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BACKGROUND: Receptor-interacting protein kinase (RIPK)3 is an essential molecule for necroptosis and its role in kidney fibrosis has been investigated using various kidney injury models. However, the relevance and the underlying mechanisms of RIPK3 to podocyte injury in albuminuric diabetic kidney disease (DKD) remain unclear. Here, we investigated the role of RIPK3 in glomerular injury of DKD. METHODS: We analyzed RIPK3 expression levels in the kidneys of patients with biopsy-proven DKD and animal models of DKD. Additionally, to confirm the clinical significance of circulating RIPK3, RIPK3 was measured by ELISA in plasma obtained from a prospective observational cohort of patients with type 2 diabetes, and estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR), which are indicators of renal function, were followed up during the observation period. To investigate the role of RIPK3 in glomerular damage in DKD, we induced a DKD model using a high-fat diet in Ripk3 knockout and wild-type mice. To assess whether mitochondrial dysfunction and albuminuria in DKD take a Ripk3-dependent pathway, we used single-cell RNA sequencing of kidney cortex and immortalized podocytes treated with high glucose or overexpressing RIPK3. RESULTS: RIPK3 expression was increased in podocytes of diabetic glomeruli with increased albuminuria and decreased podocyte numbers. Plasma RIPK3 levels were significantly elevated in albuminuric diabetic patients than in non-diabetic controls (p = 0.002) and non-albuminuric diabetic patients (p = 0.046). The participants in the highest tertile of plasma RIPK3 had a higher incidence of renal progression (hazard ratio [HR] 2.29 [1.05-4.98]) and incident chronic kidney disease (HR 4.08 [1.10-15.13]). Ripk3 knockout improved albuminuria, podocyte loss, and renal ultrastructure in DKD mice. Increased mitochondrial fragmentation, upregulated mitochondrial fission-related proteins such as phosphoglycerate mutase family member 5 (PGAM5) and dynamin-related protein 1 (Drp1), and mitochondrial ROS were decreased in podocytes of Ripk3 knockout DKD mice. In cultured podocytes, RIPK3 inhibition attenuated mitochondrial fission and mitochondrial dysfunction by decreasing p-mixed lineage kinase domain-like protein (MLKL), PGAM5, and p-Drp1 S616 and mitochondrial translocation of Drp1. CONCLUSIONS: The study demonstrates that RIPK3 reflects deterioration of renal function of DKD. In addition, RIPK3 induces diabetic podocytopathy by regulating mitochondrial fission via PGAM5-Drp1 signaling through MLKL. Inhibition of RIPK3 might be a promising therapeutic option for treating DKD.
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BACKGRUOUND: The Korean Endocrine Hormone Reference Standard Data Center (KEHRS DC) has created reference standards (RSs) for endocrine hormones since 2020. This study is the first of its kind, wherein the KEHRS DC established RSs for serum Cpeptide levels in a healthy Korean population. METHODS: Healthy Korean adults were recruited from May 2021 to September 2023. After excluding participants according to our criteria, serum samples were collected; each participant could then choose between fasting glucose only or fasting glucose plus an oral glucose tolerance test (OGTT). If their sample showed high glucose (≥100 mg/dL) or hemoglobin A1c (HbA1c) (≥5.70%), their C-peptide levels were excluded from analyzing the RSs. RESULTS: A total of 1,532 participants were recruited; however, only the data of 1,050 participants were analyzed after excluding those whose samples showed hyperglycemia or high HbA1c. Post-30-minute OGTT data from 342 subjects and post-120-minute OGTT data from 351 subjects were used. The means±2 standard deviations and expanded uncertainties of fasting, post-30-minute and 120-minute OGTT C-peptide levels were 1.26±0.82 and 0.34-3.18, 4.74±3.57 and 1.14-8.33, and 4.85±3.58 and 1.25-8.34 ng/mL, respectively. Serum C-peptide levels correlated with obesity, serum glucose levels, and HbA1c levels. CONCLUSION: The RSs for serum C-peptide levels established in this study are expected to be useful in both clinical and related fields.
Subject(s)
Blood Glucose , C-Peptide , Humans , C-Peptide/blood , Republic of Korea , Female , Male , Adult , Middle Aged , Blood Glucose/analysis , Glucose Tolerance Test/standards , Reference Standards , Reference Values , Glycated Hemoglobin/analysis , Young Adult , Aged , Biomarkers/bloodABSTRACT
BACKGRUOUND: It is well known that a large number of patients with diabetes also have dyslipidemia, which significantly increases the risk of cardiovascular disease (CVD). This study aimed to evaluate the efficacy and safety of combination drugs consisting of metformin and atorvastatin, widely used as therapeutic agents for diabetes and dyslipidemia. METHODS: This randomized, double-blind, placebo-controlled, parallel-group and phase III multicenter study included adults with glycosylated hemoglobin (HbA1c) levels >7.0% and <10.0%, low-density lipoprotein cholesterol (LDL-C) >100 and <250 mg/dL. One hundred eighty-five eligible subjects were randomized to the combination group (metformin+atorvastatin), metformin group (metformin+atorvastatin placebo), and atorvastatin group (atorvastatin+metformin placebo). The primary efficacy endpoints were the percent changes in HbA1c and LDL-C levels from baseline at the end of the treatment. RESULTS: After 16 weeks of treatment compared to baseline, HbA1c showed a significant difference of 0.94% compared to the atorvastatin group in the combination group (0.35% vs. -0.58%, respectively; P<0.0001), whereas the proportion of patients with increased HbA1c was also 62% and 15%, respectively, showing a significant difference (P<0.001). The combination group also showed a significant decrease in LDL-C levels compared to the metformin group (-55.20% vs. -7.69%, P<0.001) without previously unknown adverse drug events. CONCLUSION: The addition of atorvastatin to metformin improved HbA1c and LDL-C levels to a significant extent compared to metformin or atorvastatin alone in diabetes and dyslipidemia patients. This study also suggested metformin's preventive effect on the glucose-elevating potential of atorvastatin in patients with type 2 diabetes mellitus and dyslipidemia, insufficiently controlled with exercise and diet. Metformin and atorvastatin combination might be an effective treatment in reducing the CVD risk in patients with both diabetes and dyslipidemia because of its lowering effect on LDL-C and glucose.
Subject(s)
Atorvastatin , Cholesterol, LDL , Diabetes Mellitus, Type 2 , Drug Therapy, Combination , Dyslipidemias , Glycated Hemoglobin , Hypoglycemic Agents , Metformin , Humans , Atorvastatin/therapeutic use , Atorvastatin/administration & dosage , Metformin/therapeutic use , Metformin/administration & dosage , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/blood , Male , Female , Double-Blind Method , Middle Aged , Dyslipidemias/drug therapy , Dyslipidemias/blood , Glycated Hemoglobin/analysis , Hypoglycemic Agents/therapeutic use , Hypoglycemic Agents/administration & dosage , Aged , Cholesterol, LDL/blood , Treatment Outcome , AdultABSTRACT
BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is characterized by an increase in hepatic triglyceride content and increased inflammatory macrophage infiltration through the C-C motif chemokine receptor (CCR) 5 pathway in the liver. DA-6034 (7-carboxymethyloxy-3',4',5-trimethoxy flavone), is a synthetic derivative of eupatilin that exhibits anti-inflammatory activity in inflammatory bowel disease. However, the effect of DA-6034 on the inflammatory response in NAFLD is not well elucidated. Therefore, we aimed to determine the effect of DA-6034 on hepatic steatosis and inflammation. METHODS: Forty male C57BL/6J mice were divided into the following four groups: (1) regular diet (RD), (2) RD with DA-6034, (3) high fat diet (HFD), and (4) HFD with DA-6034. All mice were sacrificed 12 weeks after the start of the experiment. The effects of DA-6034 on macrophages were assessed using RAW264.7 cells. RESULTS: DA-6034 not only reduced hepatic triglyceride levels and lipid accumulation but also macrophage infiltration and proinflammatory cytokines in HFD-fed mice. According to fluorescence-activated cell sorter analysis, DA-6034 reduced the CD8+ T cell fraction in the liver of HFD-fed mice. DA-6034 also reduced CCR5 expression and the migration of liver macrophages in HFD-fed mice and inhibited CCR2 ligand and CCR4 ligand, which stimulated the migration of macrophages. CONCLUSION: Overall, DA-6034 attenuates hepatic steatosis and inflammation in obesity by regulating CCR5 expression in macrophages.
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BACKGROUND: Chronic kidney disease (CKD) poses a significant health challenge, yet early detection remains difficult. Resting heart rate (RHR) has been shown to be a reliable indicator of type 2 diabetes, prompting interest in its potential as an independent predictor of CKD. This study aimed to investigate the association between RHR and CKD prevalence, as well as explore potential interactions between RHR and other risk factors for CKD in a sample of 25,246 adults. METHODS: Data from the Korean National Health and Nutrition Examination Survey (2011-2014) were utilized for this study, with 19,210 participants included after screening. Logistic regression analysis was employed to examine the relationship between RHR and CKD prevalence. Stratified analyses were conducted based on known risk factors for CKD. RESULTS: Participants with an RHR ≥ 90 bpm exhibited a 2.07-fold [95% confidence interval (CI): 1.28-3.34] and 2.22-fold (95% CI: 1.42-3.48) higher prevalence of CKD in men and women, respectively, compared to those with an RHR < 60 bpm. The association between RHR and CKD prevalence was particularly pronounced in younger participants (40-59 years vs. ≥ 60 years), individuals with diabetes (yes vs. no), and those with a longer duration of diabetes (≥ 7 years vs. < 7 years). CONCLUSION: Elevated RHR was found to be significantly associated with a higher prevalence of CKD in both men and women, independent of demographic, lifestyle, and medical factors. These findings suggest that RHR could serve as a valuable predictor for undiagnosed CKD.
Subject(s)
Diabetes Mellitus, Type 2 , Renal Insufficiency, Chronic , Adult , Male , Humans , Female , Diabetes Mellitus, Type 2/epidemiology , Nutrition Surveys , Prevalence , Heart Rate/physiology , Risk Factors , Renal Insufficiency, Chronic/diagnosis , Renal Insufficiency, Chronic/epidemiology , Republic of Korea/epidemiologyABSTRACT
BACKGRUOUND: Nonalcoholic steatohepatitis (NASH) is a liver disease caused by obesity that leads to hepatic lipoapoptosis, resulting in fibrosis and cirrhosis. However, the mechanism underlying NASH is largely unknown, and there is currently no effective therapeutic agent against it. DWN12088, an agent used for treating idiopathic pulmonary fibrosis, is a selective prolyl-tRNA synthetase (PRS) inhibitor that suppresses the synthesis of collagen. However, the mechanism underlying the hepatoprotective effect of DWN12088 is not clear. Therefore, we investigated the role of DWN12088 in NASH progression. METHODS: Mice were fed a chow diet or methionine-choline deficient (MCD)-diet, which was administered with DWN12088 or saline by oral gavage for 6 weeks. The effects of DWN12088 on NASH were evaluated by pathophysiological examinations, such as real-time quantitative reverse transcription polymerase chain reaction, immunoblotting, biochemical analysis, and immunohistochemistry. Molecular and cellular mechanisms of hepatic injury were assessed by in vitro cell culture. RESULTS: DWN12088 attenuated palmitic acid (PA)-induced lipid accumulation and lipoapoptosis by downregulating the Rho-kinase (ROCK)/AMP-activated protein kinase (AMPK)/sterol regulatory element-binding protein-1c (SREBP-1c) and protein kinase R-like endoplasmic reticulum kinase (PERK)/α subunit of eukaryotic initiation factor 2 (eIF2α)/activating transcription factor 4 (ATF4)/C/EBP-homologous protein (CHOP) signaling cascades. PA increased but DWN12088 inhibited the phosphorylation of nuclear factor-κB (NF-κB) p65 (Ser536, Ser276) and the expression of proinflammatory genes. Moreover, the DWN12088 inhibited transforming growth factor ß (TGFß)-induced pro-fibrotic gene expression by suppressing TGFß receptor 1 (TGFßR1)/Smad2/3 and TGFßR1/glutamyl-prolyl-tRNA synthetase (EPRS)/signal transducer and activator of transcription 6 (STAT6) axis signaling. In the case of MCD-diet-induced NASH, DWN12088 reduced hepatic steatosis, inflammation, and lipoapoptosis and prevented the progression of fibrosis. CONCLUSION: Our findings provide new insights about DWN12088, namely that it plays an important role in the overall improvement of NASH. Hence, DWN12088 shows great potential to be developed as a new integrated therapeutic agent for NASH.
Subject(s)
Amino Acyl-tRNA Synthetases , Non-alcoholic Fatty Liver Disease , Mice , Animals , Non-alcoholic Fatty Liver Disease/complications , Liver Cirrhosis/metabolism , Fibrosis , Choline , Methionine , Transforming Growth Factor betaABSTRACT
Primary aldosteronism (PA) is a common, yet underdiagnosed cause of secondary hypertension. It is characterized by an overproduction of aldosterone, leading to hypertension and/or hypokalemia. Despite affecting between 5.9% and 34% of patients with hypertension, PA is frequently missed due to a lack of clinical awareness and systematic screening, which can result in significant cardiovascular complications. To address this, medical societies have developed clinical practice guidelines to improve the management of hypertension and PA. The Korean Endocrine Society, drawing on a wealth of research, has formulated new guidelines for PA. A task force has been established to prepare PA guidelines, which encompass epidemiology, pathophysiology, clinical presentation, diagnosis, treatment, and follow-up care. The Korean clinical guidelines for PA aim to deliver an evidence-based protocol for PA diagnosis, treatment, and patient monitoring. These guidelines are anticipated to ease the burden of this potentially curable condition.
Subject(s)
Hyperaldosteronism , Hypertension , Humans , Hyperaldosteronism/diagnosis , Hyperaldosteronism/therapy , Aldosterone , Hypertension/diagnosis , Hypertension/etiology , Hypertension/therapy , Mineralocorticoid Receptor Antagonists/therapeutic use , Republic of Korea/epidemiologyABSTRACT
BACKGRUOUND: This study investigates the long-term efficacy and safety of evogliptin add-on therapy in patients with inadequately controlled type 2 diabetes mellitus (T2DM) previously received dapagliflozin and metformin (DAPA/MET) combination. METHODS: In this multicenter randomized placebo-controlled phase 3 trial, patients with glycosylated hemoglobin (HbA1c) levels 7.0% to 10.5% (n=283) previously used DAPA 10 mg plus MET (≥1,000 mg) were randomly assigned to the evogliptin 5 mg once daily or placebo group (1:1). The primary endpoint was the difference in the HbA1c level from baseline at week 24, and exploratory endpoints included the efficacy and safety of evogliptin over 52 weeks (trial registration: ClinicalTrials.gov NCT04170998). RESULTS: Evogliptin add-on to DAPA/MET therapy was superior in HbA1c reduction compared to placebo at weeks 24 and 52 (least square [LS] mean difference, -0.65% and -0.55%; 95% confidence interval [CI], -0.79 to -0.51 and -0.71 to -0.39; P<0.0001). The proportion of patients achieving HbA1c <7% was higher in the triple combination group at week 52 (32.14% vs. 8.51% in placebo; odds ratio, 5.62; P<0.0001). Evogliptin significantly reduced the fasting glucose levels and mean daily glucose levels with improvement in homeostatic model assessment of ß-cell function (LS mean difference, 9.04; 95% CI, 1.86 to 16.21; P=0.0138). Adverse events were similar between the groups, and no serious adverse drug reactions were reported in the evogliptin group. CONCLUSION: Long-term triple combination with evogliptin added to DAPA/MET showed superior HbA1c reduction and glycemic control compared to placebo at 52 weeks and was well tolerated.
Subject(s)
Diabetes Mellitus, Type 2 , Metformin , Humans , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/chemically induced , Hypoglycemic Agents/adverse effects , Metformin/adverse effects , Glycated Hemoglobin , Drug Therapy, Combination , GlucoseABSTRACT
In vitro investigation of a glomerular filtration barrier (GFB) remains difficult because of the inability to mimic its specialized structure, although various kidney diseases are characterized by GFB dysfunction. Here, the development of a microfluidic model that replicates the physiology of the GFB has been achieved by tunable glomerular basement membrane (gBM) deposition and 3D co-culture of podocytes with glomerular endothelial cells (gECs). By precisely controlling the thickness of the gBM, our model successfully reproduced the biphasic response of the GFB, where variations in gBM thickness influence barrier properties. Moreover, this microscale proximity of gECs and podocytes facilitated their dynamic crosstalk, which is essential for maintaining the integrity and function of the GFB. We observed that addition of gBM and podocytes enhanced barrier function of gECs by inducing up-regulation of gEC's tight junctions synergistically, and moreover, found an ultrastructure of gECs-gBM-podocytes' foot process contacting each other by confocal and TEM imaging. The dynamic interaction of gECs and podocytes played a significant role in the response to drug-induced injury and the regulation of barrier properties. Nephrotoxic injury simulated in our model helped to elucidate that the over-production of vascular endothelial growth factor A from the injured podocytes mediates GFB impairment. We believe that our GFB model can provide a valuable tool for mechanistic studies such as investigating GFB biology, comprehending disease mechanisms, and evaluating potential therapeutic approaches in a controlled and physiologically relevant environment.
Subject(s)
Podocytes , Podocytes/metabolism , Glomerular Filtration Barrier , Endothelial Cells , Vascular Endothelial Growth Factor A/metabolism , Glomerular Basement Membrane/metabolism , Lab-On-A-Chip DevicesABSTRACT
The diabetes mellitus (DM) skin shows skin barrier dysfunction and skin lipid abnormality, similar to conditions induced by systemic or local glucocorticoid excess and aged skin. Inactive glucocorticoid (GC) is converted into active glucocorticoid by 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1). Hyperglycemia in DM and excessive GC are known to increase endoplasmic reticulum (ER) stress. We hypothesized that hyperglycemia affects systemic GC homeostasis and that the action of skin 11ß-HSD1 and GC contributes to increased ER stress and barrier defects in DM. We compared 11ß-HSD1, active GC, and ER stress between hyperglycemic and normoglycemic conditions in normal human keratinocytes and db/db mice. 11ß-HSD1 and cortisol increased with time in keratinocyte culture under hyperglycemic conditions. 11ß-HSD1 siRNA-transfected cells did not induce cortisol elevation in hyperglycemic condition. The production of 11ß-HSD1 and cortisol was suppressed in cell culture treated with an ER stress-inhibitor. The 14-week-old db/db mice showed higher stratum corneum (SC) corticosterone, and skin 11ß-HSD1 levels than 8-week-old db/db mice. Topical 11ß-HSD1 inhibitor application in db/db mice decreased SC corticosterone levels and improved skin barrier function. Hyperglycemia in DM may affect systemic GC homeostasis, activate skin 11ß-HSD1, and induce local GC excess, which increases ER stress and adversely affects skin barrier function.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1 , Endoplasmic Reticulum Stress , Hyperglycemia , Aged , Animals , Humans , Mice , 11-beta-Hydroxysteroid Dehydrogenase Type 1/genetics , Corticosterone , Glucocorticoids , Hydrocortisone , Mice, Inbred Strains , Endoplasmic Reticulum Stress/physiology , Skin/metabolism , Skin/pathologyABSTRACT
AIMS: To evaluate the effect of dapagliflozin on body composition such as total body fat (BF) mass, abdominal visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) areas compared with glimepiride in Korean patients with type 2 diabetes. MATERIALS AND METHODS: This was a 52-week, multicentre, randomized, parallel-group, open-label, Phase IV (NCT02564926) study. Patients with inadequate glycaemic control (glycated haemoglobin ≥7.0% and <10.0%) on metformin monotherapy (≥1000 mg/day) were randomized 1:1 to receive dapagliflozin 10 mg/day or glimepiride 1-2 mg/day for 12 months as an add-on to metformin. Baseline and end of study body composition evaluations included dual-energy X-ray absorptiometry and abdominal computed tomography scans. RESULTS: Of 124 enrolled patients from 14 centres, 121 received study treatment (dapagliflozin: 60; glimepiride: 61) and 106 (85.5%) completed the study. Over 52 weeks, the dapagliflozin group showed the following differences versus the glimepiride group: -2.59 kg BF mass, -1.94% BF%, -17.55 cm2 VAT area, -18.39 cm2 SAT area, -0.46% glycated haemoglobin, -18.25 mg/dl fasting blood glucose, -3.7 kg weight, -2.21 cm waist circumference, -1.37 kg/m2 body mass index, -6.81 mmHg systolic blood pressure and +657.71 ng/ml in adiponectin; all were statistically significant. Both groups had similar incidences of adverse events; however, hypoglycaemic events were mainly (12 of 15) reported in the glimepiride group. CONCLUSION: Dapagliflozin reduced total BF mass, abdominal VAT and SAT areas, and showed better glycaemic control than glimepiride. Being safe and well-tolerated, dapagliflozin appears to be a more favourable alternative to sulphonylureas as add-on therapy after metformin monotherapy failure in Korean patients with type 2 diabetes.
Subject(s)
Diabetes Mellitus, Type 2 , Metformin , Humans , Metformin/therapeutic use , Glycated Hemoglobin , Blood Glucose , Hypoglycemic Agents/adverse effects , Benzhydryl Compounds/adverse effects , Body Composition , Drug Therapy, Combination , Double-Blind Method , Treatment OutcomeABSTRACT
BACKGRUOUND: Curcumin 2005-8 (Cur5-8), a derivative of curcumin, improves fatty liver disease via AMP-activated protein kinase activation and autophagy regulation. EW-7197 (vactosertib) is a small molecule inhibitor of transforming growth factor ß (TGF-ß) receptor I and may scavenge reactive oxygen species and ameliorate fibrosis through the SMAD2/3 canonical pathway. This study aimed to determine whether co-administering these two drugs having different mechanisms is beneficial. METHODS: Hepatocellular fibrosis was induced in mouse hepatocytes (alpha mouse liver 12 [AML12]) and human hepatic stellate cells (LX-2) using TGF-ß (2 ng/mL). The cells were then treated with Cur5-8 (1 µM), EW-7197 (0.5 µM), or both. In animal experiments were also conducted during which, methionine-choline deficient diet, Cur5-8 (100 mg/kg), and EW-7197 (20 mg/kg) were administered orally to 8-week-old C57BL/6J mice for 6 weeks. RESULTS: TGF-ß-induced cell morphological changes were improved by EW-7197, and lipid accumulation was restored on the administration of EW-7197 in combination with Cur5-8. In a nonalcoholic steatohepatitis (NASH)-induced mouse model, 6 weeks of EW-7197 and Cur5-8 co-administration alleviated liver fibrosis and improved the nonalcoholic fatty liver disease (NAFLD) activity score. CONCLUSION: Co-administering Cur5-8 and EW-7197 to NASH-induced mice and fibrotic hepatocytes reduced liver fibrosis and steatohepatitis while maintaining the advantages of both drugs. This is the first study to show the effect of the drug combination against NASH and NAFLD. Similar effects in other animal models will confirm its potential as a new therapeutic agent.
Subject(s)
Curcumin , Non-alcoholic Fatty Liver Disease , Mice , Humans , Animals , Non-alcoholic Fatty Liver Disease/drug therapy , Curcumin/pharmacology , Curcumin/therapeutic use , Mice, Inbred C57BL , Liver Cirrhosis/drug therapy , Liver Cirrhosis/metabolism , Fibrosis , Transforming Growth Factor beta/metabolism , Transforming Growth Factors/therapeutic useABSTRACT
AIMS: To evaluate the efficacy and safety of a novel sodium-glucose cotransporter 2 inhibitor, enavogliflozin 0.3 mg monotherapy, in Korean people with type 2 diabetes mellitus (T2DM) inadequately controlled with diet and exercise. MATERIALS AND METHODS: This study was a randomized, double-blind, placebo-controlled trial conducted in 23 hospitals. Individuals with haemoglobin A1c (HbA1c) of 7.0%-10.0% after at least 8 weeks of diet and exercise modification were randomized to receive enavogliflozin 0.3 mg (n = 83) or placebo (n = 84) for 24 weeks. The primary outcome was a change in HbA1c at week 24 from baseline. Secondary outcomes included the proportion of participants achieving HbA1c <7.0%, change in fasting glucose, body weight and lipid levels. Adverse events were investigated throughout the study. RESULTS: At week 24, the placebo-adjusted mean change in HbA1c from baseline in the enavogliflozin group was -0.99% (95% confidence interval -1.24%, -0.74%). The proportions of patients achieving HbA1c <7.0% (71% vs. 24%) at week 24 was significantly higher in the enavogliflozin group (p < .0001). Placebo-adjusted mean changes in fasting plasma glucose (-40.1 mg/dl) and body weight (-2.5 kg) at week 24 were statistically significant (p < .0001). In addition, a significant decrease in blood pressure, low-density lipoprotein cholesterol, triglyceride, and homeostasis model assessment of insulin resistance were observed, along with a significant increase in high-density lipoprotein cholesterol. No significant increase in treatment-related adverse events was observed for enavogliflozin. CONCLUSIONS: Monotherapy with enavogliflozin 0.3 mg improved glycaemic control in people with T2DM. Enavogliflozin therapy also exerted beneficial effects on body weight, blood pressure and lipid profile.
Subject(s)
Diabetes Mellitus, Type 2 , Sodium-Glucose Transporter 2 Inhibitors , Humans , Blood Glucose , Body Weight , Cholesterol , Double-Blind Method , Glycated Hemoglobin , Hypoglycemic Agents/adverse effects , Hypoglycemic Agents/therapeutic use , Lipids , Republic of Korea/epidemiology , Sodium-Glucose Transporter 2 Inhibitors/adverse effects , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Treatment OutcomeABSTRACT
PURPOSE: Among the characteristics of non-alcoholic fatty liver disease (NAFLD), hepatic steatosis is due to excessive fat accumulation and causes liver damage and lipotoxicity, which are associated with insulin resistance, endoplasmic reticulum (ER) stress, and apoptosis. Umbelliferone (UMB) has various powerful pharmacological properties, such as antioxidant, anti-hyperglycemic, anti-viral, and anti-inflammatory effects. However, the mechanism of action in hepatic steatosis and lipid-induced ER stress is still unclear. Thus, the efficacy of UMB in hepatic steatosis and palmitate (PA)-induced hepatocellular lipotoxicity was evaluated in the present study. MATERIALS AND METHODS: Male C57BL/6J mice (n=40) were divided into four groups: regular diet (RD), UMB-supplemented RD, high-fat diet (HFD), and UMB-supplemented HFD. All mice were fed orally for 12 weeks. In addition, the effects of UMB on lipotoxicity were investigated in AML12 cells treated with PA (250 µM) for 24 h; Western blot analysis was used to evaluate the changes in ER stress and apoptotic-associated proteins. RESULTS: Administration with UMB in HFD-fed mice reduced lipid accumulation and hepatic triglyceride (TG) as well as serum insulin and glucose levels. In AML12 cells, UMB treatment reduced lipid accumulation as indicated by decreases in the levels of lipogenesis markers, such as SREBP1, FAS, PPAR-γ, and ADRP. Furthermore, UMB reduced both oxidative stress and ER stress-related cellular apoptosis. CONCLUSION: UMB supplementation ameliorated hepatic steatosis and improved insulin resistance by inhibiting lipid accumulation and regulating ER stress. These findings strongly suggest that UMB may be a potential therapeutic compound against NAFLD.
Subject(s)
Insulin Resistance , Non-alcoholic Fatty Liver Disease , Male , Animals , Mice , Non-alcoholic Fatty Liver Disease/drug therapy , Mice, Obese , Diet, High-Fat/adverse effects , Mice, Inbred C57BL , Liver/metabolism , Lipids , Lipid MetabolismABSTRACT
AIM: To determine whether the twice-daily (BID) regimen is superior to the once-daily (QD) regimen for managing glycaemic variability by comparing the effects of anagliptin 100 mg BID versus sitagliptin 100 mg QD. MATERIALS AND METHODS: A double-blinded, randomized, multicentre study was performed in 89 patients with type 2 diabetes treated with metformin alone (6.5% < HbA1c < 8.5%). Subjects were randomly assigned to anagliptin 100 mg BID or sitagliptin 100 mg QD in a 1:1 ratio for 12 weeks. Continuous glucose monitoring was used to measure the mean amplitude of glycaemic excursion (MAGE) and postprandial time in range (TIR) before and after dipeptidyl peptidase-4 (DPP-4) inhibitor treatment to compare glycaemic variability. RESULTS: The decrease from baseline in MAGE at 12 weeks after DPP-4 inhibitor treatment was significantly greater in the anagliptin BID group than in the sitagliptin QD group (P < .05); -30.4 ± 25.6 mg/dl (P < .001) in the anagliptin group versus -9.5 ± 38.0 mg/dl (P = .215) in the sitagliptin group. The TIR after dinner increased by 33.0% ± 22.0% (P < .001) in the anagliptin group and by 14.6% ± 28.2% (P = .014) in the sitagliptin group, with a statistically significant difference (P = .009). No statistically significant differences were observed between the groups in the changes in HbA1c and fasting plasma glucose (FPG). CONCLUSIONS: The anagliptin BID regimen for the treatment of type 2 diabetes was superior in blood glucose control after dinner to improve glycaemic variability, as indicated by MAGE and TIR, but was equivalent to the QD regimen in terms of HbA1c and FPG.
Subject(s)
Diabetes Mellitus, Type 2 , Dipeptidyl-Peptidase IV Inhibitors , Metformin , Humans , Glycated Hemoglobin , Blood Glucose Self-Monitoring , Blood Glucose , Treatment Outcome , Hypoglycemic Agents/therapeutic use , Sitagliptin Phosphate/adverse effects , Metformin/therapeutic use , Dipeptidyl-Peptidase IV Inhibitors/adverse effects , Protease Inhibitors/therapeutic use , Drug Therapy, Combination , Double-Blind MethodSubject(s)
Adenoma , Adrenal Gland Neoplasms , Cushing Syndrome , Adenoma/complications , Adenoma/surgery , Adrenal Gland Neoplasms/complications , Adrenal Gland Neoplasms/diagnosis , Adrenal Gland Neoplasms/surgery , Adrenalectomy , Cushing Syndrome/complications , Cushing Syndrome/diagnosis , Cushing Syndrome/surgery , Humans , Neoplasm Recurrence, LocalABSTRACT
AIMS/INTRODUCTION: We investigated the classification of diabetic peripheral neuropathy (DPN) patients by subjective symptoms, and identification of the relationship between the patterns and intensities of symptoms and the clustered groups of DPN patients. MATERIALS AND METHODS: This multicenter study analyzed epidemiological data and sensory symptoms of 649 patients with DPN. Cluster analysis was carried out to identify subgroups of patients with characteristic symptom profiles. Factor analysis was carried out to investigate the symptom patterns of the clustered groups of DPN patients. RESULTS: Three clusters of patients with DPN were identified: severe symptoms with decreased quality of life (cluster 1, n = 119, 18.3%), predominantly insensate symptoms with relatively good quality of life (cluster 2, n = 318, 49.0%), and moderate pain intensity and decreased quality of life (cluster 3, n = 204, 31.4%). The frequency of symptoms on each item of the Michigan Neuropathy Screening Instrument questionnaire showed a similar distribution according to pain intensities along with the three clusters. CONCLUSIONS: Our study supports the hypothesis that diversity in sensory symptoms exists in patients with DPN. Heterogeneity in DPN patients should be taken into account for a more stratified or individualized treatment approach. Based on a multicenter study, we identified three clusters of patients with DPN. Our research supports the hypothesis that diversity in sensory symptoms exists in patients with DPN. Heterogeneity in DPN patients should be taken into account for a more stratified or individualized treatment approach.
Subject(s)
Diabetes Mellitus, Type 2 , Diabetic Neuropathies , Humans , Diabetes Mellitus, Type 2/complications , Diabetic Neuropathies/epidemiology , Pain , Phenotype , Quality of LifeABSTRACT
Podocyte loss is well known to play a critical role in the early progression of diabetic nephropathy. A growing number of studies are paying attention to necroptosis, a programmed form of cell necrosis as a mechanism of podocyte loss. Although necroptosis is a recently established concept, the significance of receptor interacting serine/threonine kinase 3 (RIPK3), a gene that encodes for the homonymous enzyme RIPK3 responsible for the progression of necroptosis, is well studied. Curcumin, a natural hydrophobic polyphenol compound responsible for the yellow color of Curcuma longa, has drawn attention due to its antioxidant and anti-inflammatory effects on cells prone to necroptosis. Nonetheless, effects of curcumin on high glucose-induced podocyte necroptosis have not been reported yet. Therefore, this study investigated RIPK3 expression in high glucose-treated podocytes to identify the involvement of necroptosis via the RIPK3 pathway and the effects of curcumin treatment on RIPK3-dependent podocytopathy in a hyperglycemic environment. The study discovered that increased reactive oxygen species (ROS) in renal podocytes induced by high glucose was improved after curcumin treatment. Curcumin treatment also significantly restored the upregulated levels of VEGF, TGF-ß, and CCL2 mRNAs and the downregulated level of nephrin mRNA in cultured podocytes exposed to a high glucose environment. High glucose-induced changes in protein expression of TGF-ß, nephrin, and CCL2 were considerably reverted to their original levels after curcumin treatment. Increased expression of RIPK3 in high glucose-stimulated podocytes was alleviated by curcumin treatment as well as N-acetyl cysteine (NAC, an antioxidant) or GSK'872 (a RIPK3 inhibitor). Consistent with this, the increased necroptosis-associated molecules, such as RIPK3, pRIPK3, and pMLKL, were also restored by curcumin in high glucose-treated mesangial cells. DCF-DA assay confirmed that such a result was attributed to the reduction of RIPK3 through the antioxidant effect of curcumin. Further observations of DCF-DA-sensitive intracellular ROS in NAC-treated and GSK'872-treated podocyte groups showed a reciprocal regulatory relationship between ROS and RIPK3. The treatment of curcumin and GSK'872 in podocytes incubated with high glucose protected from excessive intracellular superoxide anion production. Taken together, these results indicate that curcumin treatment can protect against high glucose-induced podocyte injuries by suppressing the abnormal expression of ROS and RIPK3. Thus, curcumin might be a potential therapeutic agent for diabetic nephropathy as an inhibitor of RIPK3.
ABSTRACT
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.
ABSTRACT
BACKGROUND: Thiazolidinediones (TZDs) have been associated with various safety concerns including weight gain, bladder cancer, and congestive heart failure (CHF). This study evaluated the efficacy and safety of lobeglitazone, a novel TZD in patients with type 2 diabetes mellitus (T2DM) in real practice. METHODS: In this non-interventional, multi-center, retrospective, and observational study conducted at 15 tertiary or secondary referral hospitals in Korea, a total of 2,228 patients with T2DM who received lobeglitazone 0.5 mg for more than 1 year were enrolled. RESULTS: Overall adverse events (AEs) occurred in 381 patients (17.10%) including edema in 1.97% (n=44). Cerebrovascular and cardiovascular diseases were identified in 0.81% (n=18) and 0.81% (n=18), respectively. One case of CHF was reported as an AE. Edema occurred in 1.97% (n=44) of patients. Hypoglycemia occurred in 2.47% (n=55) of patients. Fracture occurred in 1.17% (n=26) of all patients. Lobeglitazone significantly decreased HbA1c level, resulting in a mean treatment difference of -1.05%± 1.35% (P<0.001), and decreased total cholesterol, triglyceride, and low-density lipoprotein cholesterol. However, it increased high-density lipoprotein cholesterol, regardless of statin administration. The patients who received lobeglitazone 0.5 mg showed an apparent reduction in glycosylated hemoglobin (HbA1c) from baseline during the first 6 months of treatment. The HbA1c levels remained stable between months 6 and 42. CONCLUSION: Lobeglitazone has long-term safety profile, good glycemic-lowering effect and long-term durability of glycemic control in real-world clinical settings.