 of the mouse huntingtin (Htt) gene homolog genetically recapitulate the mutation that causes HD, and might be favoured for preclinical studies. However, historically these mice have failed to phenotypically recapitulate the human disease. Thus, homozygous KI mice, which lack wildtype Htt, and are much less relevant to human HD, have been used. The zQ175 model was the first KI mouse to exhibit significant HD-like phenotypes when heterozygous. In an effort to exacerbate HD-like phenotypes and enhance preclinical utility, we have backcrossed zQ175 mice to FVB/N, a strain highly susceptible to neurodegeneration. These Q175F mice display significant HD-like phenotypes along with sudden early death from fatal seizures. The zQ175 KI allele retains a floxed neomycin resistance cassette upstream of the Htt gene locus and produces dramatically reduced mutant Htt as compared to the endogenous wildtype Htt allele. By intercrossing with mice expressing cre in germ line cells, we have excised the neo cassette from Q175F mice generating a new line, Q175FΔneo (Q175FDN). Removal of the neo cassette resulted in a ∼2 fold increase in mutant Htt and rescue of fatal seizures, indicating that the early death phenotype of Q175F mice is caused by Htt deficiency rather than by mutant Htt. Additionally, Q175FDN mice exhibit earlier onset and a greater variety and severity of HD-like phenotypes than Q175F mice or any previously reported KI HD mouse model, making them valuable for preclinical studies.

Progression of cardiovascular autonomic neuropathy and cardiovascular disease in type 2 diabetes.

BACKGROUND: To examine whether the progression rate of cardiovascular autonomic neuropathy (CAN) stage is an independent predictive factor for cardiovascular disease (CVD) in type 2 diabetes. METHODS: Standardized cardiovascular autonomic reflex tests (CARTs) using traditional Ewing method were performed at baseline. The follow-up CARTs was recommended once every two years. We estimated the primary CVD endpoint, defined as coronary artery disease and ischemic stroke. The association between the progression rate of CAN stage and CVD was examined using time-dependent Cox proportional hazard models. RESULTS: At baseline, 578 patients completed follow-up CARTs; the cohort comprised 329 women (56.9%) with a mean age of 58.3 ± 10.3 years and a mean diabetes duration of 10.1 ± 6.2 years. One hundred and seventy-six patients (30.4%) developed CAN progression between baseline and follow-up CARTs. In the multivariable Cox proportional hazards regression analysis, patients with CAN progression demonstrated a 3.32 times higher risk (95% confidence interval, CI 1.81-6.14, P < 0.001) of CVD than those without CAN progression. Patients who experienced CAN progression from the normal to definite stage had the greatest risk of CVD compared to other patients (hazard ratio 4.91, 95% CI 2.05-11.77, P for trend = 0.001). CONCLUSIONS: CAN stage progression was associated with an increased risk of CVD in this type 2 diabetes cohort. Patients with rapid CAN progression had the greatest risk of CVD. Thus, regular screening and risk management of CAN progression is necessary to prevent CVD.