Alcohol-induced increase in BMP levels promotes fatty liver disease in male prediabetic stage Otsuka Long-Evans Tokushima Fatty rats.

Alcohol consumption exacerbates liver abnormalities in animal models, but whether it increases the severity of liver disease in early diabetic or prediabetic rats is unclear. To investigate the molecular mechanisms underlying alcohol-induced liver steatosis or hepatitis, we used a prediabetic animal model. Otsuka Long-Evans Tokushima Fatty (OLETF) and Long-Evans Tokushima Fatty (LETO) rats were pair-fed with an ethanol-containing liquid diet for 6 weeks. Compared with controls, OLETF and LETO rats displayed more pronounced liver steatosis and higher plasma levels of serum glutamic oxaloacetic transaminase (SGOT) and serum glutamate pyruvate transaminase (SPGT), indicating liver injury. Ethanol-fed LETO (Pd-L-E) rats showed mild liver steatosis and no inflammation compared with ethanol-fed OLETF (Pd-O-E) rats. Although precursor and active SREBP-1 levels in the liver of ethanol-fed OLETF rats significantly increased compared with control diet-fed OLETF rats (Pd-O-C), those of Pd-L-E rats did not. Bone morphogenetic protein (BMP) and TGF-ß1 balance in Pd-O-E rats was significantly altered because BMP signaling was upregulated by inducing BMP2, BMP4, BMP7, BMP9, Smad1, and Smad4, whereas TGF-ß1, Smad3, and Erk were downregulated. Activation of TGF-ß/Smad signaling inhibited BMP2 and BMP9 expression and increased epithelial-mesenchymal transition (EMT) marker levels (Hepcidin, Snail, and Twist) in the liver of LETO rats. Livers of ethanol-fed OLETF rats showed increased levels of vimentin, FSP-1, α-SMA, MMP1, MMP13, and collagen III compared with rats of other groups, whereas EMT marker levels did not change. Thus, BMP exerted anti- and/or pro-fibrotic effects in ethanol-fed rats. Therefore, BMP and TGF-ß, two key members of the TGF-ß superfamily, play important but diverse roles in liver steatosis in young LETO and OLETF rats.

Renal outcomes and all-cause death associated with sodium-glucose co-transporter-2 inhibitors versus other glucose-lowering drugs (CVD-REAL 3 Korea).

AIMS: To investigate the effectiveness of sodium-glucose co-transporter-2 (SGLT2) inhibitors on the risk of progression to end-stage renal disease (ESRD) and all-cause mortality in a broad range of patients with type 2 diabetes (T2D) using a Korean nationwide cohort. MATERIALS AND METHODS: Using data from the Korean National Health Insurance Service database from January 2014 to December 2017, a total of 701 674 patients were identified with T2D. We divided these patients into new users of SGLT2 inhibitors and new users of other glucose-lowering drugs (oGLDs). Using propensity scores, patients in the two groups were matched 1:1. We assessed the risk of ESRD and all-cause death. RESULTS: There were 45 016 patients in each group, and baseline characteristics were well balanced between the groups. The patients' mean age was 58.1 ± 10.6 years and mean estimated glomerular filtration rate (eGFR) was 89.2 ± 27.4 mL/min/1.73m2 , and 8% of patients had proteinuria. We identified 167 incident ESRD cases and 1070 all-cause deaths during follow-up. Use of SGLT2 inhibitors versus oGLDs was associated with a lower risk of ESRD (hazard ratio [HR] 0.47, 95% confidence interval [CI] 0.34 to 0.65) and all-cause death (HR 0.82, 95% CI 0.73 to 0.93). In a subgroup analysis by eGFR, initiation of SGLT2 inhibitor treatment, compared with oGLD treatment, was associated with lower risk of progression to ESRD among patients with eGFR 60 to 90 mL/min/1.73m2 and those with eGFR < 60 mL/min/1.73m2 , and a lower risk of all-cause death was associated with SGLT2 inhibitors versus oGLDs in patients with eGFR ≥90 and 60 to 90 mL/min/1.73m2 . CONCLUSION: In this large nationwide study of Korean patients with T2D, initiation of SGLT2 inhibitors versus oGLDs was associated with lower risk of ESRD and all-cause death.

Effects of DA-9801 on the inflammation and apoptosis induced by angiotensin II in human dermal microvascular endothelial cells.

DA-9801, a plant-based drug used for the treatment of diabetic neuropathy, is known to improve angiotensin II (Ang II)-induced vascular endothelial cell dysfunction. However, the underlying mechanism is not fully understood. We aimed to determine whether the protective effect of DA-9801 against Ang II-induced endothelial cell dysfunction was mediated via inhibition of endothelial cell inflammation and apoptosis. Ang II-induced oxidative stress was attenuated by pretreatment of human dermal microvascular endothelial cells (HDMECs) with DA-9801. This prevented the Ang II-induced upregulation of NAD(P)H oxidase (the NOX4 and p22phox subunits) and reactive oxygen species. Further, pretreatment of HDMECs with DA-9801 ameliorated Ang II-mediated nuclear factor kappa B activity via prevention of the upregulation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase. It also decreased the Ang II-stimulated increase in inducible nitric oxide synthase (NOS) and decreased endothelial NOS protein expression. DA-9801 decreased Ang II-induced upregulation of intercellular adhesion molecule 1, vascular adhesion molecule, and E-selectin in HDMECs. Moreover, TUNEL and annexin V-FITC fluorescence staining for apoptosis and the activities of caspases 9, 7, and 3 decreased in HDMECs pretreated with DA-9801, indicating that the drug enhanced anti-apoptotic pathways. Thus, DA-9801 modulated Ang II-induced endothelial cell dysfunction via inflammatory and apoptotic pathways.

Long-term insulin treatment leads to a change in myosin heavy chain fiber distribution in OLETF rat skeletal muscle.

The objective of this study was to investigate molecular and physiological changes in response to long-term insulin glargine treatment in the skeletal muscle of OLETF rats. Male Otsuka Long-Evans Tokushima Fatty (OLETF) and Long-Evans Tokushima Otsuka (LETO) rats aged 24 weeks were randomly allocated to either treatment with insulin for 24 weeks or no treatment, resulting in three groups. Insulin glargine treatment in OLETF rats (OLETF-G) for 24 weeks resulted in changes in blood glucose levels in intraperitoneal glucose tolerance tests compared with age-matched, untreated OLETF rats (OLETF-C), and the area under the curve was significantly decreased for OLETF-G rats compared with OLETF-C rats (P < 0.05). The protein levels of MHC isoforms were altered in gastrocnemius muscle of OLETF rats, and the proportions of myosin heavy chain type I and II fibers were lower and higher, respectively, in OLETF-G compared with OLETF-C rats. Activation of myokines (IL-6, IL-15, FNDC5, and myostatin) in gastrocnemius muscle was significantly inhibited in OLETF-G compared with OLETF-C rats ( P < 0.05). MyoD and myogenin levels were decreased, while IGF-I and GLUT4 levels were increased, in the skeletal muscle of OLETF-G rats ( P < 0.05). Insulin glargine treatment significantly increased the phosphorylation levels of AMPK, SIRT1, and PGC-1α. Together, our results suggested that changes in the distribution of fiber types by insulin glargine could result in downregulation of myokines and muscle regulatory proteins. The effects were likely associated with activation of the AMPK/SIRT1/PGC-1α signaling pathway. Changes in these proteins may at least partly explain the effect of insulin in skeletal muscle of diabetes mellitus.

Long-term effects on glycaemic control and ß-cell preservation of early intensive treatment in patients with newly diagnosed type 2 diabetes: A multicentre randomized trial.

AIM: To determine the effects of early intensive glycaemic control with intensive insulin treatment (IIT) or initial combined oral antidiabetic drug (COAD) therapy on long-term glycaemic control and the preservation of ß-cell function in people with type 2 diabetes mellitus (T2DM). METHODS: Newly diagnosed drug-naïve patients with T2DM from 8 outpatient diabetes centres were randomized to receive either IIT (n = 50; glargine/glulisine) or COAD (n = 47; glimepiride/metformin) as intensive treatment until the termination criteria to ensure euglycaemia were met. After intensive treatment, the patients completed a follow-up period with either lifestyle modification (LSM) alone or rescue therapy to maintain target glycated haemoglobin levels of <7% (53 mmol/mol) up to week 104. The primary outcomes were analysed after excluding participants who were anti-glutamic acid decarboxylase autoantibody-positive. RESULTS: Both intensive treatment methods were effective for short-term glycaemic control, but improvements in the disposition index (DI) were significantly greater in the IIT group than in the COAD group (P = .021). During the follow-up period after intensive treatment, the two groups significantly differed in rescue method regarding the maintenance of comparable levels of glycaemic control (P = .010) and more participants who received IIT exhibited well-controlled glycaemia with LSM alone. Additionally, the IIT group maintained a higher DI than the COAD group during the follow-up period. Cox regression analysis showed that the IIT method was associated with a 52.5% lower risk of failing to maintain drug-free glycaemic remission compared with the COAD method (P = .015). CONCLUSIONS: The findings indicate that outpatient clinic-based IIT to ensure euglycaemia in newly diagnosed patients with T2DM might be an effective initial therapeutic option for improvements in ß-cell function and glycaemic control over the long term, without serious adverse events.

Low muscle mass and risk of type 2 diabetes in middle-aged and older adults: findings from the KoGES.

AIMS/HYPOTHESIS: Asians have a propensity to develop type 2 diabetes with a lower BMI than Western populations. This discrepancy may be due to differences in body fat and muscle mass for a given BMI. However, unlike adiposity, it is unclear whether muscle mass affects the risk of type 2 diabetes in Asian populations. METHODS: We conducted a 2-yearly prospective assessment of 6895 participants who were free of diabetes at the baseline examination as part of the Korean Genome Epidemiology Study. The muscle mass index (MMI) was defined as the weight-adjusted appendicular skeletal muscle mass. Using Cox regression models, we evaluated the association between MMI and the risk of developing type 2 diabetes across sex-specific tertiles of MMI. Low muscle mass was defined as the sex-specific lowest tertile of MMI. Main covariates included age, sex, urban or rural residence, family history of diabetes, hypertension, smoking status, education level, monthly income, physical activity, alcohol consumption and diet. In addition, body fat mass, waist circumference and BMI were controlled as categorical variables. Obesity was defined as a BMI of ≥25 kg/m2 or a waist circumference of ≥90 cm for men and ≥85 cm for women. RESULTS: During a median follow-up of 9.06 years, 1336 participants developed type 2 diabetes. At baseline, the mean age was 52.1 years and the mean BMI was 24.4 kg/m2. The mean MMI for men and women was 32.1% and 26.0%, respectively. There was an inverse association between MMI and the risk of type 2 diabetes. Multivariate-adjusted HRs for the risk of developing type 2 diabetes were 2.05 (95% CI 1.73, 2.43), 1.39 (95% CI 1.17, 1.66) and 1.0 from the lowest to highest sex-specific MMI tertile, with an HR of 1.35 (95% CI 1.26, 1.45) per SD decline in MMI. Further adjustments for fat mass, waist circumference and BMI as categorical variables did not modify the relationship (each p < 0.01). In BMI-stratified analyses, the population-attributable fraction of the lowest tertile of MMI for developing type 2 diabetes was increased by 11.9% in the non-obese group and 19.7% in the obese group. CONCLUSIONS/INTERPRETATION: Low muscle mass as defined by MMI was associated with an increased risk of type 2 diabetes, independent of general obesity, in middle-aged and older Korean adults.

High glucose and palmitate increases bone morphogenic protein 4 expression in human endothelial cells.

Here, we investigated whether hyperglycemia and/or free fatty acids (palmitate, PAL) aff ect the expression level of bone morphogenic protein 4 (BMP4), a proatherogenic marker, in endothelial cells and the potential role of BMP4 in diabetic vascular complications. To measure BMP4 expression, human umbilical vein endothelial cells (HUVECs) were exposed to high glucose concentrations and/or PAL for 24 or 72 h, and the effects of these treatments on the expression levels of adhesion molecules and reactive oxygen species (ROS) were examined. BMP4 loss-of-function status was achieved via transfection of a BMP4-specific siRNA. High glucose levels increased BMP4 expression in HUVECs in a dose-dependent manner. PAL potentiated such expression. The levels of adhesion molecules and ROS production increased upon treatment with high glucose and/or PAL, but this eff ect was negated when BMP4 was knocked down via siRNA. Signaling of BMP4, a proinflammatory and pro-atherogenic cytokine marker, was increased by hyperglycemia and PAL. BMP4 induced the expression of infl ammatory adhesion molecules and ROS production. Our work suggests that BMP4 plays a role in atherogenesis induced by high glucose levels and/or PAL.

A prospective, randomized, multicenter trial comparing the efficacy and safety of the concurrent use of long-acting insulin with mitiglinide or voglibose in patients with type 2 diabetes.

This trial was conducted to compare the efficacy and safety of combination therapy with basal insulin glargine plus mitiglinide to that of basal insulin glargine plus voglibosein patients with type 2 diabetes. This was a 20-week, randomized, multicenter non-inferiority trial. Patients with HbA1c levels over 7.0% were randomly assigned to receive either mitiglinide (10 mg tid) or voglibose (0.2 mg tid) concurrent with insulin glargine for 16 weeks after a 4-week of basal insulin glargine monotherapy. The intention-to-treat population included 156 patients; 79 were placed in the mitiglinide group, and 77 were placed in the voglibose group. At 20 weeks, there was no significant difference between the mitiglinide group and the voglibose group in terms of the mean HbA1c level or the mean decrease of the HbAlc level from baseline (-0.9% [-7.5 mmol/mol] and -0.7%, [-5.3 mmol/mol] respectively). The mean fasting plasma glucose level and data of self-monitoring blood glucosewere significantly decreased from baseline to week 20 in both groups, but there was no significant difference between the two groups. The changes in the basal insulin requirements of each group were not significant. The prevalence of adverse events and the risk of hypoglycemia were similar for both groups. Combination therapy with mitiglinide plus basal insulin glargine was non-inferior to voglibose plus basal insulin glargine in terms of the effect on overall glycemic control.

A randomized, placebo-controlled, double-blind, phase 3 trial to evaluate the efficacy and safety of anagliptin in drug-naïve patients with type 2 diabetes.

The aim of this study was to evaluate the efficacy and safety of anagliptin in drug-naïve patients with type 2 diabetes in a double-blind randomized placebo-controlled study. A total of 109 patients were randomized to 100 mg (n=37) or 200 mg (n=33) anagliptin twice daily or placebo (n=39). The primary objective was to alter HbA1c levels from baseline at a 24-week endpoint. The overall baseline mean age and body mass index were 56.20 ± 9.77 years and 25.01 ± 2.97 kg/m(2), respectively, and the HbA1c level was of 7.14 ± 0.69 %. Anagliptin at 100 mg and 200 mg produced significant reductions in HbA1c (-0.50 ± 0.45 % and -0.51 ± 0.55%, respectively), and the placebo treatment resulted in an increase in HbA1c by 0.23 ± 0.62 %. Both doses of anagliptin produced significant decreases in fasting plasma glucose (-0.53 ± 1.25 mmol/L and -0.72 ± 1.25 mmol/L, respectively) and the proinsulin/insulin ratio (-0.04 ± 0.15 and -0.07 ± 0.18, respectively) compared with placebo. No meaningful body weight changes from baseline were observed in three groups. Plasma dipeptidyl peptidase (DPP)-4 activity was significantly inhibited after 24 weeks of anagliptin treatment, and >75% and >90% inhibitions were observed during the meal tolerance tests with 100 mg and 200 mg anagliptin, respectively. The incidences of adverse or serious adverse events were similar among the three study groups. Twice-daily anagliptin therapy effectively inhibited DPP-4 activity and improved glycemic control and was well-tolerated in patients with type 2 diabetes.

Chronic Alcohol Consumption Results in Greater Damage to the Pancreas Than to the Liver in the Rats.

Alcohol consumption increases the risk of type 2 diabetes. However, its effects on prediabetes or early diabetes have not been studied. We investigated endoplasmic reticulum (ER) stress in the pancreas and liver resulting from chronic alcohol consumption in the prediabetes and early stages of diabetes. We separated Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a type-2 diabetic animal model, into two groups based on diabetic stage: prediabetes and early diabetes were defined as occurrence between the ages of 11 to 16 weeks and 17 to 22 weeks, respectively. The experimental group received an ethanol-containing liquid diet for 6 weeks. An intraperitoneal glucose tolerance test was conducted after 16 and 22 weeks for the prediabetic and early diabetes groups, respectively. There were no significant differences in body weight between the control and ethanol groups. Fasting and 120-min glucose levels were lower and higher, respectively, in the ethanol group than in the control group. In prediabetes rats, alcohol induced significant expression of ER stress markers in the pancreas; however, alcohol did not affect the liver. In early diabetes rats, alcohol significantly increased most ER stress-marker levels in both the pancreas and liver. These results indicate that chronic alcohol consumption increased the risk of diabetes in prediabetic and early diabetic OLETF rats; the pancreas was more susceptible to damage than was the liver in the early diabetic stages, and the adaptive and proapoptotic pathway of ER stress may play key roles in the development and progression of diabetes affected by chronic alcohol ingestion.

The Effect of Early Intensive Insulin Therapy on Body Fat Distribution and ß-Cell Function in Newly Diagnosed Type 2 Diabetes.

OBJECTIVES: The aim of this study was to evaluate the effects of early intensive insulin therapy on body fat distribution, lean body mass and ß-cell function in patients with newly diagnosed type 2 diabetes. METHODS: Thirty-eight subjects with newly diagnosed type 2 diabetes participated in a 12-week course of intensive insulin therapy. Patients were administered a 75 g oral glucose tolerance test (OGTT), underwent measurement of visceral and subcutaneous adipose tissues (VAT and SAT) using computed tomography and appendicular skeletal muscle (ASM) mass was assessed using dual-energy X-ray absorptiometry. RESULTS: After intensive insulin therapy, fasting plasma glucose and HbA1c levels decreased. Homeostasis model assessment (HOMA)-B, the insulinogenic index, and the C-peptide-to-glucose area under the curve (AUC) ratio increased. The insulin sensitivity index and the glucose AUC decreased after 12 weeks. The body composition analysis revealed that the VAT and the ratio of VAT to SAT decreased, whereas body weight and total fat mass increased nonsignificantly. The ASM/weight and skeletal muscle mass index increased. The restoration of ß-cell function, as identified by HOMA-B, the insulinogenic index, and the C-peptide-to-glucose AUC ratio, was correlated with the changes in VAT when controlled for age and gender. In multiple regression analyses, the decrease in VAT was shown to independently contribute to improved HbA1c over the study period, after adjusting for confounding factors. CONCLUSIONS: These results suggest that a shift in fat distribution from visceral to subcutaneous fat after early intensive insulin therapy is associated with improvements in glycemic control and ß-cell function in patients with newly diagnosed type 2 diabetes.

Risk of Pancreatic Cancer and Use of Dipeptidyl Peptidase 4 Inhibitors in Patients with Type 2 Diabetes: A Propensity Score-Matching Analysis.

BACKGRUOUND: The effects of dipeptidyl peptidase 4 (DPP-4) inhibitors over the course of long-term treatment remain unclear, and concerns have been raised regarding the role of DPP-4 inhibitors in carcinogenesis in the pancreas. Earlier studies of pancreatic adverse events have reported conflicting results. METHODS: This study analyzed Korean National Health Insurance Service data from January 2009 to December 2012. Patients who had type 2 diabetes mellitus and took two or more oral glucose-lowering drugs (GLDs) were included. Patients prescribed DPP-4 inhibitors (n=51,482) or other GLDs (n=51,482) were matched at a 1:1 ratio using propensity score matching. The risk of pancreatic cancer was calculated using Kaplan-Meier curves and Cox proportional-hazards regression analysis. RESULTS: During a median follow-up period of 7.95 years, 1,051 new cases of pancreatic cancer were identified. The adjusted hazard ratio (HR) for DPP-4 inhibitor use was 0.99 (95% confidence interval [CI], 0.88 to 1.12) compared with the other GLD group. In an analysis limited to cases diagnosed with pancreatic cancer during hospitalization, the adjusted HR for the use of DPP-4 inhibitors was 1.00 (95% CI, 0.86 to 1.17) compared with patients who took other GLDs. Using the other GLD group as the reference group, no trend was observed for elevated pancreatic cancer risk with increased DPP-4 inhibitor exposure. CONCLUSION: In this population-based cohort study, DPP-4 inhibitor use over the course of relatively long-term follow-up showed no significant association with an elevated risk of pancreatic cancer.

Risk of Cause-Specific Mortality across Glucose Spectrum in Elderly People: A Nationwide Population-Based Cohort Study.

BACKGRUOUND: This study investigated the risk of cause-specific mortality according to glucose tolerance status in elderly South Koreans. METHODS: A total of 1,292,264 individuals aged ≥65 years who received health examinations in 2009 were identified from the National Health Information Database. Participants were classified as normal glucose tolerance, impaired fasting glucose, newly-diagnosed diabetes, early diabetes (oral hypoglycemic agents ≤2), or advanced diabetes (oral hypoglycemic agents ≥3 or insulin). The risk of system-specific and disease-specific deaths was estimated using multivariate Cox proportional hazards analysis. RESULTS: During a median follow-up of 8.41 years, 257,356 deaths were recorded. Diabetes was associated with significantly higher risk of all-cause mortality (hazard ratio [HR], 1.58; 95% confidence interval [CI], 1.57 to 1.60); death due to circulatory (HR, 1.49; 95% CI, 1.46 to 1.52), respiratory (HR, 1.51; 95% CI, 1.47 to 1.55), and genitourinary systems (HR, 2.22; 95% CI, 2.10 to 2.35); and neoplasms (HR, 1.30; 95% CI, 1.28 to 1.32). Diabetes was also associated with a significantly higher risk of death due to ischemic heart disease (HR, 1.70; 95% CI, 1.63 to 1.76), cerebrovascular disease (HR, 1.46; 95% CI, 1.41 to 1.50), pneumonia (HR, 1.69; 95% CI, 1.63 to 1.76), and acute or chronic kidney disease (HR, 2.23; 95% CI, 2.09 to 2.38). There was a stepwise increase in the risk of death across the glucose spectrum (P for trend <0.0001). Stroke, heart failure, or chronic kidney disease increased the risk of all-cause mortality at every stage of glucose intolerance. CONCLUSION: A dose-dependent association between the risk of mortality from various causes and severity of glucose tolerance was noted in the elderly population.

Mortality and Severity of Coronavirus Disease 2019 in Patients with Long-Term Glucocorticoid Therapy: A Korean Nationwide Cohort Study.

BACKGRUOUND: The severity of coronavirus disease 2019 (COVID-19) among patients with long-term glucocorticoid treatment (LTGT) has not been established. We aimed to evaluate the association between LTGT and COVID-19 prognosis. METHODS: A Korean nationwide cohort database of COVID-19 patients between January 2019 and September 2021 was used. LTGT was defined as exposure to at least 150 mg of prednisolone (≥5 mg/day and ≥30 days) or equivalent glucocorticoids 180 days before COVID-19 infection. The outcome measurements were mortality, hospitalization, intensive care unit (ICU) admission, length of stay, and mechanical ventilation. RESULTS: Among confirmed patients with COVID-19, the LTGT group (n=12,794) was older and had a higher proportion of comorbidities than the control (n=359,013). The LTGT group showed higher in-hospital, 30-day, and 90-day mortality rates than the control (14.0% vs. 2.3%, 5.9% vs. 1.1%, and 9.9% vs. 1.8%, respectively; all P<0.001). Except for the hospitalization rate, the length of stay, ICU admission, and mechanical ventilation proportions were significantly higher in the LTGT group than in the control (all P<0.001). Overall mortality was higher in the LTGT group than in the control group, and the significance remained in the fully adjusted model (odds ratio [OR], 5.75; 95% confidence interval [CI], 5.31 to 6.23) (adjusted OR, 1.82; 95% CI, 1.67 to 2.00). The LTGT group showed a higher mortality rate than the control within the same comorbidity score category. CONCLUSION: Long-term exposure to glucocorticoids increased the mortality and severity of COVID-19. Prevention and early proactive measures are inevitable in the high-risk LTGT group with many comorbidities.

Efficacy of Gemigliptin Add-on to Dapagliflozin and Metformin in Type 2 Diabetes Patients: A Randomized, Double-Blind, Placebo-Controlled Study (SOLUTION).

BACKGRUOUND: This study evaluated the efficacy and safety of add-on gemigliptin in patients with type 2 diabetes mellitus (T2DM) who had inadequate glycemic control with metformin and dapagliflozin. METHODS: In this randomized, placebo-controlled, parallel-group, double-blind, phase III study, 315 patients were randomized to receive either gemigliptin 50 mg (n=159) or placebo (n=156) with metformin and dapagliflozin for 24 weeks. After the 24-week treatment, patients who received the placebo were switched to gemigliptin, and all patients were treated with gemigliptin for an additional 28 weeks. RESULTS: The baseline characteristics were similar between the two groups, except for body mass index. At week 24, the least squares mean difference (standard error) in hemoglobin A1c (HbA1c) changes was -0.66% (0.07) with a 95% confidence interval of -0.80% to -0.52%, demonstrating superior HbA1c reduction in the gemigliptin group. After week 24, the HbA1c level significantly decreased in the placebo group as gemigliptin was administered, whereas the efficacy of HbA1c reduction was maintained up to week 52 in the gemigliptin group. The safety profiles were similar: the incidence rates of treatment-emergent adverse events up to week 24 were 27.67% and 29.22% in the gemigliptin and placebo groups, respectively. The safety profiles after week 24 were similar to those up to week 24 in both groups, and no new safety findings, including hypoglycemia, were noted. CONCLUSION: Add-on gemigliptin was well tolerated, providing comparable safety profiles and superior efficacy in glycemic control over placebo for long-term use in patients with T2DM who had poor glycemic control with metformin and dapagliflozin.

Low-Density Lipoprotein Cholesterol Level, Statin Use and Myocardial Infarction Risk in Young Adults.

Objective: The consequences of blood lipid abnormalities for cardiovascular disease risk in young adults is unclear. Optimal lipid levels may also vary depending on whether a statin drug is taken. It aimed to determine whether the optimal lipid levels in young adults differ depending on statin use. Methods: Using a nationally representative database from the Korean National Health Insurance System, 6,350,400 participants aged 20-39 years who underwent a health examination between 2009-2012 were followed through to 2018. The primary outcome was incident myocardial infarction (MI). We assessed the associations between prespecified lipid levels and MI risk according to statin use. Results: Among participants not taking statins, low-density lipoprotein cholesterol (LDL-C) levels ≥120 mg/dL were significantly associated with MI risk (hazard ratio [HR], 1.33; 95% confidence interval [CI], 1.27-1.40) compared with statin nonusers with LDL-C <80 mg/dL. Statin users with LDL-C categories <80, 80-100, 100-120, and ≥120 mg/dL all had significantly higher MI risk compared with statin nonusers with LDL-C <80 mg/dL; these HRs (95% CIs) were 1.66 (1.39-1.99), 1.68 (1.36-2.09), 1.63 (1.31-2.02), and 2.32 (2.07-2.60), respectively. Conclusion: Young adults taking statins have an increased MI risk compared with statin nonusers, even when they have similar LDL-C levels. Specific lipid targets may need to differ depending on statin use.

Weight change and the incidence of heart failure in the Korean population: data from the National Health Insurance Health checkup 2005-2015.

AIMS: Heart failure (HF) is associated with obesity, but the relationship between weight change and HF is inconsistent. We examined the relationship between weight change and the incidence of HF in the Korean population. DESIGN: Retrospective cohort study design. METHODS AND RESULTS: A total of 11 210 394 subjects (6 198 542 men and 5 011 852 women) >20 years of age were enrolled in this study. Weight change over 4 years divided into seven categories from weight loss ≥15% to weight gain ≥15%. The hazard ratios (HRs) and 95% confidence intervals for the incidence of HF were analysed. The HR of HF showed a slightly reverse J-shaped curve by increasing weight change in total and >15% weight loss shows the highest HR (HR 1.647) followed by -15 to -10% weight loss (HR = 1.444). When using normal body mass index with stable weight group as a reference, HR of HF decreased as weight increased in underweight subjects and weight gain ≥15% in obesity Stage II showed the highest HR (HR = 2.97). Sustained weight for 4 years in the underweight and obesity Stages I and II increased the incidence of HF (HR = 1.402, 1.092, and 1.566, respectively). CONCLUSION: Both weight loss and weight gain increased HR for HF. Sustained weight in the obesity or underweight categories increased the incidence of HF.

Real-World Analysis of Rapid-Acting Insulin Analog Use and Its Blood Glucose Lowering Effect in Patients with Type 2 Diabetes Mellitus: Results from PASSION Disease Registry in Korea.

Purpose: Although rapid-acting insulins (RAIs) are used frequently in Korean clinical settings, evidence on their use is limited. This study explores the pattern and clinical effectiveness of the use of RAIs in Korean patients with type 2 diabetes mellitus (T2DM). Patients and Methods: This non-interventional, observational study enrolled patients (aged >18 years) with T2DM who were prescribed RAIs. The pattern of use and effectiveness of RAI analogs were evaluated over 6 months. Results: A total of 299/451 patients were analyzed. Approximately 90% (n/N=270/299) of the patients received insulin glulisine, which significantly reduced their levels of glycated hemoglobin (HbA1c: n=270, mean± standard deviation [SD]; -1.16±6.02%, p=0.0017), fasting plasma glucose (n=40; mean±SD: -54.9±90.89 mg/dl, p=0.0005), and post prandial blood glucose (n=35, mean±SD: -89.46± 105.68 mg/dl, p<0.0001) at 6 months, with a corresponding increase in body weight (BW) (n=197, mean±SD:1.45±3.64 kg, p<0.0001). At 6 months, more patients receiving an intensive regimen (basal insulin+≥2 RAI injections/day) had HbA1c <7% than those receiving a non-intensive regimen (basal insulin+1 RAI injection/day) (20.69% vs 7.46%; p=0.0333); the corresponding reduction in HbA1c was also higher in patients receiving the intensive regimen (p<0.0001). About one-fourth patients (n/N=22/95) were switched to the intensive regimen (from 1 to ≥2 RAI injections/day), and only 4.41% (n/N=9/204) of the patients were switched to 1 RAI injection/day. The patients receiving the intensive regimen showed higher levels of HbA1c reductions (mean±SD: -1.27±1.96%) compared with the maintenance group-1 RAI injection/day (mean±SD: -0.72±1.66%) (p=0.0459), without a significant increase in BW and body mass index. Conclusion: The insulin glulisine intensification regimen showed glycemic target achievement and can be considered a therapeutic tool in the management of T2DM patients.

Relationship of visceral and subcutaneous adiposity with renal function in people with type 2 diabetes mellitus.

BACKGROUND: Obesity and diabetes mellitus (DM) are established risk factors for the development of chronic kidney disease. Visceral adiposity (VAT) and subcutaneous adiposity (SAT) may be associated with the differential metabolic risk. Our study was performed to determine whether VAT or SAT was associated with the decrease of renal function in people with type 2 DM. METHODS: Nine hundred and twenty-nine people with type 2 DM and who had undergone abdominal computed tomography assessment of the SAT and VAT areas were included. The estimated glomerular filtration rate (eGFR) was calculated using the Cockcroft-Gault equation and the Modification of Diet in Renal Disease (MDRD) four-variable equation at the time of the assessment of the SAT and VAT areas. RESULTS: VAT was negatively associated with eGFR using the MDRD equation after adjustment for the clinical variables (ß-coefficient = - 0.075, P = 0.034), while SAT was not significantly associated with eGFR. There was no significant association between the abdominal adiposity measurements and the eGFR using the Cockcroft-Gault formula. When stratifying the individuals by the body mass index groups, VAT was negatively associated with eGFR by the MDRD equation and the Cockcroft-Gault formula in the overweight and obese subjects after adjustment for the clinical variables, while there was no significant association between the VAT and the eGFR in the normal weight subjects. SAT was not significantly associated with eGFR in the normal weight, overweight and obese subjects. CONCLUSIONS: Our data suggest that VAT may be an additional prognostic factor for the decrease of renal function especially in the overweight or obese subjects with type 2 DM.

Association of serum bone morphogenetic protein 4 levels with obesity and metabolic syndrome in non-diabetic individuals.

Bone morphogenetic protein 4 (BMP-4) is involved in the earliest stages of adipocyte differentiation and is recognized as an adipogenic factor for white adipose tissue. The association of serum BMP-4 levels with anthropometric and metabolic parameters has not been previously studied. We aimed to explore the relationship of serum BMP-4 levels with obesity and metabolic syndrome. Serum BMP-4 levels were measured in 104 non-diabetic individuals from the Chungju Metabolic Disease Cohort Study. Anthropometric measurements and components of metabolic syndrome were assessed in all patients. Serum BMP-4 levels were significantly increased in individuals with obesity or metabolic syndrome. After adjusting for age and gender, serum BMP-4 levels were positively correlated with body mass index, waist circumference (WC), waist-to-hip ratio, fasting plasma insulin, homeostasis model assessment index, and triglycerides and were negatively correlated with high-density lipoprotein (HDL) cholesterol. Among these parameters, WC and HDL cholesterol were found to be independent contributing factors for serum BMP-4 levels. Serum BMP-4 levels were also significantly higher in subjects with positive diagnostic criteria for each component of metabolic syndrome. The area under the receiver operating characteristic curve for BMP-4 was 0.661 (P = 0.022, 95% CI = 0.528 to 0.794) and the cut-off value was 2.84 pg/mL. This is the first demonstration that serum BMP-4 levels are associated with adiposity, insulin resistance, and the presence of metabolic syndrome. Whether BMP-4 may be involved in the pathogenesis of obesity and metabolic syndrome deserves further investigation.