Publications by authors named "Bong-Soo Cha"

248 Publications

Ipragliflozin, an SGLT2 Inhibitor, Ameliorates High-Fat Diet-Induced Metabolic Changes by Upregulating Energy Expenditure through Activation of the AMPK/SIRT1 Pathway.

Diabetes Metab J 2021 Feb 22. Epub 2021 Feb 22.

Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.

Background: Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new class of antidiabetic drugs that exhibit multiple extraglycemic effects. However, there are conflicting results regarding the effects of SGLT2 inhibition on energy expenditure and thermogenesis. Therefore, we investigated the effect of ipragliflozin (a selective SGLT2 inhibitor) on energy metabolism.

Methods: Six-week-old male 129S6/Sv mice with a high propensity for adipose tissue browning were randomly assigned to three groups: normal chow control, 60% high-fat diet (HFD)-fed control, and 60% HFD-fed ipragliflozin-treated groups. The administration of diet and medication was continued for 16 weeks.

Results: The HFD-fed mice became obese and developed hepatic steatosis and adipose tissue hypertrophy, but their random glucose levels were within the normal ranges; these features are similar to the metabolic features of a prediabetic condition. Ipragliflozin treatment markedly attenuated HFD-induced hepatic steatosis and reduced the size of hypertrophied adipocytes to that of smaller adipocytes. In the ipragliflozin treatment group, uncoupling protein 1 (Ucp1) and other thermogenesis-related genes were significantly upregulated in the visceral and subcutaneous adipose tissue, and fatty acid oxidation was increased in the brown adipose tissue. These effects were associated with a significant reduction in the insulin-to-glucagon ratio and the activation of the AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1) pathway in the liver and adipose tissue.

Conclusion: SGLT2 inhibition by ipragliflozin showed beneficial metabolic effects in 129S6/Sv mice with HFD-induced obesity that mimics prediabetic conditions. Our data suggest that SGLT2 inhibitors, through their upregulation of energy expenditure, may have therapeutic potential in prediabetic obesity.
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http://dx.doi.org/10.4093/dmj.2020.0187DOI Listing
February 2021

Nonalcoholic fatty liver disease, diastolic dysfunction, and impaired myocardial glucose uptake in patients with type 2 diabetes.

Diabetes Obes Metab 2021 Apr 15;23(4):1041-1051. Epub 2021 Jan 15.

Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.

Aims: To investigate whether degree of nonalcoholic fatty liver disease (NAFLD) is associated with myocardial dysfunction related to impaired myocardial glucose uptake in patients with type 2 diabetes.

Materials And Methods: In total, 131 patients with type 2 diabetes from a tertiary care hospital were included in this study. Myocardial glucose uptake was assessed using [ F]-fluorodeoxyglucose-positron emission tomography. Hepatic steatosis and fibrosis were determined using transient liver elastography. Echocardiography was performed to evaluate cardiac structure and function.

Results: Patients with NAFLD had cardiac diastolic dysfunction with higher left ventricular filling pressure (E/e' ratio) and left atrial (LA) volume index than patients without NAFLD (all P < 0.05). Hepatic steatosis correlated with E/e' ratio and LA volume index, and hepatic fibrosis also correlated with E/e' ratio (all P < 0.05). Even after adjusting for confounding factors, a higher degree of hepatic steatosis (r = 0.409, P = 0.041) and a higher degree of fibrosis (r = 0.423, P = 0.009) were independent contributing factors to a higher E/e' ratio. Decreased myocardial glucose uptake was associated with a higher degree of steatosis (P for trend = 0.084) and fibrosis (P for trend = 0.012). At the same time, decreased myocardial glucose uptake was an independent contributing factor for a higher E/e' ratio (r = 0.409; P = 0.040).

Conclusions: Hepatic steatosis and fibrosis were significantly associated with diastolic heart dysfunction in patients with type 2 diabetes coupled with impaired myocardial glucose uptake.
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http://dx.doi.org/10.1111/dom.14310DOI Listing
April 2021

Effect of Switching from Linagliptin to Teneligliptin Dipeptidyl Peptidase-4 Inhibitors in Older Patients with Type 2 Diabetes Mellitus.

Diabetes Metab Syndr Obes 2020 2;13:4113-4121. Epub 2020 Nov 2.

Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.

Introduction: Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely prescribed for type 2 diabetes (T2D) and their glycemic control effects are well studied. However, information regarding the effects of switching DPP-4 inhibitors is limited, especially in older patients.

Research Design And Methods: We investigated whether switching from linagliptin to teneligliptin decreases blood glucose in older (≥65 years) T2D patients. In total, 164 patients with T2D who switched from linagliptin to teneligliptin for >12 weeks were included and the primary outcome was glycemic changes.

Results: Switching from linagliptin to teneligliptin ameliorated fasting blood glucose (148.1 ± 47.1 to 139.6 ± 43.4 mg/dL), glycated hemoglobin (HbA1c; 7.9 ± 1.3 to 7.5 ± 1.2%), and postprandial blood glucose (224.8 ± 77.4 to 205.8 ± 70.8 mg/dL) levels (all P < 0.05). Low-density lipoprotein cholesterol concentration was reduced while liver and kidney functions were maintained. Subgroup analysis showed that glucose control improved more in patients with uncontrolled hyperglycemia (HbA1c > 8.0%) and chronic kidney disease (estimated glomerular filtration rate <90 mL/min/1.73m). Multiple logistic analysis indicated higher baseline HbA1c was the strongest predictor of teneligliptin switching response.

Conclusion: Switching from linagliptin to teneligliptin helps maintain kidney function and reduce blood glucose safely in older patients with T2D.
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http://dx.doi.org/10.2147/DMSO.S267994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646502PMC
November 2020

Dipeptidyl peptidase-4 inhibitor protects against non-alcoholic steatohepatitis in mice by targeting TRAIL receptor-mediated lipoapoptosis via modulating hepatic dipeptidyl peptidase-4 expression.

Sci Rep 2020 11 10;10(1):19429. Epub 2020 Nov 10.

Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.

Dipeptidyl peptidase-4 inhibitors (DPP4i) are antidiabetic medications that prevent cleavage of incretin hormones by dipeptidyl peptidase-4 (DPP4). DPP4 is ubiquitously expressed, and its hepatic DPP4 expression is upregulated under non-alcoholic steatohepatitis (NASH) conditions. We investigated the effect of DPP4i treatment on NASH pathogenesis, as well as its potential underlying molecular mechanisms. Mice were randomly divided into three groups: Group 1, chow-fed mice treated with vehicle for 20 weeks; Group 2, high-fat, high-fructose, and high-cholesterol Amylin liver NASH (AMLN) diet-fed mice treated with vehicle for 20 weeks; Group 3, AMLN diet-fed mice treated with vehicle for the first 10 weeks, followed by the DPP4i teneligliptin (20 mg/kg/day) for additional 10 weeks. DPP4i administration reduced serum liver enzyme and hepatic triglyceride levels and markedly improved hepatic steatosis and fibrosis in the AMLN diet-induced NASH model. In vivo, NASH alleviation significantly correlated with the suppression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-mediated apoptosis and downregulated hepatic DPP4 expression. In vitro, DPP4i treatment significantly decreased the markers of TRAIL receptor-mediated lipoapoptosis and suppressed DPP4 expression in palmitate-treated hepatocytes. In conclusion, DPP4i may efficiently attenuate the pathogenesis of AMLN diet-induced NASH in mice by suppressing lipotoxicity-induced apoptosis, possibly by modulating hepatic DPP4 expression.
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http://dx.doi.org/10.1038/s41598-020-75288-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655829PMC
November 2020

Hepatic fibrosis is associated with total proteinuria in Korean patients with type 2 diabetes.

Medicine (Baltimore) 2020 Aug;99(33):e21038

Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.

The association between non-alcoholic fatty liver disease (NAFLD) and diabetic kidney disease assessed using either albuminuria or proteinuria remains controversial. This study aimed to investigate the association between hepatic steatosis or fibrosis and albuminuria or proteinuria in Korean patients with type 2 diabetes mellitus (T2D).We enrolled 1108 patients with T2D and categorized as 3 groups; non-proteinuria (NP), isolated non-albumin proteinuria (iNAP), and albuminuria. Urinary albumin and protein levels were assessed as urinary albumin-to-creatinine ratio (uACR) and urinary protein-to-creatinine ratio (uPCR), respectively. Hepatic steatosis and fibrotic burden were assessed using the NAFLD liver fat score, Fibrosis-4 calculator (FIB-4) index, and NAFLD fibrosis score (NFS).The prevalence of significant steatosis was similar among groups (NP: 74.6% vs iNAP: 70.3% vs albuminuria: 79.9%, P = .085). The prevalence of significant fibrosis was significantly higher in the iNAP (18.7%) and albuminuria (16.5%) groups than in the NP group (9.5%, P = .001). Both uPCR and uACR showed a correlation with NFS (uPCR: r = 0.123, P < .001; uACR: r = 0.064, P = .033). In multivariate logistic regression analysis, uPCR ≥150 mg/g was found to have a stronger association with hepatic fibrosis than uACR ≥30 mg/g (adjusted odds ratio 1.55 [95% CI 1.03-2.33] vs adjusted odds ratio 1.16 [95% CI, 0.72-1.87]).In conclusion, patients with iNAP and albuminuria had a higher prevalence of hepatic fibrosis than those without proteinuria. Total proteinuria was associated with advanced liver fibrosis, whereas albuminuria was related to hepatic steatosis.
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http://dx.doi.org/10.1097/MD.0000000000021038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437801PMC
August 2020

Association Between Serum Bilirubin and the Progression of Carotid Atherosclerosis in Type 2 Diabetes.

J Lipid Atheroscler 2020 Jan 13;9(1):195-204. Epub 2020 Jan 13.

Huh's Diabetes Center and the 21st Century Diabetes and Vascular Research Institute, Seoul, Korea.

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; =0.008). Age (<0.001), body mass index (=0.023), and TC (=0.019) were also associated with the progression of carotid atherosclerosis in T2DM patients.

Conclusion: Total serum bilirubin is independently associated with progression of atherosclerosis in the carotid arteries in T2DM patients.
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http://dx.doi.org/10.12997/jla.2020.9.1.195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7379078PMC
January 2020

Non-alcoholic steatohepatitis and progression of carotid atherosclerosis in patients with type 2 diabetes: a Korean cohort study.

Cardiovasc Diabetol 2020 06 13;19(1):81. Epub 2020 Jun 13.

Huh's Diabetes Center and the 21st Century Diabetes and Vascular Research Institute, Seoul, Korea.

Background: There is increasing concern regarding cardiovascular risk in individuals with non-alcoholic fatty liver disease. This study was conducted to evaluate whether hepatic steatosis with or without fibrosis is associated with the progression of carotid atherosclerosis in patients with type 2 diabetes.

Methods: From a longitudinal cohort, we enrolled 1120 patients with type 2 diabetes who underwent repeated carotid artery ultrasonography every 1-2 years. Ultrasonographic findings at baseline and after 6-8 years were compared. Presence of hepatic steatosis was mainly assessed by abdominal ultrasonography; patients with hepatic steatosis were further evaluated for hepatic fibrosis according to fibrosis-4 index. We investigated the association between liver status and atherosclerosis progression.

Results: Of 1120 patients, 636 (56.8%) were classified as having hepatic steatosis at baseline. After 6-8 years, 431 (38.5%) showed atherosclerosis progression. Hepatic steatosis was significantly associated with atherosclerosis progression (adjusted odds ratio[AOR]: 1.370, 95% CI 1.025-1.832; p < 0.05). Among patients with hepatic steatosis, only individuals with fibrosis showed significant association with atherosclerosis progression (AOR: 1.615, 95% CI 1.005-2.598; p < 0.05). The association between hepatic fibrosis and atherosclerosis progression was significant in all metabolic subgroups regardless of age, body mass index, presence of metabolic syndrome, or insulin sensitivity (all p < 0.05). Furthermore, subjects with hepatic steatosis & fibrosis and ≥ 4 components of metabolic syndrome criteria showed markedly increased risk of atherosclerosis progression (AOR: 2.430, 95% CI 1.087-5.458; p < 0.05).

Conclusions: Hepatic steatosis with fibrosis is independently associated with the progression of carotid atherosclerosis in patients with type 2 diabetes.
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http://dx.doi.org/10.1186/s12933-020-01064-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293796PMC
June 2020

Non-Alcoholic Fatty Liver Disease in Patients with Type 2 Diabetes Mellitus: A Position Statement of the Fatty Liver Research Group of the Korean Diabetes Association.

Diabetes Metab J 2020 06 11;44(3):382-401. Epub 2020 May 11.

Division of Endocrinology and Metabolism, Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, Korea.

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.
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http://dx.doi.org/10.4093/dmj.2020.0010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332334PMC
June 2020

Efficacy and safety of lobeglitazone versus sitagliptin as an add-on to metformin in patients with type 2 diabetes with two or more components of metabolic syndrome over 24 weeks.

Diabetes Obes Metab 2020 10 18;22(10):1869-1873. Epub 2020 Jun 18.

Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, South Korea.

We aimed to evaluate the efficacy and safety profile of lobeglitazone compared with sitagliptin as an add-on to metformin in patients with type 2 diabetes as well as other components of metabolic syndrome. Patients inadequately controlled by metformin were randomly assigned to lobeglitazone (0.5 mg, n = 121) or sitagliptin (100 mg, n = 126) for 24 weeks. The mean changes in HbA1c of the lobeglitazone and sitagliptin groups were -0.79% and -0.86%, respectively; the between-group difference was 0.08% (95% confidence interval, -0.14% to 0.30%), showing non-inferiority. The proportion of patients having two or more factors of other metabolic syndrome components decreased to a greater extent in the lobeglitazone group than in the sitagliptin group (-11.9% vs. -4.8%; P < .0174). Favourable changes in the lipid metabolism were also observed with lobeglitazone, which had a similar safety profile to sitagliptin. Lobeglitazone was comparable with sitagliptin as an add-on to metformin in terms of efficacy and safety.
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http://dx.doi.org/10.1111/dom.14085DOI Listing
October 2020

SGLT2 inhibition modulates NLRP3 inflammasome activity via ketones and insulin in diabetes with cardiovascular disease.

Nat Commun 2020 05 1;11(1):2127. Epub 2020 May 1.

Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.

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.
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http://dx.doi.org/10.1038/s41467-020-15983-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195385PMC
May 2020

Gamma glutamyltransferase and risk of dementia in prediabetes and diabetes.

Sci Rep 2020 04 22;10(1):6800. Epub 2020 Apr 22.

Graduate School, Yonsei University College of Medicine, Seoul, Korea.

Diabetes is associated with cognitive impairment and greater risk for dementia, but the role of gamma-glutamyltransferase (γ-GT) in dementia has not been elucidated. We determined incident dementia including Alzheimer's disease and vascular dementia, analyzing data from participants aged 40 years or older in the National Health Insurance Database, collected by the National Health Insurance Service in Korea, from January 2009 to December 2015. During a median follow-up of 7.6 years, 272,657 participants were diagnosed as having dementia. Higher serum γ-GT was associated with increased risk of dementia (HR = 1.22, 95% CI = 1.20-1.24), and had a strong positive association with early onset dementia (HR = 1.32, 95% CI = 1.24-1.40). An additive impact of higher γ-GT on dementia was observed regardless of glycemic status, and prevalent diabetes with the highest γ-GT quartile had a 1.8-fold increased dementia risk (HR = 1.82, 95% CI = 1.78-1.85). This effect of γ-GT concentration in diabetes was more prominent in individuals with vascular dementia (HR = 1.94, 95% CI = 1.84-2.04). In subgroup analysis, young age, male sex, and relatively healthy subjects with a higher γ-GT quartile had more increased dementia risk. In conclusion, γ-GT concentration as well as glycemic status could be a future risk factor for dementia in the general population.
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http://dx.doi.org/10.1038/s41598-020-63803-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176727PMC
April 2020

Comparison of Renal Effects of Ezetimibe-Statin Combination versus Statin Monotherapy: A Propensity-Score-Matched Analysis.

J Clin Med 2020 Mar 15;9(3). Epub 2020 Mar 15.

Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea.

Neither lowering of blood lipid levels nor treatment with statins definitively improves renal outcomes. Ezetimibe, a non-statin antilipidemic agent, is known to not only decrease blood lipid levels but also reduce inflammatory response and activate autophagy. We evaluated the effect of adding ezetimibe to a statin on renal outcome compared with statin monotherapy by analyzing longitudinal data of 4537 patients treated with simvastatin 20 mg plus ezetimibe 10 mg (S + E) or simvastatin 20 mg alone (S) for more than 180 days. A propensity-score-based process was used to match baseline characteristics, medical history, and estimated glomerular filtration rate (eGFR) between S + E and S groups. Changes in serum creatinine and incidence of renal events, defined as doubling of serum creatinine to ≥1.5 mg/dL or occurrence of end-stage renal disease after the first day of treatment initiation, were compared between the groups. Among 3104 well-matched patients with a median follow-up of 4.2 years, the S + E group showed a significantly lower risk of renal events than the S group (hazard ratio 0.58; 95% CI 0.35-0.95, 0.032). In addition, the S + E group tended to preserve renal function compared with the S group throughout follow-up, as assessed by serum creatinine changes (-values for time-group interactions <0.001). These data support the beneficial effects on renal function when combining ezetimibe with a statin.
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http://dx.doi.org/10.3390/jcm9030798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141215PMC
March 2020

Nonalcoholic Fatty Liver Disease and Sarcopenia Are Independently Associated With Cardiovascular Risk.

Am J Gastroenterol 2020 04;115(4):584-595

Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.

Objectives: Nonalcoholic fatty liver disease (NAFLD) and sarcopenia have a close association with an increased risk of atherosclerotic cardiovascular disease (ASCVD). This study investigated the influence of NAFLD and sarcopenia on ASCVD risk.

Methods: Data from the 2008-2011 Korean National Health and Nutrition Examination Surveys database were analyzed (n = 7,191). The sarcopenia index was calculated using dual-energy x-ray absorptiometry. Sarcopenia was defined as the lowest quintile sarcopenia index value (cutoffs = 0.882 for men and 0.582 for women). NAFLD was defined as a comprehensive NAFLD score ≥40. Liver fibrosis was assessed using the fibrosis-4 (FIB-4) index. ASCVD risk was evaluated using American College of Cardiology/American Heart Association guidelines. High probability of ASCVD was defined as ASCVD risk >10%.

Results: The prevalence rates of NAFLD and sarcopenia were 31.2% (n = 2,241) and 19.5% (n = 1,400), respectively. The quartile-stratified ASCVD risk scores were positively associated with NAFLD and sarcopenia (all P for trend < 0.001). Subjects with both NAFLD and sarcopenia had a higher risk for high probability of ASCVD (odds ratio = 1.83, P = 0.014) compared with controls without NAFLD and sarcopenia. Among subjects with NAFLD, FIB-4-defined significant liver fibrosis and sarcopenia additively raised the risk for high probability of ASCVD (odds ratio = 3.56, P < 0.001) compared with controls without FIB-4-defined significant liver fibrosis or sarcopenia.

Discussion: NAFLD and sarcopenia were significantly associated with an increased risk of ASCVD in the general population. In addition, NAFLD with significant liver fibrosis and sarcopenia were significantly associated with an increased risk of ASCVD in subjects with NAFLD.
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http://dx.doi.org/10.14309/ajg.0000000000000572DOI Listing
April 2020

A novel non-PPARgamma insulin sensitizer: MLR-1023 clinicalproof-of-concept in type 2 diabetes mellitus.

J Diabetes Complications 2020 05 2;34(5):107555. Epub 2020 Feb 2.

Pennington Biomedical Research Center, 6400 Perkins Rd, Baton Rouge, LA 70808, USA. Electronic address:

Aim: MLR-1023, called Tolimidone when evaluated unsuccessfully by Pfizer for gastric ulcer disease, has been repurposed as a novel oral insulin sensitizer with its effects mediated by selective activation of Lyn kinase. We aimed to evaluate the optimal dose, efficacy and safety of MLR-1023 in patients with type 2 diabetes.

Methods: Type 2 diabetes patients (18-75 years) on diet/exercise therapy were randomized and double-blinded to receive MLR-1023 (100-mg or 200-mg, once-daily [qd] or twice-daily [bid]) or matching placebo for 28 days. The primary endpoint was postprandial glucose (PPG) area under the curve (AUC) in a mixed meal tolerance test (MMTT) at day 29. Secondary endpoints included changes in fasting plasma glucose (FPG), insulin, HbA1c, lipids and body weight and adverse events. ANCOVA model was used for efficacy analysis.

Results: The placebo-corrected least-squares mean differences (ΔLSM) in MMTT PPG AUC0-3 h (mmol/L) were -5.96 and -5.6 (both p = 0.03) in the MLR-1023 100-mg qd and 100-mg bid groups, respectively. The placebo-corrected ΔLSM in FPG (mmol/L) was -2.34 (p = 0.003) in the MLR-1023 100-mg qd group. Triglycerides improved with MLR-1023 (ΔLSM, -0.56 mmol/L, p = 0.07 and -0.59 mmol/L, p = 0.05) in the 200mgqd and 200 mg bid groups, respectively. Reductions in fasting insulin, HbA1c and body weight were not statistically significant. Most common adverse events with MLR-1023 treatment were headache (4.2%) and somnolence (2.5%).

Conclusions: MLR-1023 100-mg once-daily for 4 weeks was the most effective dose with significant reduction in PPG AUC following a MMTT. MLR-1023 was safe and well-tolerated in patients with type 2 diabetes. Clinical Trials Registration Number: NCT02317796.
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http://dx.doi.org/10.1016/j.jdiacomp.2020.107555DOI Listing
May 2020

Ipragliflozin Additively Ameliorates Non-Alcoholic Fatty Liver Disease in Patients with Type 2 Diabetes Controlled with Metformin and Pioglitazone: A 24-Week Randomized Controlled Trial.

J Clin Med 2020 Jan 18;9(1). Epub 2020 Jan 18.

Division of Endocrinology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea.

Despite the benefits of pioglitazone in the treatment of non-alcoholic fatty liver disease (NAFLD), many treated patients continue to experience disease progression. We aimed to investigate the additive effect of ipragliflozin on NAFLD in patients with type 2 diabetes treated with metformin and pioglitazone. In this 24-week randomized controlled trial, 44 patients with type 2 diabetes and comorbid NAFLD were either randomized to receive 50 mg/day of ipragliflozin as an add-on treatment ( = 29) or maintained on metformin and pioglitazone ( = 15). The fatty burden was assessed using the fatty liver index, NAFLD liver fat score, and controlled attenuation parameter (CAP). Changes in fat and muscle depots were measured by dual-energy x-ray absorptiometry and abdominal computed tomography scans. The enrolled patients were relatively controlled (mean baseline glycated hemoglobin of 6.6% ± 0.6%) and centrally obese (mean waist circumference of 101.6 ± 10.9 cm). At week 24, patients in the ipragliflozin add-on group exhibited reduced hepatic fat content (fatty liver index: -9.8 ± 1.9, = 0.002; NAFLD liver fat score: -0.5 ± 0.2, = 0.049; CAP: -8.2 ± 7.8 dB/m, = 0.133). Ipragliflozin add-on therapy also reduced whole-body visceral fat and the ratio of visceral to subcutaneous fat (change in whole-body visceral fat: -69.6 ± 21.5 g; change in abdominal visceral fat: -26.2 ± 3.7 cm; abdominal visceral to subcutaneous fat ratio: -0.15 ± 0.04; all < 0.05). In conclusion, ipragliflozin treatment significantly ameliorates liver steatosis and reduces excessive fat in euglycemic patients with type 2 diabetes and NAFLD taking metformin and pioglitazone.
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http://dx.doi.org/10.3390/jcm9010259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019437PMC
January 2020

Proteinuria is Associated with Carotid Artery Atherosclerosis in Non-Albuminuric Type 2 Diabetes: A Cross-Sectional Study.

J Clin Med 2020 Jan 3;9(1). Epub 2020 Jan 3.

Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea.

The association of specific urinary proteins other than albumin with cardiovascular (CV) outcomes in patients with type 2 diabetes (T2D) has been shown. In this respect, CV outcomes may differ in non-albuminuric T2D patients who were considered as a low risk group, according to the presence of proteinuria. We investigated the association between proteinuria and atherosclerosis assessed by carotid artery intima-media thickness (CIMT) in non-albuminuric T2D patients. 2047 T2D patients whose urine albumin-to-creatinine ratio was below 30 mg/g were recruited and classified into a non-proteinuria (NP, uPCR < 150 mg/g, n = 1865) group and a non-albuminuric proteinuria (NAP, uPCR ≥ 150 mg/g, n = 182) group. CIMT was compared between the two groups and logistic regression analysis was conducted to verify whether proteinuria could predict deteriorated CIMT status. In this cross-sectional study, mean CIMT of the NAP group were significantly thicker than those of the NP group (0.73 ± 0.16 vs. 0.70 ± 0.14, p = 0.016). The presence of proteinuria is associated with deteriorated CIMT after the adjustment for conventional risk factors (odds ratio, 2.342; 95% confidence interval, 1.082-5.070, p = 0.030) in regression analysis. We postulated that the measurement of urinary protein in conjunction with albumin might be helpful for predicting atherosclerosis, especially for non-albuminuric patients.
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http://dx.doi.org/10.3390/jcm9010136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019294PMC
January 2020

Efficacy and Safety of Gemigliptin in Post-Transplant Patients With Type 2 Diabetes Mellitus.

Transplant Proc 2019 Dec 14;51(10):3444-3448. Epub 2019 Nov 14.

Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address:

Background: 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).

Methods: 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.

Results: 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.

Conclusion: 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.
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http://dx.doi.org/10.1016/j.transproceed.2019.07.015DOI Listing
December 2019

Corrigenda: Table Correction. Nonalcoholic Fatty Liver Disease in Diabetes. Part I: Epidemiology and Diagnosis.

Diabetes Metab J 2019 Oct;43(5):731

Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.

This corrects the article on p. 31 in vol. 43, PMID: 30793550.
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http://dx.doi.org/10.4093/dmj.2019.0188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834842PMC
October 2019

The Effectiveness of Intermittent Fasting to Reduce Body Mass Index and Glucose Metabolism: A Systematic Review and Meta-Analysis.

J Clin Med 2019 Oct 9;8(10). Epub 2019 Oct 9.

Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea.

The effects of an intermittent fasting diet (IFD) in the general population are still controversial. In this study, we aimed to systematically evaluate the effectiveness of an IFD to reduce body mass index and glucose metabolism in the general population without diabetes mellitus. Cochrane, PubMed, and Embase databases were searched to identify randomized controlled trials and controlled clinical trials that compared an IFD with a regular diet or a continuous calorie restriction diet. The effectiveness of an IFD was estimated by the weighted mean difference (WMD) for several variables associated with glucometabolic parameters including body mass index (BMI) and fasting glucose. The pooled mean differences of outcomes were calculated using a random effects model. From 2814 studies identified through a literature search, we finally selected 12 articles (545 participants). Compared with a control diet, an IFD was associated with a significant decline in BMI (WMD, -0.75 kg/m; 95% CI, -1.44 to -0.06), fasting glucose level (WMD, -4.16 mg/dL; 95% CI, -6.92 to -1.40), and homeostatic model assessment of insulin resistance (WMD, -0.54; 95% CI, -1.05 to -0.03). Fat mass (WMD, -0.98 kg; 95% CI, -2.32 to 0.36) tended to decrease in the IFD group with a significant increase in adiponectin (WMD, 1008.9 ng/mL; 95% CI, 140.5 to 1877.3) and a decrease in leptin (WMD, -0.51 ng/mL; 95% CI, -0.77 to -0.24) levels. An IFD may provide a significant metabolic benefit by improving glycemic control, insulin resistance, and adipokine concentration with a reduction of BMI in adults.
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http://dx.doi.org/10.3390/jcm8101645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832593PMC
October 2019

Current Management of Type 2 Diabetes Mellitus in Primary Care Clinics in Korea.

Endocrinol Metab (Seoul) 2019 09;34(3):282-290

Graduate School, Yonsei University College of Medicine, Seoul, Korea.

Background: This study investigated the overall status of diabetes control and screening for diabetic microvascular complications in patients with type 2 diabetes mellitus attending primary care clinics in Korea.

Methods: In this cross-sectional observational study, 191 primary care clinics were randomly selected across Korea from 2015 to 2016. In total, 3,227 subjects were enrolled in the study.

Results: The patients followed at the primary care clinics were relatively young, with a mean age of 61.4±11.7 years, and had a relatively short duration of diabetes (mean duration, 7.6±6.5 years). Approximately 14% of subjects had diabetic microvascular complications. However, the patients treated at the primary care clinics had suboptimal control of hemoglobin A1c levels, blood pressure, and serum lipid levels, along with a metabolic target achievement rate of 5.9% according to the Korean Diabetes Association guidelines. The screening rates for diabetic nephropathy, retinopathy, and neuropathy within the past 12 months were 28.4%, 23.3%, and 13.3%, respectively.

Conclusion: The overall status of diabetes management, including the frequency of screening for microvascular complications, was suboptimal in the primary care clinics. More efforts should be made and more resources need to be allocated for primary care physicians to promote adequate healthcare delivery, which would result in stricter diabetes control and improved management of diabetic complications.
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http://dx.doi.org/10.3803/EnM.2019.34.3.282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769344PMC
September 2019

Predictive factors for the development of diabetes in cancer patients treated with phosphatidylinositol 3-kinase inhibitors.

Cancer Chemother Pharmacol 2019 08 27;84(2):405-414. Epub 2019 Jun 27.

Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.

Purpose: 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.

Methods: 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.

Results: 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.

Conclusions: 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.
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http://dx.doi.org/10.1007/s00280-019-03889-0DOI Listing
August 2019

Glucometabolic characteristics and higher vascular complication risk in Korean patients with type 2 diabetes with non-albumin proteinuria.

J Diabetes Complications 2019 08 28;33(8):585-591. Epub 2019 May 28.

Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address:

Objective: We investigated the clinical relevance of non-albumin proteinuria (NAP) in Korean patients with type 2 diabetes (T2D).

Research Design And Methods: 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; uPCR <150 mg/g and uACR <30 mg/g), isolated NAP (iNAP; uPCR ≥150 mg/g and uACR <30 mg/g), and albuminuria (uACR ≥30 mg/g) groups. The associations between uPCR, uACR, and several indices of glucose metabolism were investigated.

Results: 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]).

Conclusions: 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.
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http://dx.doi.org/10.1016/j.jdiacomp.2019.04.014DOI Listing
August 2019

Predictive Factors for Efficacy of AST-120 Treatment in Diabetic Nephropathy: a Prospective Single-Arm, Open-Label, Multi-Center Study.

J Korean Med Sci 2019 Apr 22;34(15):e117. Epub 2019 Apr 22.

Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Background: Removal of uremic toxins such as indoxyl sulfate by AST-120 is known to improve renal function and delay the initiation of dialysis in patients with advanced chronic kidney disease. However, it is unclear whether the addition of AST-120 to conventional treatments is effective in delaying the progression of renal dysfunction in patients with diabetic nephropathy.

Methods: A total of 100 patients with type 2 diabetes and renal dysfunction (serum creatinine levels ranging from 1.5 to 3.0 mg/dL) were recruited from eight centers in Korea and treated with AST-120 (6 g/day) for 24 weeks. The primary endpoint was improvement in renal function measured as the gradient of the reciprocal serum creatinine level (1/sCr) over time (i.e., the ratio of 1/sCr time slope for post- to pre-AST-120 therapy). A response was defined as a ratio change of the regression coefficient of 1/sCr ≤ 0.90.

Results: Renal function improved in 80.3% of patients (61/76) after 24 weeks of AST-120 treatment. There were no differences between responder and non-responder groups in baseline characteristics except for diastolic blood pressure (73.5 ± 9.5 mmHg in the responder group vs. 79.3 ± 11.1 mmHg in the non-responder group; = 0.046). Serum lipid peroxidation level decreased significantly in the responder group (from 2.25 ± 0.56 μol/L to 1.91 ± 0.72 μol/L; = 0.002) but not in the non-responder group.

Conclusion: The addition of AST-120 to conventional treatments may delay the progression of renal dysfunction in diabetic nephropathy. The antioxidant effect of AST-120 might contribute to improvement in renal function.
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http://dx.doi.org/10.3346/jkms.2019.34.e117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6473095PMC
April 2019

Nonalcoholic Fatty Liver Disease and Diabetes: Part II: Treatment.

Diabetes Metab J 2019 04;43(2):127-143

Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.

Nonalcoholic fatty liver disease (NAFLD) and diabetes are common metabolic disorders that are often comorbid conditions. Among many proposed treatments, weight reduction is the only approved option for NAFLD to date. However, it is not easy to maintain weight loss by lifestyle modification alone; pharmacological treatments are helpful in this regard. Although many drugs have been investigated, pioglitazone could be a first-line therapy in patients with NAFLD and diabetes. Many more drugs are currently being developed and investigated, and it is likely that combination strategies will be used for future treatment of NAFLD and diabetes. Attention should be paid to the management of NAFLD and diabetes and efforts should be made to intervene early and individualize treatment of NAFLD in patients with diabetes.
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http://dx.doi.org/10.4093/dmj.2019.0034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470100PMC
April 2019

Association between Non-Alcoholic Steatohepatitis and Left Ventricular Diastolic Dysfunction in Type 2 Diabetes Mellitus.

Diabetes Metab J 2020 04 28;44(2):267-276. Epub 2019 Feb 28.

Huh's Diabetes Center and the 21st Century Diabetes and Vascular Research Institute, Seoul, Korea.

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 steatohepatitis, 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 defined 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%, =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; for trend=0.003). In multivariable logistic regression, liver fibrosis was independently associated with diastolic dysfunction (odds ratio [OR], 1.58; 95% confidence interval [CI], 1.07 to 2.34; =0.022) after adjusting for insulin resistance and cardiometabolic risk factors. This association remained significant in patients without insulin resistance (OR, 4.32; 95% CI, 1.73 to 11.51; =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.
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http://dx.doi.org/10.4093/dmj.2019.0001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188976PMC
April 2020

Low-dose pioglitazone can ameliorate learning and memory impairment in a mouse model of dementia by increasing LRP1 expression in the hippocampus.

Sci Rep 2019 03 13;9(1):4414. Epub 2019 Mar 13.

Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.

Amyloid-β (Aβ) accumulation in the brain is a pathological feature of Alzheimer's disease (AD) and enhancing Aβ clearance is a potential therapeutic strategy. Pioglitazone is a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist and is widely used to treat type 2 diabetes. We previously reported that low-dose pioglitazone increased the expression of low-density lipoprotein receptor-related protein 1 (LRP1), which upregulates the clearance of Aβ, using human brain microvascular endothelial cells. We investigated whether low-dose pioglitazone can rescue the pathological phenotype and memory impairment in senescence-accelerated mouse prone-8 (SAMP8) mice by increasing LRP1 levels. SAMP8 mice were treated with vehicle or pioglitazone in dosages of 2 or 5 mg/kg/day for 7 weeks. In the water maze test, 2 mg/kg/day of pioglitazone significantly attenuated the increased escape latency in SAMP8 mice (p = 0.026), while 5 mg/kg/day of treatment did not. Compared with vehicle treatment, the hippocampi of SAMP8 mice with 2 mg/kg/day of pioglitazone exhibited fewer Aβ deposits and reduced Aβ levels, along with elevated LRP1 expression (p = 0.005). Collectively, our results proposed that a new therapeutic application of the PPAR-γ agonist for AD treatment should be considered at a lower dose than the conventional dose used to treat diabetes.
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http://dx.doi.org/10.1038/s41598-019-40736-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416325PMC
March 2019

Risk of Incident Dementia According to Metabolic Health and Obesity Status in Late Life: A Population-Based Cohort Study.

J Clin Endocrinol Metab 2019 07;104(7):2942-2952

Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.

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.
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http://dx.doi.org/10.1210/jc.2018-01491DOI Listing
July 2019

Nonalcoholic Fatty Liver Disease in Diabetes. Part I: Epidemiology and Diagnosis.

Diabetes Metab J 2019 02;43(1):31-45

Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.

Nonalcoholic fatty liver disease (NAFLD) and diabetes are common metabolic disorders whose prevalence rates are expected to rise worldwide, corresponding to aging and increasingly obese populations. Compared to the general population (around 25%), 50% to 70% of people with diabetes have NAFLD, and NAFLD severity (including fibrosis) tends to be worsened by the presence of diabetes. NAFLD is considered an emerging risk factor for type 2 diabetes mellitus and a contributor to the development of chronic diabetes-related complications. This reciprocal relationship demonstrates the importance of confirming suspected NAFLD in patients with diabetes. Due to the invasive nature of liver biopsy to assess NAFLD status, various alternative non-invasive modalities have been developed and validated. Here, we summarized the epidemiology of NAFLD in patients with diabetes and reviewed currently available imaging modalities and biomarker-based prediction models for their ability to detect liver steatosis and/or fibrosis.
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http://dx.doi.org/10.4093/dmj.2019.0011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6387876PMC
February 2019

Spontaneous ketonuria and risk of incident diabetes: a 12 year prospective study.

Diabetologia 2019 05 20;62(5):779-788. Epub 2019 Feb 20.

Department of Preventive Medicine, Ajou University School of Medicine, 164 World cup-ro, Yeongtong-gu, Suwon, 16499, Republic of Korea.

Aims/hypothesis: Ketones may be regarded as a thrifty fuel for peripheral tissues, but their clinical prognostic significance remains unclear. We investigated the association between spontaneous fasting ketonuria and incident diabetes in conjunction with changes in metabolic variables in a large population-based observational study.

Methods: We analysed 8703 individuals free of diabetes at baseline enrolled in the Korean Genome and Epidemiology Study, a community-based 12 year prospective study. Individuals with (n = 195) or without fasting ketonuria were matched 1:4 by propensity score. Incident diabetes was defined as fasting plasma glucose ≥7.0 mmol/l, post-load 2 h glucose ≥11.1 mmol/l on biennial OGTTs, or current use of glucose-lowering medication. Using Cox regression models, HRs for developing diabetes associated with the presence of ketonuria at baseline were analysed.

Results: Over 12 years, of the 925 participants in the propensity score-matched cohort, 190 (20.5%) developed diabetes. The incidence rate of diabetes was significantly lower in participants with spontaneous ketonuria compared with those without ketonuria (HR 0.63; 95% CI 0.41, 0.97). Results were virtually identical when participants with fasting ketonuria were compared against all participants without ketonuria (after multivariate adjustment, HR 0.66; 95% CI 0.45, 0.96). During follow-up, participants with baseline ketonuria maintained lower post-load 1 h and 2 h glucose levels and a higher insulinogenic index despite comparable baseline values.

Conclusions/interpretation: The presence of spontaneous fasting ketonuria was significantly associated with a reduced risk of diabetes, independently of metabolic variables. Our findings suggest that spontaneous fasting ketonuria may have a potential preventive role in the development of diabetes.
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http://dx.doi.org/10.1007/s00125-019-4829-xDOI Listing
May 2019

Predictors of the Therapeutic Efficacy and Consideration of the Best Combination Therapy of Sodium-Glucose Co-transporter 2 Inhibitors.

Diabetes Metab J 2019 04 25;43(2):158-173. Epub 2019 Jan 25.

Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.

Background: We investigated the predictive markers for the therapeutic efficacy and the best combination of sodium-glucose co-transporter 2 (SGLT2) inhibitors (empagliflozin, dapagliflozin, and ipragliflozin) therapy in patients with type 2 diabetes mellitus (T2DM).

Methods: A total of 804 patients with T2DM who had taken SGLT2 inhibitor as monotherapy or an add-on therapy were analyzed. Multivariate regression analyses were performed to identify the predictors of SGLT2 inhibitor response including the classes of baseline anti-diabetic medications.

Results: After adjusting for age, sex, baseline body mass index (BMI), diabetes duration, duration of SGLT2 inhibitor use, initial glycosylated hemoglobin (HbA1c) level, estimated glomerular filtration rate (eGFR), and other anti-diabetic agent usage, multivariate analysis revealed that shorter diabetes duration, higher initial HbA1c and eGFR were associated with better glycemic response. However, baseline BMI was inversely correlated with glycemic status; lean subjects with well-controlled diabetes and obese subjects with inadequately controlled diabetes received more benefit from SGLT2 inhibitor treatment. In addition, dipeptidyl peptidase 4 (DPP4) inhibitor use was related to a greater reduction in HbA1c in patients with higher baseline HbA1c ≥7%. Sulfonylurea users experienced a larger change from baseline HbA1c but the significance was lost after adjustment for covariates and metformin and thiazolidinedione use did not affect the glycemic outcome.

Conclusion: A better response to SGLT2 inhibitors is expected in Korean T2DM patients who have higher baseline HbA1c and eGFR with a shorter diabetes duration. Moreover, the add-on of an SGLT2 inhibitor to a DPP4 inhibitor is likely to show the greatest glycemic response.
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http://dx.doi.org/10.4093/dmj.2018.0057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470102PMC
April 2019