Efficacy and Safety of Metformin and Atorvastatin Combination Therapy vs. Monotherapy with Either Drug in Type 2 Diabetes Mellitus and Dyslipidemia Patients (ATOMIC): Double-Blinded Randomized Controlled Trial.

Background: It is well known that a large number of patients with diabetes also have dyslipidemia, which significantly increases the risk of cardiovascular disease (CVD). This study aimed to evaluate the efficacy and safety of combination drugs consisting of metformin and atorvastatin, widely used as therapeutic agents for diabetes and dyslipidemia. Methods: This randomized, double-blind, placebo-controlled, parallel-group and phase III multicenter study included adults with glycosylated hemoglobin (HbA1c) levels >7.0% and <10.0%, low-density lipoprotein cholesterol (LDL-C) >100 and <250 mg/dL. One hundred eighty-five eligible subjects were randomized to the combination group (metformin+atorvastatin), metformin group (metformin+atorvastatin placebo), and atorvastatin group (atorvastatin+metformin placebo). The primary efficacy endpoints were the percent changes in HbA1c and LDL-C levels from baseline at the end of the treatment. Results: After 16 weeks of treatment compared to baseline, HbA1c showed a significant difference of 0.94% compared to the atorvastatin group in the combination group (0.35% vs. -0.58%, respectively; P<0.0001), whereas the proportion of patients with increased HbA1c was also 62% and 15%, respectively, showing a significant difference (P<0.001). The combination group also showed a significant decrease in LDL-C levels compared to the metformin group (-55.20% vs. -7.69%, P<0.001) without previously unknown adverse drug events. Conclusion: The addition of atorvastatin to metformin improved HbA1c and LDL-C levels to a significant extent compared to metformin or atorvastatin alone in diabetes and dyslipidemia patients. This study also suggested metformin's preventive effect on the glucose-elevating potential of atorvastatin in patients with type 2 diabetes mellitus and dyslipidemia, insufficiently controlled with exercise and diet. Metformin and atorvastatin combination might be an effective treatment in reducing the CVD risk in patients with both diabetes and dyslipidemia because of its lowering effect on LDL-C and glucose.

Efficacy and Safety of Alogliptin-Pioglitazone Combination for Type 2 Diabetes Mellitus Poorly Controlled with Metformin: A Multicenter, Double-Blind Randomized Trial.

Background: Guidelines for switching to triple combination therapy directly after monotherapy failure are limited. This study investigated the efficacy, long-term sustainability, and safety of either mono or dual add-on therapy using alogliptin and pioglitazone for patients with type 2 diabetes mellitus (T2DM) who did not achieve their target glycemic range with metformin monotherapy. Methods: The Practical Evidence of Antidiabetic Combination Therapy in Korea (PEAK) was a multicenter, placebo-controlled, double-blind, randomized trial. A total of 214 participants were randomized to receive alogliptin+pioglitazone (Alo+Pio group, n=70), alogliptin (Alo group, n=75), or pioglitazone (Pio group, n=69). The primary outcome was the difference in glycosylated hemoglobin (HbA1c) levels between the three groups at baseline to 24 weeks. For durability, the achievement of HbA1c levels <7% and <6.5% was compared in each group. The number of adverse events was investigated for safety. Results: After 24 weeks of treatment, the change of HbA1c in the Alo+Pio, Alo, and Pio groups were -1.38%±0.08%, -1.03%±0.08%, and -0.84%±0.08%, respectively. The Alo+Pio group had significantly lower HbA1c levels than the other groups (P=0.0063, P<0.0001) and had a higher proportion of patients with target HbA1c achievement. In addition, insulin sensitivity and ß-cell function, lipid profiles, and other metabolic indicators were also improved. There were no significant safety issues in patients treated with triple combination therapy. Conclusion: Early combination triple therapy showed better efficacy and durability than the single add-on (dual) therapy. Therefore, combination therapy with metformin, alogliptin, and pioglitazone is a valuable early treatment option for T2DM poorly controlled with metformin monotherapy.

Real-World Outcomes of Individualized Targeted Therapy with Insulin Glargine 300 Units/mL in Insulin-Naïve Korean People with Type 2 Diabetes: TOBE Study.

INTRODUCTION: The TOujeo BEyond glucose control (TOBE) study evaluated clinical outcomes with insulin glargine 300 units/mL (Gla-300) in insulin-naïve Korean people with type 2 diabetes mellitus (T2DM) in a real-world setting. METHODS: This 24-week, prospective, non-interventional, multicenter, open-label, single-arm, observational study included adults aged ≥ 20 years with T2DM suboptimally controlled with oral hypoglycemic agents and/or glucagon-like peptide 1 receptor agonists who require basal insulin. Eligible participants were assigned to either general target glycated hemoglobin (HbA1c < 7%) or individualized target groups as per physician's discretion considering guidelines and participants' characteristics. The primary endpoint was the proportion of participants achieving the HbA1c target (individualized or general) at 24 weeks. RESULTS: Among 369 participants, 19.5% (72/369) of participants achieved the HbA1c target at week 24; 37.5% (33/88) in the individualized and 13.9% (39/281) in the general target group. In both target groups, similar reductions in fasting plasma glucose and body weight were observed, with low incidence of hypoglycemia, and T2DM duration was significantly shorter in participants who did versus those who did not achieve the target HbA1c (individualized target group: 9.6 ± 8.0 versus 13.1 ± 8.4 years, P = 0.0454; general target group: 10.2 ± 8.6 versus 12.8 ± 7.4 years, P = 0.0378). CONCLUSIONS: This study showed that initiation of insulin therapy with Gla-300 in people with T2DM using an individualized approach is more effective in achieving an HbA1c target. Moreover, earlier initiation of insulin therapy in people with suboptimally controlled T2DM may increase the success rate of glycemic control. A graphical abstract is available with this article.

Despite various efforts in managing diabetes, individuals with type 2 diabetes mellitus (T2DM) encounter numerous challenges to achieve good glycemic control. The major cause is failure to initiate insulin therapy in a timely manner, primarily because of the fear of hypoglycemia. Insulin glargine 300 units/mL (Gla-300) has smooth and prolonged activity resulting in stable and sustained glycemic control, thus reducing the risk of hypoglycemia. Studies on efficacy and safety of Gla-300 in various populations have been published globally. However, there are limited real-world studies in Asian populations. This study evaluated effectiveness and safety of Gla-300 in Korean people with T2DM who were not on insulin prior to this study but were taking oral glucose-lowering medications. The participants were assigned to two groups: general glycated hemoglobin (HbA1c) target (HbA1c < 7%) and individualized HbA1c target according to the participant's characteristics. Results showed that Gla-300 helped to achieve the glycemic target more effectively using an individualized approach. In both groups, similar reductions in fasting plasma glucose and body weight were observed, with low incidence of hypoglycemia. People who achieve glycemic target had a shorter duration of T2DM than those who did not achieve their glycemic target. This suggests that earlier insulin initiation may be a better approach and may increase the success rate of insulin therapy.

Comparison of the Efficacy of Ezetimibe Combination Therapy and High-Intensity Statin Monotherapy in Type 2 Diabetes.

CONTEXT: Low-density lipoprotein cholesterol (LDL-C)-lowering therapy is considerably important in preventing cardiovascular disease (CVD) among patients with diabetes. Studies comparing CVD, stroke, and mortality outcomes of low- or moderate-intensity statins with ezetimibe combination therapy and high-intensity statin monotherapy in patients with diabetes remain lacking. OBJECTIVE: This study compared the primary prevention effect of myocardial infarction (MI), stroke, and all-cause death between combination therapy of low- or moderate-intensity statins and ezetimibe and high-intensity statin monotherapy in patients with diabetes using the Korean National Health Insurance claims database. METHODS: Patients aged ≥20 years with type 2 diabetes and dyslipidemia were enrolled. The combination therapy of low- or moderate-intensity statin and ezetimibe was compared with high-intensity statin monotherapy after a propensity score-matched analysis. The incidence of composite outcomes consisting of MI, stroke, and all-cause death and each component were analyzed. RESULTS: In moderate-intensity statin therapy with ezetimibe combination therapy, LDL-C (74 ± 37.9 mg/dL vs 80.8 ± 38.8 mg/dL, P < .001) and the incidence of composite outcomes were lower (hazard ratio 0.85, 95% CI 0.74-0.98) than those in high-intensity statin monotherapy. Meanwhile, no significant difference was observed in the LDL-C levels and composite outcomes between low-intensity statins with ezetimibe combination therapy and high-intensity statin monotherapy. CONCLUSION: Adding ezetimibe to a moderate-intensity statin in patients with type 2 diabetes has a greater LDL-C-lowering effect and greater primary prevention of composite outcomes than that of high-intensity statin monotherapy.

Safety and Clinical Outcomes of Insulin Degludec in Korean Patients with Diabetes in Real-World Practices: A Prospective, Observational Study.

INTRODUCTION: To investigate the safety and effectiveness of insulin degludec (IDeg) in a real-world population of Korean patients with diabetes requiring insulin therapy. METHODS: This was a multicenter, prospective, single-arm, open-label, non-interventional study. Patients aged ≥ 12 months and treated with previous glucose-lowering medications were eligible to switch to IDeg. The primary endpoint was the incidence of adverse events (AEs), and the secondary endpoints were changes in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), postprandial glucose (PPG), and target HbA1c < 7.0%. RESULTS: In total, 3225 and 2450 patients were included in the safety analysis set (SAS) and effectiveness analysis set (EAS), respectively. The mean baseline HbA1c and duration of diabetes were 9.4% and 13.0 years, respectively. Adverse events were reported in 740 patients (22.9%); the majority were mild and resolved. Significant improvements were observed in HbA1c, FPG, and PPG at week 26 (all p < 0.0001). The target of HbA1c < 7% was achieved in 22.2% of patients at week 26. CONCLUSION: In real-world clinical practice, 26 weeks of IDeg treatment resulted in significant reductions in glycemic parameters with a low incidence of AEs in Korean patients with diabetes. No new safety signals were observed. CLINICAL TRIALS REGISTRY AND REGISTRATION NUMBER: This trial is registered under ClinicalTrials.gov (NCT02779413) and the universal trial number is [U1111-1176-2287].

Peroxisome proliferator-activated receptor γ activation ameliorates liver fibrosis-differential action of transcription factor EB and autophagy on hepatocytes and stellate cells.

BACKGROUND: Peroxisome proliferator-activated receptor γ (PPARγ) activation suppresses HSC activation and liver fibrosis. Moreover, autophagy is implicated in hepatic lipid metabolism. Here, we determined whether PPARγ activation ameliorates HSC activation by downregulating transcription factor EB (TFEB)-mediated autophagy. METHODS AND RESULTS: Atg7 or Tfeb knockdown in human HSC line LX-2 cells downregulated the expression of fibrogenic markers including α smooth muscle actin, glial fibrillary acidic protein, and collagen type 1. Conversely, Atg7 or Tfeb overexpression upregulated fibrogenic marker expression. Rosiglitazone (RGZ)-mediated PPARγ activation and/or overexpression in LX-2 cells and primary HSCs decreased autophagy, as indicated by LC3B conversion, total and nuclear-TFEB contents, mRFP-LC3 and BODIPY 493/503 colocalization, and GFP-LC3 and LysoTracker colocalization. RGZ treatment decreased liver fat content, liver enzyme levels, and fibrogenic marker expression in high-fat high-cholesterol diet-fed mice. Electron microscopy showed that RGZ treatment restored the high-fat high-cholesterol diet-mediated lipid droplet decrease and autophagic vesicle induction in primary HSCs and liver tissues. However, TFEB overexpression in LX-2 cells offset the aforementioned effects of RGZ on autophagic flux, lipid droplets, and fibrogenic marker expression. CONCLUSIONS: Activation of PPARγ with RGZ ameliorated liver fibrosis and downregulation of TFEB and autophagy in HSCs may be important for the antifibrotic effects of PPARγ activation.

Subtypes of type 2 diabetes and their association with outcomes in Korean adults - A cluster analysis of community-based prospective cohort.

BACKGROUND: Little is known about the subtypes of type 2 diabetes (T2D) and their association with clinical outcomes in Asians. METHODS: We performed data-driven cluster analysis in patients with newly diagnosed drug-naive T2D (n = 756) from the Korean Genome and Epidemiology Study. Clusters were based on five variables (age at diagnosis, BMI, HbA1c, and HOMA2 ß-cell function, and insulin resistance). RESULTS: We identified four clusters of patients with T2D according to k-means clustering: cluster 1 (22.4 %, severe insulin-resistant diabetes [SIRD]), cluster 2 (32.7 %, mild age-related diabetes [MARD]), cluster 3 (32.7 %, mild obesity-related diabetes [MOD]), and cluster 4 (12.3 %, severe insulin-deficient diabetes [SIDD]). During 14 years of follow-up, individuals in the SIDD cluster had the highest risk of initiation of glucose-lowering therapy compared to individuals in the other three clusters. Individuals in the MARD and SIDD clusters showed the highest risk of chronic kidney disease and cardiovascular disease, and individuals in the MOD clusters showed the lowest risk after adjusting for other risk factors (P < 0.05). CONCLUSIONS: Patients with T2D can be categorized into four subgroups with different glycemic deterioration and risks of diabetes complications. Individualized management might be helpful for better clinical outcomes in Asian patients with different T2D subgroups.

Anagliptin twice-daily regimen improves glycaemic variability in subjects with type 2 diabetes: A double-blind, randomized controlled trial.

AIM: To determine whether the twice-daily (BID) regimen is superior to the once-daily (QD) regimen for managing glycaemic variability by comparing the effects of anagliptin 100 mg BID versus sitagliptin 100 mg QD. MATERIALS AND METHODS: A double-blinded, randomized, multicentre study was performed in 89 patients with type 2 diabetes treated with metformin alone (6.5% < HbA1c < 8.5%). Subjects were randomly assigned to anagliptin 100 mg BID or sitagliptin 100 mg QD in a 1:1 ratio for 12 weeks. Continuous glucose monitoring was used to measure the mean amplitude of glycaemic excursion (MAGE) and postprandial time in range (TIR) before and after dipeptidyl peptidase-4 (DPP-4) inhibitor treatment to compare glycaemic variability. RESULTS: The decrease from baseline in MAGE at 12 weeks after DPP-4 inhibitor treatment was significantly greater in the anagliptin BID group than in the sitagliptin QD group (P < .05); -30.4 ± 25.6 mg/dl (P < .001) in the anagliptin group versus -9.5 ± 38.0 mg/dl (P = .215) in the sitagliptin group. The TIR after dinner increased by 33.0% ± 22.0% (P < .001) in the anagliptin group and by 14.6% ± 28.2% (P = .014) in the sitagliptin group, with a statistically significant difference (P = .009). No statistically significant differences were observed between the groups in the changes in HbA1c and fasting plasma glucose (FPG). CONCLUSIONS: The anagliptin BID regimen for the treatment of type 2 diabetes was superior in blood glucose control after dinner to improve glycaemic variability, as indicated by MAGE and TIR, but was equivalent to the QD regimen in terms of HbA1c and FPG.

Trends in the Prevalence of Obesity and Its Phenotypes Based on the Korea National Health and Nutrition Examination Survey from 2007 to 2017 in Korea.

This study used data from the Korea National Health and Nutrition Examination Survey IV-VII from 2007 to identify the prevalence of obesity and its phenotypes (metabolically unhealthy obesity [MUO] and metabolically healthy obesity [MHO]) and their secular changes. The prevalence of obesity in Korea increased with significant secular changes observed (ß=0.326, P trend <0.01) between 2007 and 2017, and especially in men (ß=0.682, P trend <0.001) but not in women. The changes in the prevalence of obesity during the study period were different between men and women (P=0.001). The prevalence of MUO significantly increased only in men (ß=0.565, P trend <0.01), while that of MHO increased only in women (ß=0.179, P<0.05), especially in the younger age group (ß=0.308, P<0.01).

The efficacy and safety of Dendropanax morbifera leaf extract on the metabolic syndrome: a 12-week, placebo controlled, double blind, and randomized controlled trial.

BACKGROUND/OBJECTIVES: The extract from Dendropanax morbifera exhibited diverse therapeutic potentials. We aimed to evaluate the efficacy and safety of D. morbifera leaf extract for improving metabolic parameters in human. SUBJECTS/METHODS: A 12-week, double blind, placebo-controlled and randomized trial included a total of 74 adults, and they were assigned to the placebo group (n = 38) or 700 mg/day of D. morbifera group (n = 36). The efficacy endpoints were changes in glycemic, lipid, obesity, and blood pressure (BP) parameters, in addition to the prevalence of metabolic syndrome (MetS) and the numbers of MetS components. Safety was assessed by monitoring adverse events (AEs). RESULTS: After 12 weeks of treatment, the hemoglobin A1c (HbA1c) level significantly decreased in the D. morbifera group compared to that of the placebo group (difference: -0.13 ± 0.20% vs. 0.00 ± 0.28%, P = 0.031; % of change: -2.27 ± 3.63% vs. 0.10 ± 5.10%, P = 0.025). The homeostatic model assessment for insulin resistance level also decreased significantly from its baseline in the D. morbifera group. The systolic BP of D. morbifera group decreased significantly than that of placebo group (difference: -3.9 ± 9.8 mmHg vs. 3.3 ± 11.7 mmHg, P = 0.005; % of change: -2.8 ± 7.7% vs. 3.3 ± 10.2%, P = 0.005). However, the lipid parameters and body composition including body weight did not differ between the groups. The prevalence of MetS (36.8% vs. 13.9%, P = 0.022) and the incidence of MetS (10.5% vs. 13.9%, P = 0.027) at 12 weeks was significantly lower in the D. morbifera group than it was in the placebo group. No serious AEs occurred in either group. CONCLUSIONS: Supplementation with D. morbifera extracts over a 12-week period improved metabolic parameters such as HbA1c and BP and reduced the prevalence of MetS. TRIAL REGISTRATION: Clinical Research Information Service Identifier: KCT0004672.

Framingham Risk Score Assessment in Subjects with Pre-diabetes and Diabetes: A Cross-Sectional Study in Korea.

BACKGROUND: This study aimed to evaluate cardiovascular risk in subjects with pre-diabetes and diabetes in Korea. METHODS: In this pan-Korean, non-interventional, cross-sectional study, data were collected from medical records of 10 hospitals between November 2013 and June 2014. Subjects (aged ≥40 years) with medical records of dysglycemia and documentation of total cholesterol level, high-density lipoprotein cholesterol level, systolic blood pressure, and smoking status in the past 6 months were included. The primary endpoint was to determine the Framingham risk score (FRS). The relationships between FRS and cardiovascular risk factors, glycated hemoglobin, and insulin usage were determined by multiple linear regression analyses. RESULTS: Data from 1,537 subjects with pre-diabetes (n=1,025) and diabetes (n=512) were analyzed. The mean FRS (mean±standard deviation) in subjects with pre-diabetes/diabetes was 13.72±8.77. FRS was higher in subjects with diabetes than pre-diabetes (P<0.001). FRS in men with pre-diabetes was comparable to that in women with diabetes (13.80±7.37 vs. 13.35±7.13). FRS was elevated in subjects who consumed alcohol (2.66, P=0.033) and with obesity-class II (6.10, P=0.015) among subjects with diabetes (n=199), and was elevated in patients with left ventricular hypertrophy (11.10, P=0.005), those who consumed alcohol (3.06, P=0.000), were pre-obese (3.21, P=0.002), or were obesity-class I (2.89, P=0.002) among subjects with pre-diabetes (n=306) in comparison to subjects without these coexisting risk factors. CONCLUSION: Overall, Korean subjects with pre-diabetes and diabetes have an increased cardiovascular risk, which is significantly higher in those subjects with diabetes than with pre-diabetes. The present data can be used to develop measures to prevent and manage cardiovascular complications in Koreans with impaired glucose metabolism.

Efficacy and Safety of Switching to Teneligliptin in Patients with Type 2 Diabetes Inadequately Controlled with Dipeptidyl Peptidase-4 Inhibitors: 52-Week Results from a Prospective Observational Study.

INTRODUCTION: The aim of this study was to assess the efficacy and safety of switching to teneligliptin from other dipeptidyl peptidase-4 (DPP-4) inhibitors in patients with type 2 diabetes mellitus (T2DM) inadequately controlled despite treatment with a stable dose of other DPP-4 inhibitors. METHODS: Patients with glycosylated hemoglobin (HbA1c) ≥ 7% despite taking DPP-4 inhibitors other than teneligliptin, with or without other antidiabetic agents, for at least 3 months were enrolled in this study. Patients on DPP-4 inhibitors administered prior to participation in this study were switched to 20 mg teneligliptin once daily and the dose was maintained for the 52-week study period. The primary endpoint was the change in HbA1c at week 12. Fasting plasma glucose (FPG) and the blood lipid profile were also evaluated. Adverse events were monitored for safety assessment. RESULTS: At weeks 12, 24, and 52, the HbA1c values significantly decreased by - 0.39, - 0.44, and - 0.52%, respectively, compared to the baseline value (p < 0.0001); in addition, 56.3, 60.3, and 62.3% of patients, respectively, achieved decreases in HbA1c of at least 0.3%, and 40.1, 46.5, and 52.4% of patients, respectively, achieved decreases in HbA1c of at least 0.5%. The proportion of the patient population achieving HbA1c < 7.0% increased throughout the study period, reaching 30.4, 35.4, and 36.9% at weeks 12, 24, and 52, respectively; at these same time points, the percentage of patients achieving HbA1c < 6.5% increased to 9.5, 11.9, and 13.2% of the total study population. FPG levels and lipid parameters were also significantly decreased after teneligliptin treatment. There were no significant safety concerns. CONCLUSION: Our results suggest the significant glucose-lowering effect of teneligliptin after switching from other DPP-4 inhibitors in patients with T2DM. The improvement in glycemic control was maintained for up to 52 weeks without safety concerns.

Statin use for primary prevention in patients with type 2 diabetes: Can it benefit all ages? - A nationwide propensity-matched cohort study.

AIMS: This study aims to investigate whether statin use is associated with a reduction in CVD and mortality in patients with type 2 diabetes without pre-existing CVD. METHODS: A propensity score-matched cohort analysis using retrospective data was created. Statin users received at least a 90-day prescription, and never used statin before initiation of the study. Statin non-users never received statin throughout the study. Primary outcome was a composite of myocardial infarction (MI), stroke, and all-cause death, and secondary outcome was an individual event. RESULTS: The propensity score matched cohort included 168,045 statin users and 168,045 non-users (mean age 57 years; median follow-up 5.0 years). Compared to statin non-users, the hazard ratio (HR) was 0.72 (95% confidence interval [CI] 0.70-0.73; P < 0.001) for composite outcomes, 0.80 (0.76-0.84; P < 0.001) for MI, 0.74 (0.71-0.76; P < 0.001) for stroke, and 0.68 (0.66-0.70; P < 0.001) for all-cause death in statin users. The risk reduction was most prominent in subjects aged 40-74 years, attenuated but significant in those aged ≥75 years, and not significant in those aged <40 years. CONCLUSIONS: Statin showed a protective effect against CVD and all-cause death in type 2 diabetes; this effect was reduced beyond the age of 75 years and disappeared in young patients aged <40 years.

Allopurinol ameliorates high fructose diet induced hepatic steatosis in diabetic rats through modulation of lipid metabolism, inflammation, and ER stress pathway.

Excess fructose consumption contributes to development obesity, metabolic syndrome, and nonalcoholic fatty liver disease (NAFLD). Uric acid (UA), a metabolite of fructose metabolism, may have a direct role in development of NAFLD, with unclear mechanism. This study aimed to evaluate role of fructose and UA in NAFLD and explore mechanisms of allopurinol (Allo, a UA lowering medication) on NAFLD in Otsuka Long-Evans Tokushima Fatty (OLETF) rats fed a high fructose diet (HFrD), with Long-Evans Tokushima Otsuka (LETO) rats used as a control. There were six groups: LETO, LETO-Allo, OLETF, OLETF-Allo, OLETF-HFrD, and OLETF-HFrD-Allo. HFrD significantly increased body weight, epididymal fat weight, and serum concentrations of UA, cholesterol, triglyceride, HbA1c, hepatic enzymes, HOMA-IR, fasting insulin, and two hour-glucose after intraperitoneal glucose tolerance tests, as well as NAFLD activity score of liver, compared to the OLETF group. Allopurinol treatment significantly reduced hepatic steatosis, epididymal fat, serum UA, HOMA-IR, hepatic enzyme levels, and cholesterol in the OLETF-HFrD-Allo group. Additionally, allopurinol significantly downregulated expression of lipogenic genes, upregulated lipid oxidation genes, downregulated hepatic pro-inflammatory cytokine genes, and decreased ER-stress induced protein expression, in comparison with the OLETF-HFrD group. In conclusion, allopurinol ameliorates HFrD-induced hepatic steatosis through modulation of hepatic lipid metabolism, inflammation, and ER stress pathway. UA may have a direct role in development of fructose-induced hepatic steatosis, and allopurinol could be a candidate for prevention or treatment of NAFLD.

Fenofibrate, a PPARα agonist, reduces hepatic fat accumulation through the upregulation of TFEB-mediated lipophagy.

BACKGROUND: Recent studies have shown that dysregulation of autophagy is involved in the development of nonalcoholic fatty liver disease (NAFLD). Transcription factors E3 (TFE3) and EB (TFEB) are master regulators of the transcriptional response of basic cellular processes such as lysosomal biogenesis and autophagy. Here, we investigated the role of fenofibrate, a PPARα agonist, in promotion of intracellular lipid clearance by upregulation of TFEB/TFE3. METHODS: We investigated whether the effects of fenofibrate on livers were dependent on TFEB in high fat diet (HFD)-fed mice and in vivo Tfeb knockdown mice. These mice were analyzed for characteristics of obesity and diabetes; the effects of fenofibrate on hepatic fat content, glucose sensitivity, insulin resistance, and autophagy functional dependence on TFEB were investigated. HepG2, Hep3B, TSC2+/+ and tsc2-/- MEFs, tfeb wild type- and tfeb knockout-HeLa cells were used for in vitro experiments. RESULTS: Fenofibrate treatment activated autophagy and TFEB/TFE3 and reduced hepatic fat accumulation in an mTOR-independent manner. Knockdown of TFEB offset the effects of fenofibrate on autophagy and hepatic fat accumulation. In addition, fenofibrate treatment induced lysosomal Ca2+ release through mucolipin 1, activated calcineurin and the CaMKKß-AMPK-ULK1 pathway, subsequently promoted TFEB and TFE3 dephosphorylation and nuclear translocation. Treatment with calcium chelator or knockdown of mucolipin 1 in hepatocytes offset the effects of fenofibrate treatment on autophagy and hepatic fat accumulation. CONCLUSION: Activation of PPARα ameliorates hepatic fat accumulation via activation of TFEB and lipophagy induction. Lysosomal calcium signaling appears to play a critical role in this process. In addition, activation of TFEB by modulating nuclear receptors including PPARα with currently available drugs or new molecules might be a therapeutic target for treatment of NAFLD and other cardiometabolic diseases.

Low Skeletal Muscle Mass Is Associated With the Presence, Incidence, and Progression of Coronary Artery Calcification.

BACKGROUND: Low skeletal muscle mass (SMM) is an emerging risk factor of cardiovascular disease (CVD). We investigated the association between SMM and coronary artery calcification (CAC). METHODS: We enrolled 19,728 adults free of CVD who underwent computed tomographic estimation of Agatston CAC scores for cross-sectional analysis. Among them, 5,401 subjects who had at least 2 follow-up CAC scores were included in longitudinal analysis. Relative SMM is presented as the skeletal muscle mass index [SMI (%) = total appendicular muscle mass (kg)/body weight (kg) × 100]. CAC presence and incidence were defined as CAC score > 0, and CAC progression was defined as √CAC score (follow-up) - √CAC score (baseline) > 2.5. RESULTS: Among all of the subjects (mean age 53.4 years, 80.8% male), the prevalence of CAC was 36.7%. The incidence of CAC was 17.4% during a mean of 3.6 years, and the progression of CAC was 49.9% during a mean of 2.3 years. The lowest SMI quartile was significantly associated with an increased risk of CAC presence (adjusted odds ratio 2.75, 95% confidence interval [CI] 2.45-3.05; P < 0.001), incidence (adjusted hazard ratio [AHR] 1.99, 95% CI 1.36-2.91; P < 0.001), and progression (AHR 1.48, 95% CI 1.25-1.77; P < 0.001) compared with the highest quartile. SMI as a continuous value was also significantly inversely associated with CAC. SMI was the best parameter to be related to CAC among other quantitative indices such as height or body mass index adjusted. CONCLUSIONS: Low SMM is significantly associated with an elevated risk of CAC, independently of other cardiometabolic parameters.

Increased Visit-to-Visit Liver Enzyme Variability Is Associated with Incident Diabetes: A Community-Based 12-Year Prospective Cohort Study.

BACKGROUND: Fatty liver and/or increased liver enzyme values have been reported to be associated with incident diabetes. We sought to determine whether increased visit-to-visit liver enzyme variability is associated with incident diabetes. METHODS: Study participants were recruited from the Korean Genome and Epidemiologic Study (KoGES). A total of 4,151 people aged 40 to 69 years was recruited and tested every 2 years for up to 12 years. Visit-to-visit aspartate aminotransferase (AST) and alanine aminotransferase (ALT) variability was evaluated in first the 6-year period through the use of various variability measurements: standard deviation (SD), average successive variability, coefficient of variation (CV), and variation independent of mean (VIM). Oral glucose tolerance test was performed at every visit. RESULTS: During the 6-year follow-up appointments, 13.0% (538/4,151) of people developed incident diabetes. Visit-to-visit AST variability was associated with an increased risk of diabetes independent of conventional risk factors for diabetes (hazard ratio per 1-SD increment [95% confidence interval]: 1.06 [1.00 to 1.11], 1.12 [1.04 to 1.21], and 1.13 [1.04 to 1.22] for SD, CV, and VIM, respectively; all P<0.05); however, no such associations were observed in the visit-to-visit ALT variability. According to alcohol consumption status, both AST and ALT variability were independent predictors for incident diabetes in subjects with heavy alcohol consumption; however, neither AST nor ALT variability was associated with diabetes risk in subjects who did not drink alcohol heavily. CONCLUSION: Visit-to-visit liver enzyme variability is an independent predictor of incident diabetes. Such association was more evident in those who consumed significant amounts of alcohol.

Pancreatic fat accumulation is associated with decreased ß-cell function and deterioration in glucose tolerance in Korean adults.

AIMS: This study was designed to investigate the association between pancreatic fat content (PFC) and insulin secretory capacity as well as glucose tolerance in Korean adults. MATERIALS: A total of 39 participants (mean age 49.9 years, 53% males) without a previous history of diabetes, or those previously diagnosed as having diabetes but with less than 10 years of disease duration and no medication history were included. They were stratified according to the results of the oral glucose tolerance test (OGTT): normal glucose tolerance, prediabetes, and diabetes. METHODS: All participants underwent the proton magnetic resonance spectroscopy (1 H-MRS) to assess PFC. Insulin sensitivity and ß-cell function were measured by the frequently sampled intravenous glucose tolerance tests (FSIVGTT) and OGTT-derived indices. RESULTS: As glucose tolerance deteriorated, parameters such as Stumvoll index, oral glucose insulin sensitivity index, homeostatic model assessment (HOMA)-ß, insulinogenic index and oral disposition index from the OGTT, and acute insulin response to glucose (AIR) and disposition index (DI) from the FSIVGTT were decreased. PFC increased with deterioration in glucose tolerance (NGT: 12.0%, prediabetes: 23.7%, and diabetes: 31.9%). Correlation analysis indicated that glucose levels at 60 and 120 min during the OGTT were positively correlated with PFC. Also, there was a significant negative correlation between PFC and DI as well as AIR derived from the FSIVGTT. CONCLUSIONS: PFC evaluated by 1 H-MRS in Korean adults was higher in those diagnosed with diabetes than those with normal glucose tolerance status. PFC also showed a significant negative correlation with indices reflecting beta cell function.

The association between lipoprotein (a) and carotid atherosclerosis in patients with type 2 diabetes without pre-existing cardiovascular disease: A cross-sectional study.

AIMS: Lipoprotein (a) [Lp(a)] has been considered a determinant of residual cardiovascular risk. We aimed to investigate associations between serum Lp(a) levels and carotid atherosclerosis. METHODS: This cross-sectional study included 662 type 2 diabetic patients without cardiovascular disease. The mean value of three right and left measurements was used to indentify increased carotid intima-media thickness (CIMT). A carotid plaque was defined as a focal wall thickening >50% of the surrounding IMT or its CIMT ≥1.5 mm. The presence of carotid atherosclerosis was defined as having CIMT ≥1.0 mm or carotid plaque. RESULTS: A total of 34.3% of patients had carotid atherosclerosis. The median Lp(a) level was significantly higher in subjects with carotid atherosclerosis (14.6 vs. 10.2 mg/dL, P < 0.001). The log-transformed Lp(a) level per 1-standard deviation increase was significantly associated with higher risk of the presence of carotid atherosclerosis (odds ratio [OR] 1.46; 95% confidence interval [CI] 1.16 - 1.84, P = 0.001) after adjusting other parameters. The log Lp(a) level was still significantly associated with the risk of carotid atherosclerosis in subjects with optimal low-density lipoprotein cholesterol (LDL-C) <100 mg/dL (OR 1.48; 95% CI 1.16 - 1.88, P = 0.001). Higher Lp(a) and LDL-C had an additive effect on the presence of carotid atherosclerosis. CONCLUSION: Elevated Lp(a) was significantly associated with the presence of carotid atherosclerosis in patients with type 2 diabetes, independent of conventional cardiometabolic risk factors.

Clinical Characteristics and Prevalence of Comorbidities according to Metformin Use in Korean Patients with Type 2 Diabetes.

METHODS: This cross-sectional study based on the Korean National Diabetes Program 2 registry used its baseline clinical data collected from seven participating university hospitals in Korea. Patients with no significant changes in their oral hypoglycemic agents and no diabetes-related complications within the year prior to participation were enrolled. Patients' clinical characteristics according to metformin use were analyzed. RESULTS: Among 858 subjects included in the analyses, 706 were metformin users and 152 were nonmetformin users. Metformin users were significantly younger and had higher and glycated hemoglobin with significantly lower rates of accompanying microvascular complications such as retinopathy, cataracts, overt proteinuria, renal insufficiency, and peripheral neuropathy than nonusers. Meanwhile, there was a significantly lower prevalence of malignancy and depression among metformin users. These associations remained significant in multivariate analyses. The prevalence rate of macrovascular complications was not significantly different between the two groups. CONCLUSIONS: There were significant differences with respect to clinical characteristics and comorbidity prevalence according to metformin use among Korean type 2 diabetes patients. Long-term follow-up of these patients is necessary to observe how this difference will affect clinical outcomes for these patients.