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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.

The causal relationship between low muscle mass and development of chronic kidney disease (CKD) is uncertain in patients with type 2 diabetes mellitus (T2DM). We aimed to investigate the association between low muscle mass or sarcopenic obesity and the risk of incident CKD in patients with T2DM. A total of 3,123 patients with T2DM with preserved renal function were followed up for incident CKD. Skeletal muscle mass was estimated from bioelectrical impedance analysis. CKD was defined as an estimated glomerular filtration rate < 60 mL/min/1.73m2. Sarcopenic obesity was defined as the coexistence of sarcopenia and abdominal obesity. During 8.9 years of follow-up, 530 (17.0%) patients developed incident CKD. When subjects were divided into three groups based on sex-specific tertiles, lower muscle mass was not associated with an increased risk of incident CKD after adjustment for risk factors. However, when patients were divided into four groups according to the presence of sarcopenia and obesity, sarcopenic obesity was associated with an increased risk of incident CKD (adjusted hazard ratio 1.77; 95% confidence interval 1.24-2.51; p=0.001) compared to the other groups. Sarcopenic obesity, but not low muscle mass alone, may increase the risk of CKD in patients with T2DM.

A ketogenic diet (KD) is known to have beneficial health effects. Various types of KD interventions have been applied to manage metabolic syndrome based on modification of diet parameters such as duration of intervention, macronutrient components, and total calories. Nevertheless, the beneficial health impact of isocaloric KD is largely unknown, especially in healthy subjects. The present study investigated the acute effects of a 3-day isocaloric KD. In this non-randomized intervention study, we recruited 15 healthy volunteers aged 24-38 years (7 men and 8 women) and placed them on an isocaloric KD restricting intake of carbohydrates but not energy (75% fat, 20% protein, 5% carbohydrate) for 3 days. Biochemical profiles and laboratory measurements were performed. Peripheral blood monocular cells were cultured, and measured cell stimulated cytokines. After short-term isocaloric KD, subjects lost body weight and serum free fatty acid levels were increased. These results accompanied elevated serum β-hydroxybutyrate (BHB) concentration and fibroblast growth factor 21 (FGF21) levels and improved insulin sensitivity. Regarding the direct effect of BHB on inflammasome activation, interleukin-1β (IL-1β) and tumor necrosis factor-α secretion in response to adenosine triphosphate or palmitate stimulation in human macrophages decreased significantly after isocaloric KD. Inclinicaltrials.gov (NCT02964572).

To date, no study has compared the effects of adding sodium glucose cotransporter-2 (SGLT-2) inhibitors to the combination of metformin plus dipeptidyl peptidase-4 (DPP-4) inhibitors to the effects of adding other conventional anti-diabetic drugs (ADDs) to the dual therapy. We aimed to compare the effect of adding SGLT-2 inhibitors with that of adding sulfonylurea (SU) in type 2 diabetes (T2D) patients inadequately controlled with metformin plus DPP-4 inhibitors.This study was designed to evaluate the non-inferiority of SGLT-2 inhibitor to SU as an add-on therapy to the dual combination of metformin plus DPP-4 inhibitors. A total of 292 T2D patients who started SU or SGLT-2 inhibitors as an add-on therapy to metformin plus DPP-4 inhibitors due to uncontrolled hyperglycemia, defined as glycated hemoglobin (HbA1c) ≥7%, were recruited. After propensity score matching, 90 pairs of patients remained, and 12-week changes in HbA1c levels were reviewed to assess glycemic effectiveness. Data from these patients were analyzed retrospectively.After 12 weeks of triple therapy, both groups showed significant changes in HbA1c levels, with a mean of -0.9% in each group. The inter-group difference was 0.01% [95% confidence interval (CI): -0.26-0.27], and the upper limit of the 95% CI was within the limit for non-inferiority (0.40%). There were no inter-group differences in the changes of liver enzyme levels and kidney function.Adding SGLT-2 inhibitors is not inferior to adding SU as a third-line ADD to metformin plus DPP-4 inhibitor combination therapy.

Background: Cardiovascular disease (CVD) is associated with morbidity and mortality in patients with type 2 diabetes mellitus (T2D). However, the role of serum uric acid as a risk factor for developing cardiovascular disease is controversial. This study investigated whether uric acid variability was associated with new-onset symptomatic CVD in patients with T2D, requiring percutaneous coronary intervention.Methods: A total of 1,071 patients were enrolled in this retrospective cross-sectional study after propensity score matching. Patients with T2D and new-onset symptomatic CVD who received percutaneous coronary intervention for the first time, and with at least three consecutive 6-monthly measurements of serum uric acid were recruited from Severance Hospital between January 2015 and December 2019. Uric acid variability was measured by average successive variability (ASV) and analyzed to evaluate a possible correlation with the risk of developing CVD.Results: The patients were divided into quartiles based on the uric acid variability. Patients in the highest quartile were older and presented lower renal function and a higher mortality from CVD. There was a linear association between a high uric acid variability and the development of CVD. Compared to the lowest quartile, patients in the higher quartiles had a higher risk of CVD [quartile 3: adjusted odds ratio (aOR) = 1.76; 95% confidence interval (CI), 1.20–2.82; P = 0.019; quartile 4 aOR = 2.89; 95% CI, 1.74–4.80; P < 0.001].Conclusion: High uric acid variability is independently associated with an increased risk of new-onset symptomatic CVD requiring percutaneous coronary intervention in patients with T2D. Thus, maintaining serum uric acid in a narrow range by prescribing effective medications is essential to prevent new-onset CVD in patients with T2D. Nonetheless, the potential use of uric acid variability as a predictive marker of CVD in patients with T2D needs further validation.

Introduction: Increasing number of clinical guidelines are adopting comprehensive cardiovascular risk assessment tools for treatment decision and disease management in the context of primary and secondary prevention. Yet, little is known regarding the exact cardiovascular risks associated with length of favorable cardiometabolic health sustenance in midlife. Methods: From the Korean Genome and Epidemiology Study Ansung-Ansan cohort, we included 7,854 middle-aged adults without chronic kidney disease and 7,796 without cardiovascular disease at baseline. Duration of ideal cardiovascular health was the sum of time spent with ideal body mass index, blood pressure, fasting glucose, total cholesterol, non-smoking, alcohol drinking, and physical activity levels. We employed Cox proportional hazards model to assess chronic kidney disease and cardiovascular events risks. Results: The median age of the participants was 50.0 years and 47.9% were male. Over a median follow-up of 15.0 years, 1,401 new chronic kidney disease and 493 new cardiovascular disease occurred. With P trend, 0.0057). Similarly, participants lived with longer ideal cardiovascular health had significantly lower cardiovascular disease (5 to 10 years, 0.83 [0.54-1.27]; ≥10 years, 0.22 [0.08-0.60]). Subtype-specific analyses indicated negatively graded risks for coronary artery disease ( P trend, 0.0239) and cerebrovascular disease ( P trend, 0.0514). Conclusions: Our findings confer that maintaining favorable health behaviors and clinical cardiometabolic profile in midlife will improve later-life cardiovascular outcomes.

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.

Saline or local anesthetic injection into the epidural space increases intracranial pressure (ICP), at least transiently. Measurement of the optic nerve sheath diameter (ONSD) using ocular ultrasonography is one of the noninvasive methods for ICP assessment.The purpose of this study is to investigate the effects of the different volume on the ONSD and cerebral oxygen saturation (rSO2) during thoracic epidural saline injection under awake conditions.Prospective randomized, controlled trial.An interventional pain management practice in South Korea.This study included 71 patients receiving thoracic epidural catheterization for pain management, following upper abdominal or thoracic surgery. Following successful epidural space confirmation, patients were randomly allocated to receive 5 mL (5 mL group), 10 mL (10 mL group), and 20 mL (20 mL group) of epidural normal saline. Transorbital sonography was performed to measure the ONSD. This was measured at 3 mm posterior to the optic nerve head. An rSO2 was measured using cerebral oximeter sensors.All 3 groups showed significant increases of ONSD from 10 minutes to 40 minutes as compared to baseline (before procedure). Among the 3 groups, the 20 mL group demonstrated the most significantly increased ONSD, as compared to the 5 mL and 10 mL groups. At the 20 minute and 40 minute time points, the ONSD showed a volume-dependent increase (P = 0.0005, P = 0.014). All 3 groups showed the rSO2 to be distributed between 60~70% without any statistical difference.We could not determine the returning point of the normalized ONSD value.Twenty milliliters of normal saline epidural injection resulted in a significant increase of ONSD, as compared to the 5 mL and 10 mL groups. Our results also indicate that an increase of ONSD occurs in accordance with the injected volume of normal saline.

Transforaminal epidural injection (TFEI) is a useful intervention for radicular leg pain. Compared to TFEI in lumbar level, S1 TFEI is reported to have higher incidence rates of intravascular injection as well as technical difficulties.The purpose of this study is to compare the incidence rates of intravascular injection and foramen passage time between anteroposterior (AP) and oblique (OB) approaches.Prospective randomized trial.An interventional pain management practice in South Korea.One hundred forty-seven patients receiving S1 TFEI for radicular leg pain were randomly assigned to one of 2 approach methods (AP view vs OB view). For S1 TFEI in the OB view group, lineup of the L5-S1 endplate was performed by adjusting the cephalad-caudad tilt. Then C-arm was rotated at an ipsilateral oblique angle, approximately 10° to 15°. After final confirmation of intravascular injection with real time fluoroscopy, the foramen passage time and amount of radiation exposure during S1 TFEI were measured.The incidence rate of intravascular injection in the AP view group was 24.2% (24/99), whereas that of intravascular injection in the OB view group was 10.1% (17/99, P = 0.008). The radiation dose required to pass the S1 foramen was significantly higher in the AP view group than in the OB view group (51.3 ± 27.2 cGy/cm2 vs 41.0 ± 17.0 cGy/cm2, P = 0.002). The foramen passage time during S1 TFEI was significantly higher in the AP view group than in the OB view group (103.5 ± 44.1 second vs 84.9 ± 21.0 second, P = 0.001). The failure rate of S1 TFEI was significantly higher in the AP view group than in the OB view group (13% vs 4%, P = 0.022).The physicians involved in the present study were not blinded to the type of approach method (AP view vs OB view) by fluoroscopy.Our study demonstrated reduced incidence rates of intravascular injection and reduced foramen passage time and radiation dosage with the use of OB view method during S1 TFEI.

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.

Methyl bromide (MB) has been used in a wide range of applications, but since it was determined to be an ozone-depleting compound, it has only been used for pre-shipment and quarantine purposes in trade. Phosphine (PH3) is currently the ideal fumigant as an MB alternative worldwide. However, the development of PH3 resistance in the target insect pest and longer PH3 fumigation treatment times raise questions about the continued use of PH3. This study attempted to shorten treatment time via combination treatment with ethyl formate (EF). Planococcus citri was used as the main quarantine pest in Korea, and the acute toxicity of EF, PH3, and EF + PH3 was determined at every developmental stage. EF treatment at 4 h showed LCT99 values of 45.85~65.43 mg∙h/L, and PH3 treatment at 20 h showed that of 0.13~0.83 mg∙h/L depending on the developmental stage. The efficacy of PH3 decreased after reducing the treatment time, but synergistic effects were observed at all stages of development of P. citri when both fumigants were used simultaneously for 4 h. After combined treatment, dihydrolipoyl dehydrogenase expression and the production of two phospholipids, PI(O-16:0) and PC(18:2), were significantly reduced in treated P. citri adults compared with the control. Therefore, combined treatments might be key to reducing the treatment time and resistance of PH3 in the field.

The influence of the sequence of surgery in the development of prevertebral soft tissue swelling (PSTS) in staged combined multilevel anterior–posterior complex spine surgery was examined. This study was conducted as a retrospective study of patients who underwent staged combined multilevel anterior–posterior complex cervical spine surgery from March 2014 to February 2021. Eighty-two patients were identified, of which fifty-seven were included in the final analysis after screening. PSTS was measured from routine serial monitoring lateral cervical radiographs prior to and after surgery for five consecutive days at each cervical level from C2 to C7 in patients who underwent anterior then posterior (AP) and posterior then anterior–posterior (PAP) surgery. The mean PSTS measurements significantly differed from the preoperative to postoperative monitoring days at all cervical levels (p = 0.0000) using repeated measures analysis of variance in both groups. PSTS was significantly greater in PAP than in AP at level C2 on postoperative day (POD) 1 (p = 0.0001). PSTS was more prominent at levels C2–4 during PODs 2–4 for both groups. In staged combined multilevel anterior–posterior complex spine surgery, PSTS is an inevitable complication. Therefore, surgeons should monitor PSTS after surgery when performing anterior–posterior complex cervical spine surgery, especially in the immediate postoperative period after PAP surgery.

The world’s population continues to increase, meaning we require more consistent protein supply to meet demand. Despite the availability of plant-based protein alternatives, animal meat remains a popular, high-quality protein source. Research studies have focused on cultured meat (meat grown in vitro) as a safe and more efficient alternative to traditional meat. Cultured meat is produced by in vitro myogenesis, which involves the processing of muscle satellite and mature muscle cells. Meat culture efficiency is largely determined by the culture conditions, such as the cell type and cell culture medium used and the biomolecular composition. Protein production can be enhanced by providing the optimum biochemical and physical conditions for skeletal muscle cell growth, while myoblasts play important roles in skeletal muscle formation and growth. This review describes the cell types used to produce cultured meat and the biological effects of various myokines and cytokines, such as interleukin-6, leukemia inhibitory factor, interleukin-4, interleukin-15, and interleukin-1β, on skeletal muscle and myogenesis and their potential roles in cultured meat production.

Context There are few studies focused on the relationship between hypoglycemia and new-onset dementia in patients with type 2 diabetes and no study regarding mortality of dementia after hypoglycemia. Objective We investigated the effect of severe hypoglycemia on dementia subtypes and its relation to overall mortality in patients with type 2 diabetes. Methods We evaluated incident dementia, including Alzheimer disease and vascular dementia, among health checkup participants aged 40 years or older in the National Health Insurance System in Korea from January 2009 to December 2015. Episodes of severe hypoglycemia were examined for 3 years before the date of the health checkup. Results Among 2 032 689 participants (1 172 271 men, 860 418 women), 14 443 (0.7%) experienced severe hypoglycemia, during a mean follow-up period of 6.9 ± 1.7 years. Individuals in the severe hypoglycemia group were more likely to be diagnosed with dementia compared to individuals without severe hypoglycemia (23.3% vs 7.3%; P Conclusion Severe hypoglycemia is associated with dementia, especially Alzheimer disease and mortality; together, they have an additive effect on overall mortality.

The objective of this study was to investigate fibromodulin (FMOD) and myostatin (MSTN) gene expressions during skeletal muscle aging and to understand their involvements in this process. The expressions of genes related to muscle aging (Atrogin 1 and Glb1), diabetes (RAGE and CD163), and lipid accumulation (CD36 and PPARγ) and those of FMOD and MSTN were examined in CTX-injected, aged, MSTN−/−, and high-fat diet (HFD) mice and in C2C12 myoblasts treated with ceramide or grown under adipogenic conditions. Results from CTX-injected mice and gene knockdown experiments in C2C12 cells suggested the involvement of FMOD during muscle regeneration and myoblast proliferation and differentiation. Downregulation of the FMOD gene in MSTN−/− mice, and MSTN upregulation and FMOD downregulation in FMOD and MSTN knockdown C2C12 cells, respectively, during their differentiation, suggested FMOD negatively regulates MSTN gene expression, and MSTN positively regulates FMOD gene expression. The results of our in vivo and in vitro experiments indicate FMOD inhibits muscle aging by negatively regulating MSTN gene expression or by suppressing the action of MSTN protein, and that MSTN promotes muscle aging by positively regulating the expressions of Atrogin1, CD36, and PPARγ genes in muscle.

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.

Metabolic dysfunction associated fatty liver disease (MAFLD) has recently been introduced to compensate for the conventional concept of nonalcoholic fatty liver disease (NAFLD). We explored whether fibrotic burden determines the risk of atherosclerotic cardiovascular disease (ASCVD) among subjects with MAFLD.We recruited 9,444 participants from the Korea National Health and Nutrition Examination Survey (2008 to 2011). Liver fibrosis was identified using the fibrosis-4 (FIB-4) index and NAFLD fibrosis score. The 10-year ASCVD risk score (gt;10%) was used to determine a high probability ASCVD risk. For sensitivity analysis, propensity score matching was assessed to subjects with aged 40 to 75 years free from ASCVD.The prevalence of MAFLD was 38.0% (n=3,592). The ASCVD risk scores stratified in quartile were positively correlated to MAFLD and FIB-4 defined-significant liver fibrosis (p for trendlt;0.001). Individuals with both MAFLD and FIB-4 defined-significant liver fibrosis had a greater chance of high probability ASCVD risk (odds ratio [OR]=2.40; plt;0.001) than those without MAFLD. The impact of MAFLD on high probability ASCVD risk was greater than that of significant liver fibrosis (OR=4.72 for MAFLD vs OR=1.88 for FIB-4 defined-significant liver fibrosis; all plt;0.001). Among participants with MAFLD, low muscle mass enhanced the risk of significant liver fibrosis (OR=1.56 to 2.43; plt;0.001). When NAFLD fibrosis score was applied to define significant liver fibrosis, similar findings were observed.Individuals with MAFLD had a substantial ASCVD risk compared to those without MAFLD. Accompanying significant liver fibrosis further enhanced the risk of ASCVD among subjects with MAFLD.

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 report an efficient and broadly applicable palladium‐catalyzed iodination of inexpensive and abundant aryl and vinyl carboxylic acids via in situ activation to the acid chloride and formation of a phosphonium salt. The use of 1‐iodobutane as iodide source in combination with a base and a deoxychlorinating reagent gives access to a wide range of aryl and vinyl iodides under Pd/Xantphos catalysis, including complex drug‐like scaffolds. Stoichiometric experiments and kinetic analysis suggest a unique mechanism involving C−P reductive elimination to form the Xantphos phosphonium chloride, which subsequently initiates an unusual halogen exchange by outer sphere nucleophilic substitution., An efficient and broadly applicable palladium‐catalyzed iodination of inexpensive and abundant aryl and vinyl carboxylic acids via in situ activation to the acid chloride and formation of a phosphonium salt was developed. The use of 1‐iodobutane as iodide source in combination with a base and a deoxychlorinating reagent gives access to a wide range of aryl and vinyl iodides under Pd/Xantphos catalysis.

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 Elucidation of the basic molecular mechanism of autophagy was a breakthrough in understanding various physiological events and pathogenesis of diverse diseases. In the fields of diabetes and metabolism, many cellular events associated with the development of disease or its treatment cannot be explained well without taking autophagy into account. While a grand picture of autophagy has been established, detailed aspects of autophagy, particularly that of selective autophagy responsible for homeostasis of specific organelles or metabolic intermediates, are still ambiguous and currently under intensive research. Scope of review Here, results from previous and current studies on the role of autophagy and its dysregulation in the physiology of metabolism and pathogenesis of diabetes are summarized, with an emphasis on the pancreatic β-cell autophagy. In addition to nonselective (bulk) autophagy, machinery and significance of selective autophagy such as mitophagy of pancreatic β-cells is discussed. Novel findings regarding autophagy types other than macroautophagy are also covered, since several types of autophagy or lysosomal degradation pathways other than macroautophagy coexist in pancreatic β-cells. Major conclusion Autophagy plays a critical role in cellular metabolism, homeostasis of the intracellular environment and function of organelles such as mitochondria and endoplasmic reticulum. Impaired autophagic activity due to aging, obesity or genetic predisposition could be a factor in the development of β-cell dysfunction and diabetes associated with lipid overload or human-type diabetes characterized by islet amyloid deposition. Modulation of autophagy of pancreatic β-cells is likely to be possible in the near future, which would be valuable in the treatment of diabetes associated with lipid overload or accumulation of islet amyloid., Highlights • Autophagy is critical for cellular metabolism, homeostasis and organelle function. • Impaired autophagic activity could predispose to β-cell dysfunction and diabetes. • Several types of autophagy coexist in pancreatic β-cells.

Between August and September 2017, zonate leaf spots with severe defoliation were observed on Parthenocissus tricuspidata in Gimcheon, Korea. The initial symptoms included water-soaked, gray to grayish brown, circular or irregular-shaped leaf spots. As the disease progressed, the spots enlarged, coalesced, and became cream-colored with characteristic target-shaped rings, leading to leaf blight and premature defoliation. Based on cultural and morphological characteristics, the fungus associated with the symptoms was identified as Grovesinia moricola. The identity of this fungus was confirmed by analyzing sequences of the internal transcribed spacer region of ribosomal DNA. The pathogenicity of the isolate was demonstrated by artificial inoculation. To our knowledge, this is the first report of G. moricola occurring on P. tricuspidata globally as well as in Korea.

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.

Acetaminophen (APAP) overdose can cause hepatotoxicity by inducing mitochondrial damage and subsequent necrosis in hepatocytes. Sirtuin2 (Sirt2) is an NAD+-dependent deacetylase that regulates several biological processes, including hepatic gluconeogenesis, as well as inflammatory pathways. We show that APAP decreases the expression of Sirt2. Moreover, the ablation of Sirt2 attenuates APAP-induced liver injuries, such as oxidative stress and mitochondrial damage in hepatocytes. We found that Sirt2 deficiency alleviates the APAP-mediated endoplasmic reticulum (ER) stress and phosphorylation of the p70 ribosomal S6 kinase 1 (S6K1). Moreover, Sirt2 interacts with and deacetylates S6K1, followed by S6K1 phosphorylation induction. This study elucidates the molecular mechanisms underlying the protective role of Sirt2 inactivation in APAP-induced liver injuries. [BMB Reports 2019; 52(3): 190-195].

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.

Non-alcoholic fatty liver disease (NAFLD) is the major cause of chronic liver disease, yet cost-effective and non-invasive diagnostic tools to monitor the severity of the disease are lacking. We aimed to investigate the metabolomic changes in NAFLD associated with therapeutic responses. It was conducted in 63 patients with NAFLD who received either ezetimibe plus rosuvastatin or rosuvastatin monotherapy. The treatment response was determined by MRI performed at baseline and week 24. The metabolites were measured at baseline and week 12. In the combination group, a relative decrease in xanthine was associated with a good response to liver fat decrease, while a relative increase in choline was associated with a good response to liver stiffness. In the monotherapy group, the relative decreases in triglyceride (TG) 20:5_36:2, TG 18:1_38:6, acetylcarnitine (C2), fatty acid (FA) 18:2, FA 18:1, and docosahexaenoic acid were associated with a decrease in liver fat, while hexosylceramide (d18:2/16:0) and hippuric acid were associated with a decrease in liver stiffness. Models using the metabolite changes showed an AUC of >0.75 in receiver operating curve analysis for predicting an improvement in liver fat and stiffness. This approach revealed the physiological impact of drugs, suggesting the mechanism underlying the development of this disease.

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.

Senescent T cells have been implicated in chronic inflammatory and cardiovascular diseases. In this study, we explored the relationship between senescent T cells and glycemic status in a cohort of 805 participants by investigating the frequency of CD57+ or CD28null senescent T cells in peripheral blood. Participants with normal glucose tolerance (NGT) with follow-up data (N = 149) were included to determine whether hyperglycemia (prediabetes or type 2 diabetes) developed during follow-up (mean 2.3 years). CD8+CD57+ and CD8+CD28null T-cell frequencies were significantly higher in prediabetes and type 2 diabetes compared with NGT. Increased CD57+ or CD28null cells in the CD8+ T-cell subset were independently associated with hyperglycemia. Furthermore, among participants with baseline NGT, the frequency of CD8+CD57+ T cells was an independent predictor of hyperglycemia development. Immunofluorescent analyses confirmed that CD8+CD57+ T-cell infiltration was increased in visceral adipose tissue of patients with prediabetes or type 2 diabetes compared with those with NGT. Our data suggest that increased frequency of senescent CD8+ T cells in the peripheral blood is associated with development of hyperglycemia.

Diabetes & Metabolism - In Press.Proof corrected by the author Available online since vendredi 15 decembre 2017

Post-translational modifications, including O-GlcNAcylation, play fundamental roles in modulating cellular events, including transcription, signal transduction, and immune signaling. Several molecular targets of O-GlcNAcylation associated with pathogen-induced innate immune responses have been identified; however, the direct regulatory mechanisms linking O-GlcNAcylation with antiviral RIG-I-like receptor signaling are not fully understood. In this study, we found that cellular levels of O-GlcNAcylation decline in response to infection with Sendai virus. We identified a heavily O-GlcNAcylated serine-rich region between amino acids 249–257 of the mitochondrial antiviral signaling protein (MAVS); modification at this site disrupts MAVS aggregation and prevents MAVS-mediated activation and signaling. O-GlcNAcylation of the serine-rich region of MAVS also suppresses its interaction with TRAF3; this prevents IRF3 activation and production of interferon-β. Taken together, these results suggest that O-GlcNAcylation of MAVS may be a master regulatory event that promotes host defense against RNA viruses.