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There are inconsistent results on the impacts of controlling blood pressure (BP) on the risk of dementia. We investigated the association between BP and risk of dementia subtypes by antihypertensive treatment and comorbidities. Using the Korean National Health Insurance Service-Health Screening Database from 2009 to 2012, a total of 4 522 447 adults aged 60+ years without a history of dementia were analyzed and followed up for a mean of 5.4 years. Individuals were classified according to their baseline systolic BP (SBP) and diastolic BP; SBP 130 to

Background: The prevalence of non-alcoholic fatty liver disease (NAFLD) has rapidly increased worldwide. The aim of this study was to investigate whether there is an independent relationship between regional fat distribution, especially leg fat mass, and the presence of NAFLD using nationally representative data in Korea.Methods: This cross-sectional study analyzed data from 14,502 participants in the Korea National Health and Nutrition Examination Survey 2008 to 2011. Total fat mass, leg fat mass, and appendicular skeletal muscle mass were measured by dual-energy X-ray absorptiometry. Validated NAFLD prediction models and scoring systems for hepatic fibrosis were used.Results: The leg fat to total fat (LF/TF) ratio showed a negative relationship with many factors, including body mass index, waist circumference, blood pressure, fasting blood glucose, and liver enzyme levels. When the LF/TF ratio and indices of hepatic steatosis were stratified by quartiles, the LF/TF ratio showed a negative correlation with the scoring systems that were used. The LF/TF ratio showed better accuracy in predicting NAFLD than total fat mass or leg fat mass alone. After adjusting for various traditional and lifestyle factors, a low LF/TF ratio remained a risk factor for NAFLD. Among NAFLD subjects, the LF/TF ratio showed a negative relationship with hepatic fibrosis.Conclusion: A lower LF/TF ratio was markedly associated with a higher risk of hepatic steatosis and advanced hepatic fibrosis using various predictive models in a Korean population. Therefore, the LF/TF ratio could be a useful anthropometric parameter to predict NAFLD or advanced hepatic fibrosis.

Background: Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new class of antidiabetic drugs that exhibit multiple extraglycemic effects. However, there are conflicting results regarding the effects of SGLT2 inhibition on energy expenditure and thermogenesis. Therefore, we investigated the effect of ipragliflozin (a selective SGLT2 inhibitor) on energy metabolism.Methods: Six-week-old male 129S6/Sv mice with a high propensity for adipose tissue browning were randomly assigned to three groups: normal chow control, 60% high-fat diet (HFD)-fed control, and 60% HFD-fed ipragliflozin-treated groups. The administration of diet and medication was continued for 16 weeks.Results: The HFD-fed mice became obese and developed hepatic steatosis and adipose tissue hypertrophy, but their random glucose levels were within the normal ranges; these features are similar to the metabolic features of a prediabetic condition. Ipragliflozin treatment markedly attenuated HFD-induced hepatic steatosis and reduced the size of hypertrophied adipocytes to that of smaller adipocytes. In the ipragliflozin treatment group, uncoupling protein 1 (Ucp1) and other thermogenesis-related genes were significantly upregulated in the visceral and subcutaneous adipose tissue, and fatty acid oxidation was increased in the brown adipose tissue. These effects were associated with a significant reduction in the insulin-to-glucagon ratio and the activation of the AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1) pathway in the liver and adipose tissue.Conclusion: SGLT2 inhibition by ipragliflozin showed beneficial metabolic effects in 129S6/Sv mice with HFD-induced obesity that mimics prediabetic conditions. Our data suggest that SGLT2 inhibitors, through their upregulation of energy expenditure, may have therapeutic potential in prediabetic obesity.

BackgroundGasserian ganglion radiofreqeucy thermoablation is a good treatment option for the management of pain in trigeminal neuralgia. We report a case in which the patient of trigeminal neuralgia combined with anterior cerebral artery aneurysm was treated successfully by gasserian ganglion thermoablation without any complication.CaseAn 85-year-old female presenting with electric shock like sensation in the gum and molar teeth was diagnosed as trigeminal neuralgia. Carbamazepine medication and trigeminal nerve blockade relieved her pain partially, but severe side effects of carbamazepine occurred. Magnetic resonance angiography of the brain showed saccular aneurysm in inferior aspect of the anterior communicating artery. Gasserian ganglion thermoablation under sedation anesthesia using nicardipine was performed carefully without any rupture of the cerebral aneurysm.ConclusionsGasserian ganglion thermoablation could be performed safely in a patient with cerebral aneurysm without any inadvertent event.

Background: Insulin resistance (IR) and inflammation are closely related to each other and share common pathophysiological and metabolic mechanisms. We aimed to investigate the combined effect of IR and inflammation on comorbidities of type 2 diabetes mellitus (T2DM). Methods: A total 3,758 patients with T2DM were recruited through Huh’s Diabetes Center from January 2003 to June 2009. Insulin sensitivity was measured by a rate constant for plasma glucose disappearance (Kitt , %/min) using short insulin tolerance test. High sensitivity C-reactive protein (hs-CRP) was used as a surrogate for inflammation.Results: Patients with the lowest tertile of Kitt (IR group) showed worse cardio-metabolic parameters while those with the highest tertile of hs-CRP levels had worse cardio-metabolic parameters. The prevalence of metabolic syndrome, fatty liver, albuminuria, and carotid atherosclerosis decreased with Kitt tertile, but increased with hs-CRP tertile. In multiple regression analysis, both Kitt and hs-CRP were independent risk factors for comorbidities of T2DM. In addition, they showed synergistic effects on these comorbidities. Conclusion: Both IR and inflammation were significantly associated with comorbidities of T2DM in a dose dependent manner. In addition, the coexistence of IR and inflammation may synergistically contribute to increased comorbidities of T2DM.

Background: Nonalcoholic fatty liver disease (NAFLD) is the most prevalent cause of chronic liver disease worldwide. Type 2 diabetes mellitus (T2DM) is a risk factor that accelerates NAFLD progression, leading to fibrosis and cirrhosis. Thus, here we aimed to develop a simple model to predict the presence of NAFLD based on clinical parameters of patients with T2DM.Methods: A total of 698 patients with T2DM who visited five medical centers were included. NAFLD was evaluated using transient elastography. Univariate logistic regression analyses were performed to identify potential contributors to NAFLD, followed by multivariable logistic regression analyses to create the final prediction model for NAFLD.Results: Two NAFLD prediction models were developed, with and without serum biomarker use. The non-laboratory model comprised six variables: age, sex, waist circumference, body mass index (BMI), dyslipidemia, and smoking status. For a cutoff value of ≥60, the prediction accuracy was 0.780 (95% confidence interval [CI], 0.743 to 0.817). The second comprehensive model showed an improved discrimination ability of up to 0.815 (95% CI, 0.782 to 0.847) and comprised seven variables: age, sex, waist circumference, BMI, glycated hemoglobin, triglyceride, and alanine aminotransferase to aspartate aminotransferase ratio. Our non-laboratory model showed non-inferiority in the prediction of NAFLD versus previously established models, including serum parameters.Conclusion: The new models are simple and user-friendly screening methods that can identify individuals with T2DM who are at high-risk for NAFLD. Additional studies are warranted to validate these new models as useful predictive tools for NAFLD in clinicalpractice.

BACKGROUND AND AIM Cardiovascular disease (CVD) is the principal cause of death in patients with type 2 diabetes (T2D). In this study, we assessed whether liver fibrosis predicted the risk of CVD in patients with T2D. METHODS A total of 1481 patients who had commenced oral antidiabetic drugs to treat newly diagnosed T2D between 2006 and 2010 were recruited. The fibrosis-4 index (FIB-4), non-alcoholic fatty liver disease fibrosis score (NFS), and BARD score were used to assess fibrotic burden at the time of T2D diagnosis. RESULTS During the follow-up period (median 88.1 [interquartile range 36.6-113.6] months), 242 (16.3%) patients developed CVD. CVD occurred frequently in older patients and was associated with hypertension; metabolic syndrome; obesity; smoking; administration of statin, which is an antihyperlipidemic drug; lower platelet counts; lower alanine aminotransferase, total cholesterol, and HbA1c levels; higher C-peptide and homeostatic model assessment of insulin resistance levels; and higher FIB-4, NFS, and BARD score (all P

AIM To evaluate the effectiveness and safety of adding either a sodium-glucose co-transporter-2 inhibitor (SGLT2i) or thiazolidinedione (TZD) in patients with type 2 diabetes (T2D) inadequately controlled with triple therapy. MATERIALS AND METHODS In this prospective, open-label, multicentre, 24-week clinical trial, we randomly assigned 119 patients with T2D who failed to achieve glycaemic control (7%

Background: Risk assessment tools have been actively studied, and they summarize key predictors with relative weights/importance for a disease. Currently, standardized screening scores for type 2 diabetes mellitus (DM) and chronic kidney disease (CKD)—two key global health problems—are available in United States and Korea. We aimed to compare and evaluate screening scores for DM (or combined with prediabetes) and CKD, and assess the risk in contemporary United States and Korean populations.Methods: Four (2×2) models were evaluated in the United States-National Health and Nutrition Examination Survey (NHANES 2015–2018) and Korea-NHANES (2016–2018)—8,928 and 16,209 adults. Weighted statistics were used to describe population characteristics. We used logistic regression for predictors in the models to assess associations with study outcomes (undiagnosed DM and CKD) and diagnostic measures for temporal and cross-validation.Results: Korean adult population (mean age 47.5 years) appeared to be healthier than United States counterpart, in terms of DM and CKD risks and associated factors, with exceptions of undiagnosed DM, prediabetes and prehypertension. Models performed well in own country and external populations regarding predictor-outcome association and discrimination. Risk tests (high vs. low) showed area under the curve >0.75, sensitivity >84%, specificity >45%, positive predictive value >8%, and negative predictive value >99%. Discrimination was better for DM, compared to the combined outcome of DM and prediabetes, and excellent for CKD due to age.Conclusion: Four easy-to-use screening scores for DM and CKD are well-validated in contemporary United States and Korean populations. Prevention of DM and CKD may serve as first-step in public health, with these self-assessment tools as basic tools to help health education and disparity.

Introduction Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely prescribed for type 2 diabetes (T2D) and their glycemic control effects are well studied. However, information regarding the effects of switching DPP-4 inhibitors is limited, especially in older patients. Research Design and Methods We investigated whether switching from linagliptin to teneligliptin decreases blood glucose in older (≥65 years) T2D patients. In total, 164 patients with T2D who switched from linagliptin to teneligliptin for >12 weeks were included and the primary outcome was glycemic changes. Results Switching from linagliptin to teneligliptin ameliorated fasting blood glucose (148.1 ± 47.1 to 139.6 ± 43.4 mg/dL), glycated hemoglobin (HbA1c; 7.9 ± 1.3 to 7.5 ± 1.2%), and postprandial blood glucose (224.8 ± 77.4 to 205.8 ± 70.8 mg/dL) levels (all P 8.0%) and chronic kidney disease (estimated glomerular filtration rate

Background and aims Sarcopenia is associated with fibrotic burden in patients with chronic hepatitis B. We investigated the dynamic association between fibrosis changes and appendicular skeletal muscle mass during antiviral therapy in patients with chronic hepatitis B. Methods Between 2015 and 2018, chronic hepatitis B patients who received paired transient elastography to assess fibrotic burden in the liver and bioelectrical impedance analysis to assess appendicular skeletal muscle mass were recruited retrospectively. The sarcopenia index was calculated as total appendicular skeletal muscle mass/body mass index. Significant liver fibrosis was defined as a liver stiffness value≥8 kPa. Results In total, 223 (53.7%) received antiviral therapy, whereas 192 (46.3%) did not. Appendicular skeletal muscle mass decreased significantly in the antiviral therapy group (mean 21.16→21.00 kg, P = 0.01), but not in the non-antiviral therapy group (mean 20.77→20.64 kg, P = 0.134). In a subgroup with significant liver fibrosis, similar findings were observed (mean 20.73→20.54 kg in antiviral therapy group, P = 0.037; mean 21.39→21.07 kg in the non-antiviral therapy group, P = 0.097). Older age, male gender, higher body mass index, and higher aspartate aminotransferase were significantly associated with the increased risk of appendicular skeletal muscle mass reduction (≥5% from the baseline). Conclusions Appendicular skeletal muscle mass significantly decreased during antiviral therapy in patients with chronic hepatitis B patients.

Background and aims Sarcopenia leads to metabolic and vascular abnormalities. However, little is known regarding the independent relationship between skeletal muscle mass and atherosclerosis in patients with type 2 diabetes mellitus (T2DM). This study aimed to evaluate the association between skeletal muscle mass and carotid atherosclerosis in men and women with T2DM. Methods In this cross-sectional study, a total of 8202 patients with T2DM were recruited from the Seoul Metabolic Syndrome cohort. Skeletal muscle mass was estimated using bioimpedance analysis, while skeletal muscle mass index (SMI, %) was defined as total skeletal muscle mass (kg)/body weight (kg) × 100. Both carotid arteries were examined by B-mode ultrasound. Carotid atherosclerosis was defined by having a carotid plaque or mean carotid intima-media thickness (IMT) ≥1.1 mm. Results Among the entire population, 4299 (52.4%) subjects had carotid atherosclerosis. The prevalence of carotid atherosclerosis increased with decreasing SMI quartiles for both sexes. The odds ratios for carotid atherosclerosis were 2.33 (95% confidence interval [CI], 1.17–4.63) and 2.24 (95% CI, 1.06–4.741) in the lowest versus highest SMI quartile in men and women, respectively, after the adjustment for clinical risk factors. In men, the risk of atherosclerosis increased linearly with decreasing SMI quartiles (p for trend = 0.036). Conclusions Low skeletal muscle mass was independently associated with the presence of carotid atherosclerosis in men and women with T2DM.

This clinical practice position statement, a product of the Fatty Liver Research Group of the Korean Diabetes Association, proposes recommendations for the diagnosis, progression and/or severity assessment, management, and follow-up of non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM). Patients with both T2DM and NAFLD have an increased risk of non-alcoholic steatohepatitis (NASH) and fibrosis and a higher risk of cardiovascular diseases and diabetic complications compared to those without NAFLD. With regards to the evaluation of patients with T2DM and NAFLD, ultrasonography-based stepwise approaches using noninvasive biomarker models such as fibrosis-4 or the NAFLD fibrosis score as well as imaging studies such as vibration-controlled transient elastography with controlled attenuation parameter or magnetic resonance imaging-proton density fat fraction are recommended. After the diagnosis of NAFLD, the stage of fibrosis needs to be assessed appropriately. For management, weight reduction achieved by lifestyle modification has proven beneficial and is recommended in combination with antidiabetic agent(s). Evidence that some antidiabetic agents improve NAFLD/NASH with fibrosis in patients with T2DM is emerging. However, there are currently no definite pharmacologic treatments for NAFLD in patients with T2DM. For specific cases, bariatric surgery may be an option if indicated.

Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular events in humans with type 2 diabetes (T2D); however, the underlying mechanism remains unclear. Activation of the NLR family, pyrin domain-containing 3 (NLRP3) inflammasome and subsequent interleukin (IL)-1β release induces atherosclerosis and heart failure. Here we show the effect of SGLT2 inhibitor empagliflozin on NLRP3 inflammasome activity. Patients with T2D and high cardiovascular risk receive SGLT2 inhibitor or sulfonylurea for 30 days, with NLRP3 inflammasome activation analyzed in macrophages. While the SGLT2 inhibitor’s glucose-lowering capacity is similar to sulfonylurea, it shows a greater reduction in IL-1β secretion compared to sulfonylurea accompanied by increased serum β-hydroxybutyrate (BHB) and decreased serum insulin. Ex vivo experiments with macrophages verify the inhibitory effects of high BHB and low insulin levels on NLRP3 inflammasome activation. In conclusion, SGLT2 inhibitor attenuates NLRP3 inflammasome activation, which might help to explain its cardioprotective effects., SGLT2 inhibitors, a class of type 2 diabetes medication, reduce cardiovascular events in patients beyond expectation from blood sugar control. Here the authors report a randomized controlled trial showing that SGLT2 inhibitors reduce inflammasome activation in peripheral macrophages, which may contribute to the cardiovascular protection.

Objective: This study investigated whether serum bilirubin levels can predict the progression of carotid atherosclerosis in individuals with type 2 diabetes mellitus (T2DM). Methods: This observational study included 1,381 subjects with T2DM in whom serial measurements of carotid intima-media thickness (CIMT) were made at 1- to 2-year intervals for 6–8 years. The progression of carotid atherosclerosis was defined as newly detected plaque lesions on repeat ultrasonography. After dividing total serum bilirubin levels into tertiles, the association between total serum bilirubin at baseline and plaque progression status was analyzed. Results: Among 1,381 T2DM patients, 599 (43.4%) were categorized as having plaque progression in their carotid arteries. Those with plaque progression were significantly older; showed a higher prevalence of hypertension, abdominal obesity, and chronic kidney disease; and had a longer duration of T2DM, higher levels of total cholesterol (TC), triglycerides, and insulin resistance, and lower total bilirubin concentrations than those with no plaque progression. When total serum bilirubin levels were divided into tertiles, the highest tertile group was younger than the lowest tertile group, with higher levels of TC and high-density lipoprotein cholesterol. Multiple logistic regression analysis demonstrated that higher serum bilirubin levels were associated with a significantly lower risk of CIMT progression (odds ratio, 0.584; 95% confidence interval, 0.392–0.870; p=0.008). Age (p

Gemigliptin is a potent, selective dipeptidyl peptidase (DPP)-4 inhibitor that does not require any dosage adjustment based on renal function. It is also known to have no apparent interaction with commonly used drugs. In the present study, we aimed to evaluate the glucose-lowering efficacy and safety of gemigliptin in post-transplant patients with type 2 diabetes mellitus (T2D).A total of 84 patients who were prescribed gemigliptin for more than 180 days after transplantation were analyzed retrospectively. Six-month changes in blood glucose and glycated hemoglobin (HbA1c) levels were checked to assess glycemic efficacy. Safety was evaluated by examining its influence on immunosuppressive treatment, as determined by the blood trough level and dosage of calcineurin inhibitors, as well as changes in parameters related to liver and renal function.Six months of gemigliptin treatment significantly lowered blood glucose level (HbA1c: 8.16 ± 1.69 to 7.44 ± 1.26%; P .001). There were no significant changes in blood trough levels of immunosuppressants, including tacrolimus, cyclosporine, and sirolimus. The dosage of immunosuppressants was also stable. In addition, there were no significant changes in the levels of liver enzymes and renal function during 6 months of treatment.Gemigliptin robustly lowered blood glucose levels without exerting any significant effect on immunosuppressive treatment, renal function, and liver enzymes in post-transplant patients with T2D.

Background In this prospective, multicenter, non-comparative observational study, the effectiveness and safety of the triple single-pill combination (SPC) of olmesartan/amlodipine/hydrochlorothiazide (OM/AML/HCTZ) were evaluated in a real clinical practice setting in Korean patients with essential hypertension. Methods A total of 3752 patients were enrolled and followed for 12 months after administration of OM/AML/HCTZ. Primary endpoint was change from baseline to month 6 in the mean systolic blood pressure (SBP). Secondary endpoints included changes from baseline in the mean SBP at month 3, 9, 12 and the mean diastolic blood pressure (DBP) at month 3, 6, 9, 12; changes in the mean SBP/DBP according to age and underlying risk factors; and blood pressure control rate (%) at different time points. Adherence to and satisfaction with OM/AML/HCTZ treatment among patients and physicians were assessed by medication possession ratio (MPR) and numeric rating scale, respectively, as exploratory endpoints. Safety was evaluated by the incidence and severity of adverse events (AEs) as well as the discontinuation rate due to AEs. Results OM/AML/HCTZ administration led to significant reductions in the mean SBP/DBP by 11.5/6.6, 12.3/7.0, 12.3/7.2, and 12.8/7.4 mmHg from baseline to month 3, 6, 9 and 12, respectively (P Conclusions Treatment with the triple SPC of OM/AML/HCTZ demonstrated significant effectiveness in reducing SBP/DBP and achieving target BP control with high adherence over the 1-year observation period in Korean hypertensive patients and was well-tolerated. Trial registration CRIS, KCT0002196, Registered 3 May 2016.

Simple Summary The spatial distribution and invasion risk of 10 intentionally introduced alien plant species (IIAPS) in South Korea were predicted from a species distribution model via a maximum entropy modeling approach. According to the model predictions, future environmental changes are likely to enlarge the range of the spatial distribution of all studied IIAPS in South Korea except Medicago sativa. We classified the IIAPS into three categories based on their spatial distribution and potential to spread; this revealed that four species (Coreopsis lanceolate, Eragrostis curvula, Ageratina altissima, and Lolium perenne) have the highest potential for invasion. Moreover, we classified invasion risk into three categories, low, moderate, and high, and estimated the area in each category. We found that, under current conditions, much of the country is at low risk (47.96%) of invasion, but by 2050 >54% of the country’s total area will be at high risk of invasion by IIAPS. Serious invasion of IIAPS into cropland, pastures, and forests results in the loss of native biodiversity and damage to the national economy. Therefore, immediate action is required to control and manage IIAPS in South Korea. Abstract Predicting the regions at risk of invasion from IIAPS is an integral horizon-scanning activity that plays a crucial role in preventing, controlling, and eradicating invasive species. Here, we quantify the spatial distribution area and invasion risk of IIAPS using a species distribution model under different levels of environmental change in South Korea. From the model predictions, the current average spatial extent of the 10 IIAPS is 33,948 km2, and the individual spatial extents are estimated to change by −7% to 150% by 2050 and by −9% to 156% by 2070. The spatial invasion risk assessment shows that, currently, moderate-to-high invasion risk is limited to coastal areas and densely populated metropolitan cities (e.g., Seoul, Busan, and Gwangju), but that the area with this level of risk is expected to spread toward the central and northern regions of the country in the future, covering 86.21% of the total area of the country by 2070. These results demonstrate that the risk of invasion by IIAPS is estimated to enlarge across the whole country under future environmental changes. The modeling system provided in this study may contribute to the initial control and strategic management of IIAPS to maintain the dynamic ecosystems of South Korea.

Currently there is no FDA-approved drug to treat nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), rates of which are increasing worldwide. Although NAFLD/NASH are highly complex and heterogeneous conditions, most pharmacotherapy pipelines focus on a single mechanistic target. Considering the importance of the gut-liver axis in their pathogenesis, we investigated the therapeutic effect of a long-acting dual agonist of glucagon-like peptide (GLP)-1 and GLP-2 receptors in mice with NAFLD/NASH. C57BL/6J mice were fed a choline-deficient high fat diet/high fructose and sucrose solution. After 16 weeks, mice were randomly allocated to receive vehicle, GLP1-Fc, GLP2-Fc, or GLP1/2-Fc subcutaneously every two days for four weeks. Body weight was monitored, insulin/glucose tolerance tests were performed, feces were collected, and microbiome profiles were analyzed. Immobilized cell systems were utilized to evaluate direct peptide effect. Immunohistochemistry, qPCR, immunoblot analysis, tunnel assay, and biochemical assays were performed to assess drug effects on inflammation, hepatic fibrosis, cell death, and intestinal structures. The mice had well-developed NASH phenotypes. GLP1/2-Fc reduced body weight, glucose levels, hepatic triglyceride levels, and cellular apoptosis. It improved liver fibrosis, insulin sensitivity, and intestinal tight junctions, and increased microvillus height, crypt depth, goblet cells of intestine compared to a vehicle group. Similar effects of GLP1/2-Fc were found in in vitro cell systems. GLP1/2-Fc also changed microbiome profiles. We applied fecal microbiota transplantation (FMT) in order to gain further insight into the mechanism of GLP1/2-Fc-mediated protection. We confirmed that FMT exerted an additive effect on GLP1-Fc group, including the body weight change, liver weight, hepatic fat accumulation, inflammation and hepatic fibrosis. CONCLUSION: A long-acting dual agonist of GLP-1 and GLP-2 receptors is a promising therapeutic strategy to treat NAFLD/NASH.

Alzheimer’s disease (AD) is characterized by memory loss and cognitive decline. Additionally, abnormal extracellular amyloid plaques accumulation and nerve damage caused by intracellular neurofibrillary tangles, and tau protein are characteristic of AD. Furthermore, AD is associated with oxidative stress, impaired mitochondrial structure and function, denormalization, and inflammatory responses. Recently, besides the amyloid β hypothesis, another hypothesis linking AD to systemic diseases has been put forth by multiple studies as a probable cause for AD. Particularly, type 2 diabetes mellitus (T2DM) and its features, including hyperinsulinemia, and chronic hyperglycemia with an inflammatory response, have been shown to be closely related to AD through insulin resistance. The brain cannot synthesize or store glucose, but it does require glucose, and the use of glucose in the brain is higher than that in any other organ in the mammalian body. One of the therapeutic drugs for T2DM, dipeptidyl peptidase-4 (DPP-4) inhibitor, suppresses the degradation of incretins, glucagon-like peptides and glucose-dependent insulinotropic peptide. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, recently used in T2DM treatment, have a unique mechanism of action via inhibition of renal glucose reabsorption, and which is different from the mechanisms of previously used medications. This manuscript reviews the pathophysiological relationship between the two diseases, AD and T2DM, and the pharmacological effects of therapeutic T2DM drugs, especially DPP-4 inhibitors, and SGLT2 inhibitors.

Aims Obesity is the most common risk factor for type 2 diabetes. However, not all obese individuals develop diabetes. In the era of precision medicine, metabolomics may reveal the fundamental metabolic status of an individual. Our aim was to assess the association of metabolites with incident type 2 diabetes in obese individuals using Korean Genome and Epidemiology Cohort Study. Methods Using 12 years of metabolomic data from 2,580 individuals, we performed a metabolomic study to define metabolically healthy obesity in an obese population (n = 704) with incident type 2 diabetes. Cox proportional hazards regression model and survival analysis were performed adjusted for the traditional risk factors of type 2 diabetes. Results Our study revealed that spermine, acyl-alkyl phosphatidylcholines (C34:3, C36:3, C42:1), hydroxy sphingomyelin (C22:2, C14:1), and sphingomyelin (C16:0) were associated with incident type 2 diabetes in obese individuals after the adjustment for risk factors and correction of multiple comparisons by Bonferroni method. Five metabolites (except hydroxy sphingomyelin C14:1 and sphingomyelin C16:0) were also significantly associated with incident type 2 diabetes in lean individuals. Conclusions This study highlights the need for defining metabolically healthy obesity based on serum metabolites and elucidates potential biomarkers for type 2 diabetes in an obese population.

Objectives: Nonalcoholic fatty liver disease (NAFLD) is associated with chronic kidney disease (CKD). However, the causal relationship between NAFLD and the development of CKD is uncertain, particularly in patients with type 2 diabetes. We aimed to investigate the association between the presence and severity of NAFLD and incident CKD in patients with type 2 diabetes. Research Design and Methods: In this longitudinal cohort study of patients with type 2 diabetes, 3,188 patients with preserved renal function were followed for the occurrence of incident CKD. NAFLD was defined as the presence of hepatic steatosis on ultrasonography without any other causes of chronic liver diseases. Advanced liver fibrosis of NAFLD was defined as NAFLD fibrosis score >0.675. CKD was defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2. Results: At baseline, 1,729 (54.2%) patients had NAFLD, of whom 94 (5.4%) had advanced liver fibrosis. During the follow-up of 8.3 ± 3.6 years, 472 (14.8%) patients developed incident CKD, 220 (15.1%) in the non-NAFLD group, 226 (12.8%) in the hepatic steatosis alone group and 26 (27.7%) in the advanced liver fibrosis group. There was no increased risk of incident CKD in the NAFLD group compared with the non-NAFLD group (p = 0.79). However, among patients with NAFLD, advanced liver fibrosis was associated with an increased risk of CKD (adjusted hazard ratio [HR] 1.78 (95% confidence interval [CI] 1.14-2.76), p=0.011). Conclusions: Advanced liver fibrosis in NAFLD is independently associated with an increased risk of incident CKD in patients with type 2 diabetes. Disclosure D. Seo: None. Y. Cho: None. S. Ahn: None. S. Seo: None. S. Hong: None. Y. Lee: None. S. Kim: None. Funding National Research Foiundation (2017R1D-1A1B03034581)

Background: Nonalcoholic steatohepatitis is closely associated with the progression of diabetic kidney disease (DKD) in type 2 diabetes (T2D). We investigated whether urinary N-acetyl-β-D- glucosaminidase(u-NAG), an early renal tubular damage biomarker in DKD, could be related to the degree of hepatic fibrosis in patients with T2D. Methods: A total of 300 patients with T2D were enrolled in the study. Hepatic steatosis and fibrosis were determined using transient elastography. The levels of urinary biomarkers, including u-NAG, albumin, protein, and creatinine, and glucometabolic parameters were measured. Results: Based on the median value of u-NAG to creatinine (u-NCR), subjects were divided into normal and high u-NCR groups. The high u-NCR group showed a significantly longer duration of diabetes, worsened hyperglycemia, and a more enhanced hepatic fibrosis index. A higher u-NCR was associated with a greater odds ratio for the risk of higher hepatic fibrosis stage (F2 OR 1.99; 95% CI [1.04-3.82]; F3 and F4 OR 2.40, 95% CI [1.52-3.80]). In addition, u-NCR was an independent predictive marker for more advanced hepatic fibrosis even after adjusting for several confounding factors (β = 1.58, P Conclusions: The elevation of u-NAG was independently associated with a higher degree of hepatic fibrosis in patients with T2D. Considering the common metabolic milieu of renal and hepatic fibrosis in T2D, the potential use of u-NAG as an effective urinary biomarker reflecting hepatic fibrosis in T2D needs to be validated in the future. Disclosure H. Kim: None. Y. Kim: None. M. Lee: None. Y. Lee: None. E. Kang: None. B. Cha: None. B. Lee: None.

We investigated the clinical relevance of non-albumin proteinuria (NAP) in Korean patients with type 2 diabetes (T2D).We enrolled 883 T2D patients who had both their urinary albumin-to-creatinine ratio (uACR) and protein-to-creatinine ratio (uPCR) measured. We classified the patients into non-proteinuria (NP; uPCR150 mg/g and uACR30 mg/g), isolated NAP (iNAP; uPCR ≥150 mg/g and uACR30 mg/g), and albuminuria (uACR ≥30 mg/g) groups. The associations between uPCR, uACR, and several indices of glucose metabolism were investigated.The glucometabolic pathophysiology of iNAP (96 [10.9%]) group was more associated with a decrease in homeostatic model assessment (HOMA)-beta value (aOR 1.89 [95% CI, 1.21-2,96]) than with an increase in HOMA-insulin resistance (aOR 1.29 [95% CI, 0.83-2.01]). uPCR ≥150 mg/g was also found to have more consistent and stronger association with vascular complications than uACR ≥30 mg/g (aOR 1.44 [95% CI, 1.03-2.02] vs. 1.26 [95% CI, 0.89-1.79]).The nephropathy of iNAP may be mainly attributed to decreased beta cell function. Furthermore, uPCR might be a more sensitive urinary biomarker than uACR for the detection of vascular complications in T2D patients.

Targeted therapy using phosphatidylinositol 3-kinase (PI3K) inhibitors is used to treat cancer such as lymphoma. In animal studies, its use raised concern about alteration of glucose metabolism. To date, clinical data are inconclusive; therefore, we investigated the incidence and clinical manifestations of diabetes in cancer patients treated with PI3K inhibitors. In a retrospective review of diabetes-free patients with advanced solid tumors treated with PI3K inhibitor, we performed Cox regression to identify independent predictors for the development of diabetes. Of 38 patients (mean age: 54.5 years, 23.7% female) having a mean duration of follow-up of 238.5 days who initiated PI3K inhibitors, 55.3% developed diabetes during treatment (mean 29.1 days); among these, 28.6% experienced remission of diabetes after discontinuing PI3K inhibitors (mean 72.1 days). Patients with incident diabetes had higher anti-hypertensive medication use, higher HbA1c levels and fasting glucose at baseline, and longer duration of PI3K inhibitor use (P = 0.024, P = 0.005, P = 0.008, and P = 0.023, respectively). Previous steroid use and lower baseline HbA1c level were significantly associated with development of diabetes (HR = 8.41, 95% CI 1.89–37.33; HR = 2.16, 95% CI 1.09–4.25, respectively). Patients whose diabetes remitted after discontinuing PI3K inhibitors were younger (P = 0.035) and had lower fasting glucose levels during PI3K inhibitor treatment (P = 0.001) compared to those non-remitters. Previous steroid use and lower baseline HbA1c level may be important predictors for developing diabetes in patients with advanced solid tumors treated with PI3K inhibitors, warranting close observation and careful intervention.

Background: Cardiovascular risk remains increased despite optimal low density lipoprotein cholesterol (LDL-C) level induced by intensive statin therapy. Therefore, recent guidelines recommend non-high density lipoprotein cholesterol (non-HDL-C) as a secondary target for preventing cardiovascular events. The aim of this study was to assess the efficacy and tolerability of omega-3 fatty acids (OM3-FAs) in combination with atorvastatin compared to atorvastatin alone in patients with mixed dyslipidemia. Methods: This randomized, double-blind, placebo-controlled, parallel-group, and phase III multicenter study included adults with fasting triglyceride (TG) levels ≥200 and

Background Bile acids (BAs) have been demonstrated to exert a variety of metabolic effects and alterations in BAs have been reported in patients with obesity, insulin resistance (IR) and type 2 diabetes mellitus (T2DM). However, it is unclear which metabolic condition is the main contributor to alterations in BAs. In this study, we investigate the associations between different BA profiles with glycemia, obesity or IR status. Methods Fasting serum concentrations of 15 BA species were determined in a total of 241 individuals (71 drug-naïve patients with T2DM, 95 patients with impaired fasting glucose [IFG], and 75 healthy controls. Results A comparison of the mean values of the BAs revealed no significant differences between normoglycemic controls and patients with IFG or T2DM. However, when the entire cohort was divided according to the presence of IR as determined by a homeostasis model assessment of insulin resistance (HOMA-IR) value >2.5, the levels of total BA and most species of BAs were significantly higher in patients with IR than in patients without. In the correlation analysis, most species of BAs, as well as total BA, were significantly associated with HOMA-IR levels. Furthermore, when the subjects were divided into four groups according to IR and diabetic status, subjects with IR had significantly higher total BAs than participants without IR both in diabetic and non-diabetic groups. Ultimately, multiple linear regression analysis identified HOMA-IR as the only significant contributor to most serum BA species. Conclusions Our findings support the essential role of IR in regulating BA metabolism and that this effect is independent of diabetic status.

Aim To investigate sodium-glucose cotransporter 2 inhibitor (SGLT2i)-induced changes in ketogenic enzymes and transporters in normal and diabetic mice models. Materials and methods Normal mice were randomly assigned to receive either vehicle or SGLT2i (25 mg/kg/d by oral gavage) for 7 days. Diabetic mice were treated with vehicle, insulin (4.5 units/kg/d by subcutaneous injection) or SGLT2i (25 mg/kg/d by intra-peritoneal injection) for 5 weeks. Serum and tissues of ketogenic organs were analysed. Results In both normal and diabetic mice, SGLT2i increased beta-hydroxybutyrate (BHB) content in liver, kidney and colon tissue, as well as in serum and urine. In these organs, SGLT2i upregulated mRNA expression of ketogenic enzymes, 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2 and 3-hydroxy-3-methylglutaryl-coenzyme A lyase. Similar patterns were observed in the kidney, ileum and colon for mRNA and protein expression of sodium-dependent monocarboxylate transporters (SMCTs), which mediate the cellular uptake of BHB and butyrate, an important substrate for intestinal ketogenesis. In diabetic mice under euglycaemic conditions, SGLT2i increased major ketogenic enzymes and SMCTs, while insulin suppressed ketogenesis. Conclusions SGLT2i increased systemic and tissue BHB levels by upregulating ketogenic enzymes and transporters in the liver, kidney and intestine, suggesting the integrated physiological consequences for ketone body metabolism of SGLT2i administration.

Context The risk for dementia among subjects who are obese with normal metabolic profiles, or called metabolically healthy obese (MHO), remains uninvestigated. Objective To determine the association between late-life metabolic health and obesity status and risk of incident dementia. Design Retrospective cohort study. Setting The National Health Insurance System, Republic of Korea. Patients A total of 12,296,863 adults >50 years old who underwent health examinations from 2009 to 2012 without baseline history of dementia. Main outcome measure Incident overall dementia, Alzheimer's disease (AD), and vascular dementia (VaD). Results Among subjects ≥60 years old, 363,932 (6.4%) developed dementia during a median follow-up of 65 months (interquartile range 51 to 74 months). The MHO group showed the lowest incidence of overall dementia [hazard ratio (HR) 0.85; 95% CI, 0.84 to 0.86] and AD (HR 0.87; 95% CI, 0.86 to 0.88), but not VaD, compared with the metabolically healthy nonobese group. All components of metabolic syndrome except obesity significantly elevated the risk of dementia, and these associations were more pronounced in VaD. In particular, being underweight dramatically increased the risk of dementia. Conclusions The MHO phenotype in late life demonstrated lower risk of overall dementia and AD but not VaD. Additional studies in other populations are warranted to elucidate current results and may predict individuals most at risk for developing dementia.

Background: Impaired diastolic heart function has been observed in persons with non-alcoholic fatty liver disease (NAFLD) and/or with type 2 diabetes mellitus (T2DM). However, it is unclear whether NAFLD fibrotic progression, i.e., non-alcoholic ste atohepatitis, poses an independent risk for diastolic dysfunction in T2DM. We investigated the association between liver fibrosis and left ventricular (LV) diastolic dysfunction in T2DM. Methods: We analyzed 606 patients with T2DM, aged ≥50 years, who had undergone liver ultrasonography and pulsed-wave Doppler echocardiography. Insulin sensitivity was measured by short insulin tolerance test. Presence of NAFLD and/or advanced liver fibrosis was determined by abdominal ultrasonography and NAFLD fibrosis score (NFS). LV diastolic dysfunction was de fined according to transmitral peak early to late ventricular filling (E/A) ratio and deceleration time, using echocardiography. Results: LV diastolic dysfunction was significantly more prevalent in the NAFLD versus non-NAFLD group (59.7% vs. 49.0%, P=0.011). When NAFLD was stratified by NFS, subjects with advanced liver fibrosis exhibited a higher prevalence of diastolic dysfunction (49.0%, 50.7%, 61.8%; none, simple steatosis, advanced fibrosis, respectively; P for trend=0.003). In multivariable lo gistic regression, liver fibrosis was independently associated with diastolic dysfunction (odds ratio [OR], 1.58; 95% confidence in terval [CI], 1.07 to 2.34; P=0.022) after adjusting for insulin resistance and cardiometabolic risk factors. This association re mained significant in patients without insulin resistance (OR, 4.32; 95% CI, 1.73 to 11.51; P=0.002). Conclusions: Liver fibrosis was associated with LV diastolic dysfunction in patients with T2DM and may be an independent risk factor for diastolic dysfunction, especially in patients without systemic insulin resistance.

Microneedles (MNs) are being developed to overcome the limitations of the conventional hypodermic needle, e.g. the injection pain. In this study, we conducted an analysis of clinical pain and bleeding at the site of MN insertion and evaluated the insulin pharmacodynamic profile compared with parameters obtained with a conventional pen needle. MN insertion into the skin of 25 healthy adults or 15 patients with type 2 diabetes (T2D) revealed significantly less pain relative to a conventional hypodermic pen needle, thus reducing pain scores from 2.1±1.9 to 1.3±1.4 (mean±standard deviation [SD]). Besides, no bleeding was observed when the MN was used. In the insulin pharmacodynamic assay, no significant differences were observed in the blood glucose-lowering effect between the pen needle and MN. Based on these results, the MN is expected to be a good substitute for conventional hypodermic pen needles and improve the quality of life of patients by significantly reducing the pain associated with insulin treatment.

Advanced microelectromechanical system (MEMS) magnetic field sensor applications demand ultra-high detectivity down to the low magnetic fields. To enhance the detection limit of the magnetic sensor, a resistance compensator integrated self-balanced bridge type sensor was devised for low-frequency noise reduction in the frequency range of 0.5 Hz to 200 Hz. The self-balanced bridge sensor was a NiFe (10 nm)/IrMn (10 nm) bilayer structure in the framework of planar Hall magnetoresistance (PHMR) technology. The proposed resistance compensator integrated with a self-bridge sensor architecture presented a compact and cheaper alternative to marketable MEMS MR sensors, adjusting the offset voltage compensation at the wafer level, and led to substantial improvement in the sensor noise level. Moreover, the sensor noise components of electronic and magnetic origin were identified by measuring the sensor noise spectral density as a function of temperature and operating power. The lowest achievable noise in this device architecture was estimated at ~3.34 nV/Hz at 100 Hz.

This study aimed to investigate the risk and prognosis of Alzheimer's disease (AD) and vascular dementia (VaD) in patients with insomnia using the National Health Insurance Service database covering the entire population of the Republic of Korea from 2007 to 2014. In total, 2,796,871 patients aged 40 years or older with insomnia were enrolled, and 5,593,742 controls were matched using a Greedy digit match algorithm. Mortality and the rate of admission to a long-term care facility were estimated using multivariable Cox analysis. Of all patients with insomnia, 138,270 (4.94%) and 26,706 (0.96%) were newly diagnosed with AD and VaD, respectively. The incidence rate ratios for AD and VaD were 1.73 and 2.10, respectively, in patients with insomnia compared with those without. Higher mortality rates and long-term care facility admission rates were also observed in patients with dementia in the insomnia group. Known cardiovascular risk factors showed interactions with the effects of insomnia on the risk of AD and VaD. However, the effects of insomnia on the incidence of AD and VaD were consistent between the groups with and without cardiovascular risk factors. Insomnia is a medically modifiable and policy-accessible risk factor and prognostic marker of AD and VaD.

Background Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in patients with type 2 diabetes and is associated with cardiovascular risk. We investigated whether the degree of NAFLD was associated with myocardial dysfunction related to impaired myocardial glucose uptake in patients with type 2 diabetes. Methods In total, 131 patients with type 2 diabetes from a tertiary care hospital were included. Myocardial glucose uptake was assessed using [18F]-fluorodeoxyglucose-positron emission tomography. Hepatic steatosis and fibrosis were determined using transient liver elastography. Echocardiography was performed to evaluate cardiac structure and function. Results Patients with NAFLD revealed cardiac diastolic dysfunction with higher left ventricular filling pressure (E/e’ ratio) and left atrial volume index (LAVI) than patients without NAFLD (all p p r2 = 0.409; p = 0.041) and a higher degree of fibrosis (r2 = 0.423; p = 0.009) were independent determinants for a higher E/e’ ratio even after adjusting for confounding factors. Decreased myocardial glucose uptake was associated with a higher degree of steatosis (p for trend = 0.084) and fibrosis (p for trend = 0.012). In addition, decreased myocardial glucose uptake was an independent determinant factor for a higher E/e’ ratio (r2 = 0.409; p = 0.04). Conclusions Hepatic steatosis and fibrosis are significantly associated with diastolic heart dysfunction in patients with type 2 diabetes coupled with impaired myocardial glucose uptake.

Background: Non-alcoholic steatohepatitis is closely associated with the progression of diabetic kidney disease (DKD) in type 2 diabetes mellitus (T2DM). We investigated whether urinary N-acetyl-β-D-glucosaminidase (u-NAG), an early renal tubular damage biomarker in DKD, could be related to the degree of hepatic fibrosis in patients with T2DM.Methods: A total of 300 patients with T2DM were enrolled in this study. Hepatic steatosis and fibrosis were determined using transient elastography. The levels of urinary biomarkers, including u-NAG, albumin, protein, and creatinine, and glucometabolic parameters were measured.Results: Based on the median value of the u-NAG to creatinine ratio (u-NCR), subjects were divided into low and high u-NCR groups. The high u-NCR group showed a significantly longer duration of diabetes, worsened hyperglycemia, and a more enhanced hepatic fibrosis index. A higher u-NCR was associated with a greater odds ratio for the risk of higher hepatic fibrosis stage (F2: odds ratio, 1.99; 95% confidence interval [CI], 1.04 to 3.82). Also, u-NCR was an independent predictive marker for more advanced hepatic fibrosis, even after adjusting for several confounding factors (β=1.58, P

Dipeptidyl peptidase-4 inhibitors (DPP4i) are antidiabetic medications that prevent cleavage of incretin hormones by dipeptidyl peptidase-4 (DPP4). DPP4 is ubiquitously expressed, and its hepatic DPP4 expression is upregulated under non-alcoholic steatohepatitis (NASH) conditions. We investigated the effect of DPP4i treatment on NASH pathogenesis, as well as its potential underlying molecular mechanisms. Mice were randomly divided into three groups: Group 1, chow-fed mice treated with vehicle for 20 weeks; Group 2, high-fat, high-fructose, and high-cholesterol Amylin liver NASH (AMLN) diet-fed mice treated with vehicle for 20 weeks; Group 3, AMLN diet-fed mice treated with vehicle for the first 10 weeks, followed by the DPP4i teneligliptin (20 mg/kg/day) for additional 10 weeks. DPP4i administration reduced serum liver enzyme and hepatic triglyceride levels and markedly improved hepatic steatosis and fibrosis in the AMLN diet-induced NASH model. In vivo, NASH alleviation significantly correlated with the suppression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-mediated apoptosis and downregulated hepatic DPP4 expression. In vitro, DPP4i treatment significantly decreased the markers of TRAIL receptor-mediated lipoapoptosis and suppressed DPP4 expression in palmitate-treated hepatocytes. In conclusion, DPP4i may efficiently attenuate the pathogenesis of AMLN diet-induced NASH in mice by suppressing lipotoxicity-induced apoptosis, possibly by modulating hepatic DPP4 expression.

Background & Aims An international expert panel proposed a new definition for metabolic dysfunction–associated fatty liver disease (MAFLD) as a name change from nonalcoholic fatty liver disease (NAFLD). The clinical impact of this change on the assessment of cardiovascular disease (CVD) risk is yet unknown. We evaluated the prevalence of fatty liver disease (FLD) and the associated CVD risk using each of these definitions. Methods From a nationwide health screening database, we included 9,584,399 participants (48.5% male) aged 40-64 years between 2009 and 2010. Participants were categorized by presence of NAFLD and MAFLD, separately, and by the combination of the 2 definitions—Neither-FLD, NAFLD-only, MAFLD-only, or Both-FLD. The primary outcome was a composite CVD event, including myocardial infarction, ischemic stroke, heart failure, or CVD-related death. Results The prevalence of NAFLD and MAFLD was 28.0% and 37.3%, respectively. After excluding those with prior CVD, 8,962,813 participants were followed for a median of 10.1 years. NAFLD and MAFLD were each associated with significantly higher risk for CVD events. When the Neither-FLD group was the reference, multivariable-adjusted hazard ratios (95% confidence interval) for CVD events were 1.09 (1.03-1.15) in the NAFLD-only group, 1.43 (1.41-1.45) in the MAFLD-only group, and 1.56 (1.54-1.58) in the Both-FLD group. Conclusions A considerable proportion of middle-aged Korean adults have MAFLD without satisfying the former definition of NAFLD. The change from NAFLD to MAFLD criteria may identify a greater number of individuals with metabolically complicated fatty liver and increased risk for CVD.

INTRODUCTION: Clinical studies have produced conflicting results on the effects of metformin on gastrointestinal cancer development. We aimed to investigate the association between metformin use and stomach, colon, liver, and pancreatic cancer development among patients with newly diagnosed, drug-naïve type 2 diabetes. METHODS: This retrospective study evaluated propensity score-matched patients with newly diagnosed type 2 diabetes from the Korean National Health Insurance Service database. Metformin users were categorized into tertiles according to the cumulative dose or duration of metformin treatment, and the risks of gastrointestinal cancers were compared. RESULTS: Metformin users had reduced risks of developing stomach cancer (hazard ratio [HR]: 0.841, 95% confidence interval [CI]: 0.797–0.887), colon cancer (HR: 0.865, 95% CI: 0.822–0.91), and liver cancer (HR: 0.709, 95% CI: 0.675–0.746; P < 0.001). However, metformin users did not have a reduced overall risk of pancreatic cancer (HR: 1.335, 95% CI: 1.209–1.475; P < 0.001). The risks tended to decrease at higher cumulative doses and durations of metformin use, with significantly reduced risks of all 4 cancers at the highest cumulative dose (≥1,200,000 mg) and the longest duration (≥2,000 days) of metformin use. DISCUSSION: This population-based data suggest that metformin could be associated with reductions in the risks of stomach, colon, and liver cancers, as well a reduced risk of pancreatic cancer in some subgroups. Metformin has benefit as a first-line treatment for type 2 diabetes mellitus. A further role in cancer risk reduction could be studied in controlled trials.

The association between non-alcoholic fatty liver disease (NAFLD) and diabetic kidney disease assessed using either albuminuria or proteinuria remains controversial. This study aimed to investigate the association between hepatic steatosis or fibrosis and albuminuria or proteinuria in Korean patients with type 2 diabetes mellitus (T2D). We enrolled 1108 patients with T2D and categorized as 3 groups; non-proteinuria (NP), isolated non-albumin proteinuria (iNAP), and albuminuria. Urinary albumin and protein levels were assessed as urinary albumin-to-creatinine ratio (uACR) and urinary protein-to-creatinine ratio (uPCR), respectively. Hepatic steatosis and fibrotic burden were assessed using the NAFLD liver fat score, Fibrosis-4 calculator (FIB-4) index, and NAFLD fibrosis score (NFS). The prevalence of significant steatosis was similar among groups (NP: 74.6% vs iNAP: 70.3% vs albuminuria: 79.9%, P = .085). The prevalence of significant fibrosis was significantly higher in the iNAP (18.7%) and albuminuria (16.5%) groups than in the NP group (9.5%, P = .001). Both uPCR and uACR showed a correlation with NFS (uPCR: r = 0.123, P

Background There is increasing concern regarding cardiovascular risk in individuals with non-alcoholic fatty liver disease. This study was conducted to evaluate whether hepatic steatosis with or without fibrosis is associated with the progression of carotid atherosclerosis in patients with type 2 diabetes. Methods From a longitudinal cohort, we enrolled 1120 patients with type 2 diabetes who underwent repeated carotid artery ultrasonography every 1–2 years. Ultrasonographic findings at baseline and after 6–8 years were compared. Presence of hepatic steatosis was mainly assessed by abdominal ultrasonography; patients with hepatic steatosis were further evaluated for hepatic fibrosis according to fibrosis-4 index. We investigated the association between liver status and atherosclerosis progression. Results Of 1120 patients, 636 (56.8%) were classified as having hepatic steatosis at baseline. After 6–8 years, 431 (38.5%) showed atherosclerosis progression. Hepatic steatosis was significantly associated with atherosclerosis progression (adjusted odds ratio[AOR]: 1.370, 95% CI 1.025–1.832; p p p p Conclusions Hepatic steatosis with fibrosis is independently associated with the progression of carotid atherosclerosis in patients with type 2 diabetes.

Background: Recent studies investigated the association between nonalcoholic fatty liver disease (NAFLD) and diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus (T2DM) but the results are inconclusive. Here we aimed to investigate the effect of obesity on the association between NAFLD and DKD in a large cohort of participants with T2DM. Methods: In this cross-sectional study, a total of 3,439 patients (1,710 men and 1,729 women) with T2DM were recruited from the Seoul Metabolic Syndrome cohort between 2003 and 2016. NAFLD was defined by ultrasonographic detection of steatosis in the absence of other liver diseases. Advanced fibrosis was defined as FIB4 index ≥ 1.45. DKD was defined as an estimated glomerular filtration rate (eGFR) of < 60 mL/min/1.73 m2. Obesity was defined as body mass index (BMI) ≥ 25 kg/m2. Results: The mean age was 57.4 ± 10.3 years and duration of diabetes was 7.7 ± 7.1 years. Two hundred and fifty subjects (7.3%) had DKD and 1869 (54.3%) subjects had NAFLD. The prevalence of DKD were 7.0%, 4.5% and 11.9% in no-NAFLD group, liver steatosis only group and advanced fibrosis group respectively (p Conclusion: This study suggests that advanced liver fibrosis, a severe form of NAFLD, was independently associated with increased risk of DKD in non-obese patients with T2DM. Disclosure D. Seo: None. Y. Cho: None. S. Ahn: None. S. Hong: None. Y. Lee: None. Y. Choi: None. B. Huh: None. K. Huh: None. S. Kim: None.

Neither lowering of blood lipid levels nor treatment with statins definitively improves renal outcomes. Ezetimibe, a non-statin antilipidemic agent, is known to not only decrease blood lipid levels but also reduce inflammatory response and activate autophagy. We evaluated the effect of adding ezetimibe to a statin on renal outcome compared with statin monotherapy by analyzing longitudinal data of 4537 patients treated with simvastatin 20 mg plus ezetimibe 10 mg (S + E) or simvastatin 20 mg alone (S) for more than 180 days. A propensity-score-based process was used to match baseline characteristics, medical history, and estimated glomerular filtration rate (eGFR) between S + E and S groups. Changes in serum creatinine and incidence of renal events, defined as doubling of serum creatinine to &ge, 1.5 mg/dL or occurrence of end-stage renal disease after the first day of treatment initiation, were compared between the groups. Among 3104 well-matched patients with a median follow-up of 4.2 years, the S + E group showed a significantly lower risk of renal events than the S group (hazard ratio 0.58, 95% CI 0.35-0.95, P = 0.032). In addition, the S + E group tended to preserve renal function compared with the S group throughout follow-up, as assessed by serum creatinine changes (P-values for time&ndash, group interactions &lt, 0.001). These data support the beneficial effects on renal function when combining ezetimibe with a statin.

OBJECTIVE To assess the effects of empagliflozin, a selective sodium–glucose cotransporter 2 (SGLT2) inhibitor, on broad biological systems through proteomics. RESEARCH DESIGN AND METHODS Aptamer-based proteomics was used to quantify 3,713 proteins in 144 paired plasma samples obtained from 72 participants across the spectrum of glucose tolerance before and after 4 weeks of empagliflozin 25 mg/day. The biology of the plasma proteins significantly changed by empagliflozin (at false discovery rate–corrected P < 0.05) was discerned through Ingenuity Pathway Analysis. RESULTS Empagliflozin significantly affected levels of 43 proteins, 6 related to cardiomyocyte function (fatty acid–binding protein 3 and 4 [FABPA], neurotrophic receptor tyrosine kinase, renin, thrombospondin 4, and leptin receptor), 5 to iron handling (ferritin heavy chain 1, transferrin receptor protein 1, neogenin, growth differentiation factor 2 [GDF2], and β2-microglobulin), and 1 to sphingosine/ceramide metabolism (neutral ceramidase), a known pathway of cardiovascular disease. Among the protein changes achieving the strongest statistical significance, insulin-like binding factor protein-1 (IGFBP-1), transgelin-2, FABPA, GDF15, and sulphydryl oxidase 2 precursor were increased, while ferritin, thrombospondin 3, and Rearranged during Transfection (RET) were decreased by empagliflozin administration. CONCLUSIONS SGLT2 inhibition is associated, directly or indirectly, with multiple biological effects, including changes in markers of cardiomyocyte contraction/relaxation, iron handling, and other metabolic and renal targets. The most significant differences were detected in protein species (GDF15, ferritin, IGFBP-1, and FABP) potentially related to the clinical and metabolic changes that were actually measured in the same patients. These novel results may inform further studies using targeted proteomics and a prospective design.

The association of specific urinary proteins other than albumin with cardiovascular (CV) outcomes in patients with type 2 diabetes (T2D) has been shown. In this respect, CV outcomes may differ in non-albuminuric T2D patients who were considered as a low risk group, according to the presence of proteinuria. We investigated the association between proteinuria and atherosclerosis assessed by carotid artery intima-media thickness (CIMT) in non-albuminuric T2D patients. 2047 T2D patients whose urine albumin-to-creatinine ratio was below 30 mg/g were recruited and classified into a non-proteinuria (NP, uPCR &lt, 150 mg/g, n = 1865) group and a non-albuminuric proteinuria (NAP, uPCR &ge, 150 mg/g, n = 182) group. CIMT was compared between the two groups and logistic regression analysis was conducted to verify whether proteinuria could predict deteriorated CIMT status. In this cross-sectional study, mean CIMT of the NAP group were significantly thicker than those of the NP group (0.73 &plusmn, 0.16 vs. 0.70 &plusmn, 0.14, p = 0.016). The presence of proteinuria is associated with deteriorated CIMT after the adjustment for conventional risk factors (odds ratio, 2.342, 95% confidence interval, 1.082&ndash, 5.070, p = 0.030) in regression analysis. We postulated that the measurement of urinary protein in conjunction with albumin might be helpful for predicting atherosclerosis, especially for non-albuminuric patients.

Despite the benefits of pioglitazone in the treatment of non-alcoholic fatty liver disease (NAFLD), many treated patients continue to experience disease progression. We aimed to investigate the additive effect of ipragliflozin on NAFLD in patients with type 2 diabetes treated with metformin and pioglitazone. In this 24-week randomized controlled trial, 44 patients with type 2 diabetes and comorbid NAFLD were either randomized to receive 50 mg/day of ipragliflozin as an add-on treatment (n = 29) or maintained on metformin and pioglitazone (n = 15). The fatty burden was assessed using the fatty liver index, NAFLD liver fat score, and controlled attenuation parameter (CAP). Changes in fat and muscle depots were measured by dual-energy x-ray absorptiometry and abdominal computed tomography scans. The enrolled patients were relatively controlled (mean baseline glycated hemoglobin of 6.6% &plusmn, 0.6%) and centrally obese (mean waist circumference of 101.6 &plusmn, 10.9 cm). At week 24, patients in the ipragliflozin add-on group exhibited reduced hepatic fat content (fatty liver index: &minus, 9.8 &plusmn, 1.9, p = 0.002, NAFLD liver fat score: &minus, 0.5 &plusmn, 0.2, p = 0.049, CAP: &minus, 8.2 &plusmn, 7.8 dB/m2, p = 0.133). Ipragliflozin add-on therapy also reduced whole-body visceral fat and the ratio of visceral to subcutaneous fat (change in whole-body visceral fat: &minus, 69.6 &plusmn, 21.5 g, change in abdominal visceral fat: &minus, 26.2 &plusmn, 3.7 cm2, abdominal visceral to subcutaneous fat ratio: &minus, 0.15 &plusmn, 0.04, all p &lt, 0.05). In conclusion, ipragliflozin treatment significantly ameliorates liver steatosis and reduces excessive fat in euglycemic patients with type 2 diabetes and NAFLD taking metformin and pioglitazone.

We describe a general strategy for the intermolecular synthesis of polysubstituted cyclopentenones using palladium catalysis. Overall, this reaction is achieved via a molecular shuffling process involving an alkyne, an alpha,beta-unsaturated acid chloride, which serves as both the alkene and carbon monoxide source, and a hydrosilane to create three new C-C bonds. This new carbon monoxide-free pathway delivers the products with excellent yields. Furthermore, the regioselectivity is complementary to conventional methods for cyclopentenone synthesis. In addition, a set of regio- and chemodivergent reactions are presented to emphasize the synthetic potential of this novel strategy., Journal of the American Chemical Society, 142 (50), ISSN:0002-7863, ISSN:1520-5126