Cysteine-rich 61 inhibition attenuates hepatic insulin resistance and improves lipid metabolism in high-fat diet fed mice and HepG2 cells.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly associated with insulin resistance development. Hepatic lipid accumulation and inflammation are considered the main drivers of hepatic insulin resistance in MASLD. Cysteine-rich 61 (Cyr61 also called CCN1), a novel secretory matricellular protein, is implicated in liver inflammation, and its role in MASLD is not clearly understood. Therefore, we investigated the role of Cyr61 in hepatic insulin resistance and lipid metabolism as major factors in MASLD pathogenesis. In high-fat diet (HFD)-fed C57BL/6J mice, Cyr61 was downregulated or upregulated via viral transduction. Measurements of glucose homeostasis, histological assessment of liver tissues, and gene expression and signaling pathways of lipogenesis, fatty acid oxidation, and inflammation were performed using liver samples from these mice. Cyr61 levels in HepG2 cells were reduced using RNAi-mediated gene knockdown. Inflammation and insulin resistance were evaluated using real-time polymerase chain reaction and western blotting. HFD/AAV-shCyr61 mice exhibited enhanced glucose tolerance via the protein kinase B pathway, reduced hepatic inflammation, decreased lipogenesis, and increased fatty acid oxidation. Notably, HFD/AAV-shCyr61 mice showed elevated protein expression of sirtuin 6 and phosphorylated-AMP-activated protein kinase. In vitro experiments demonstrated that inhibition of Cyr61 downregulated pro-inflammatory cytokines such as interleukin-1 beta, IL-6, and tumor necrosis factor-alpha via the nuclear factor kappa B/c-Jun N-terminal kinase pathway, and alleviated insulin resistance. Cyr61 affected hepatic inflammation, lipid metabolism, and insulin resistance. Inhibition of Cyr61 reduced inflammation, recovered insulin resistance, and altered lipid metabolism in vivo and in vitro. Therefore, Cyr61 is a potential therapeutic target in MASLD.

Maternal mRNAs with distinct 3' UTRs define the temporal pattern of Ccnb1 synthesis during mouse oocyte meiotic maturation.

The final stages of female gamete maturation occur in the virtual absence of transcription, with gene expression driven by a program of selective unmasking, translation, and degradation of maternal mRNAs. Here we demonstrate that the timing of Ccnb1 mRNA translation in mouse oocytes is dependent on the presence of transcripts with different 3' untranslated regions (UTRs). This 3' UTR heterogeneity directs distinct temporal patterns of translational activation or repression. Inclusion or exclusion of cis-acting elements is responsible for these divergent regulations. Our findings reveal an additional layer of translation control through alternative polyadenylation usage required to fine-tune the timing of meiosis progression.

Efficacy and safety of dapagliflozin add-on to evogliptin plus metformin therapy in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled study.

AIM: To evaluate the efficacy and safety of dapagliflozin versus placebo as an add-on in patients with type 2 diabetes who did not achieve adequate glycaemic control with evogliptin and metformin combination. PATIENTS AND METHODS: In this multicentre, randomized, double-blind, placebo-controlled Phase 3 trial, patients with glycated haemoglobin (HbA1c) levels ≥7.0% (≥53 mmol/mol) and ≤10.5% (≤91 mmol/mol) who had received stable-dose metformin (≥1000 mg) and evogliptin (5 mg) for at least 8 weeks were randomized to receive dapagliflozin 10 mg or placebo once daily for 24 weeks. Participants continued treatment with metformin and evogliptin. The primary endpoint was change in HbA1c level after 24 weeks of treatment from baseline level. RESULTS: In total, 198 patients were randomized, and 195 patients were included in the efficacy analyses (dapagliflozin: 96, placebo: 99). At Week 24, dapagliflozin significantly reduced HbA1c levels. The least squares mean difference in HbA1c level change from baseline after 24 weeks of treatment was -0.70% (-7.7 mmol/mol) (p < 0.0001). The proportion of participants achieving HbA1c <7.0% (≥53 mmol/mol) was higher in the dapagliflozin group than in the placebo group. Compared to placebo, dapagliflozin significantly reduced fasting plasma glucose, mean daily glucose, 2-h postprandial plasma glucose, fasting insulin, uric acid and gamma-glutamyl transferase levels, homeostatic model assessment for insulin resistance index, body weight, hepatic steatosis index, and albuminuria. Adiponectin level significantly increased from baseline level after 24 weeks of dapagliflozin treatment. Adverse event rates were similar in the two groups. CONCLUSION: Dapagliflozin add-on to evogliptin plus metformin improved glycaemic control and was well tolerated by the target patients.

Imeglimin attenuates NLRP3 inflammasome activation by restoring mitochondrial functions in macrophages.

Imeglimin is a novel oral antidiabetic drug for treating type 2 diabetes. However, the effect of imeglimin on NLRP3 inflammasome activation has not been investigated yet. Here, we aimed to investigate whether imeglimin reduces LPS-induced NLRP3 inflammasome activation in THP-1 macrophages and examine the associated underlying mechanisms. We analyzed the mRNA and protein expression levels of NLRP3 inflammasome components and IL-1ß secretion. Additionally, reactive oxygen species (ROS) generation, mitochondrial membrane potential, and mitochondrial permeability transition pore (mPTP) opening were measured by flow cytometry. Imeglimin inhibited NLRP3 inflammasome-mediated IL-1ß production in LPS-stimulated THP-1-derived macrophages. In addition, imeglimin reduced LPS-induced mitochondrial ROS production and mitogen-activated protein kinase phosphorylation. Furthermore, imeglimin restored the mitochondrial function by modulating mitochondrial membrane depolarization and mPTP opening. We demonstrated for the first time that imeglimin reduces LPS-induced NLRP3 inflammasome activation by inhibiting mPTP opening in THP-1 macrophages. These results suggest that imeglimin could be a promising new anti-inflammatory agent for treating diabetic complications.

Amphiregulin Induces iNOS and COX-2 Expression through NF-κB and MAPK Signaling in Hepatic Inflammation.

Background: Inflammation is a major cause of hepatic tissue damage and accelerates the progression of nonalcoholic fatty liver disease (NAFLD). Amphiregulin (AREG), an epidermal growth factor receptor ligand, is associated with human liver cirrhosis and hepatocellular carcinoma. We aimed to investigate the effects of AREG on hepatic inflammation during NAFLD progression, in vivo and in vitro. Methods: AREG gene expression was measured in the liver of mice fed a methionine choline-deficient (MCD) diet for 2 weeks. We evaluated inflammatory mediators and signaling pathways in HepG2 cells after stimulation with AREG. Nitric oxide (NO), prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) were analyzed using an enzyme-linked immunosorbent assay and western blotting. Nuclear transcription factor kappa-B (NF-κB) and mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase, were analyzed using western blotting. Results: Proinflammatory cytokines (interleukin (IL)-6, IL-1ß, and IL-8) and immune cell recruitment (as indicated by L3T4, F4/80, and ly6G mRNA expression) increased, and expression of AREG increased in the liver of mice fed the MCD diet. AREG significantly increased the expression of IL-6 and IL-1ß and the production of NO, PGE2, and IL-8 in HepG2 cells. It also activated the protein expression of iNOS and COX-2. AREG-activated NF-κB and MAPKs signaling, and together with NF-κB and MAPKs inhibitors, AREG significantly reduced the protein expression of iNOS and COX-2. Conclusion: AREG plays a role in hepatic inflammation by increasing iNOS and COX-2 expression via NF-κB and MAPKs signaling.

Meiotic Cell Cycle Progression in Mouse Oocytes: Role of Cyclins.

All eukaryotic cells, including oocytes, utilize an engine called cyclin-dependent kinase (Cdk) to drive the cell cycle. Cdks are activated by a co-factor called cyclin, which regulates their activity. The key Cdk-cyclin complex that regulates the oocyte cell cycle is known as Cdk1-cyclin B1. Recent studies have elucidated the roles of other cyclins, such as B2, B3, A2, and O, in oocyte cell cycle regulation. This review aims to discuss the recently discovered roles of various cyclins in mouse oocyte cell cycle regulation in accordance with the sequential progression of the cell cycle. In addition, this review addresses the translation and degradation of cyclins to modulate the activity of Cdks. Overall, the literature indicates that each cyclin performs unique and redundant functions at various stages of the cell cycle, while their expression and degradation are tightly regulated. Taken together, this review provides new insights into the regulatory role and function of cyclins in oocyte cell cycle progression.

Mitochondrial protease ClpP supplementation ameliorates diet-induced NASH in mice.

BACKGROUND & AIMS: Mitochondrial dysfunction is considered a pathogenic linker in the development of non-alcoholic steatohepatitis (NASH). Inappropriate mitochondrial protein-quality control, possibly induced by insufficiency of the mitochondrial matrix caseinolytic protease P (ClpP), can potentially cause mitochondrial dysfunction. Herein, we aimed to investigate hepatic ClpP levels in a diet-induced model of NASH and determine whether supplementation of ClpP can ameliorate diet-induced NASH. METHODS: NASH was induced by a high-fat/high-fructose (HF/HFr) diet in C57BL/6J mice. Stress/inflammatory signals were induced in mouse primary hepatocytes (MPHs) by treatment with palmitate/oleate (PA/OA). ClpP levels in hepatocytes were reduced using the RNAi-mediated gene knockdown technique but increased through the viral transduction of ClpP. ClpP activation was induced by administering a chemical activator of ClpP. RESULTS: Hepatic ClpP protein levels in C57BL/6J mice fed a HF/HFr diet were lower than the levels in those fed a normal chow diet. PA/OA treatment also decreased the ClpP protein levels in MPHs. Overexpression or activation of ClpP reversed PA/OA-induced mitochondrial dysfunction and stress/inflammatory signal activation in MPHs, whereas ClpP knockdown induced mitochondrial dysfunction and stress/inflammatory signals in these cells. On the other hand, ClpP overexpression or activation improved HF/HFr-induced NASH characteristics such as hepatic steatosis, inflammation, fibrosis, and injury in the C57BL/6J mice, whereas ClpP knockdown further augmented steatohepatitis in mice fed a HF/HFr diet. CONCLUSIONS: Reduced ClpP expression and subsequent mitochondrial dysfunction are key to the development of diet-induced NASH. ClpP supplementation through viral transduction or chemical activation represents a potential therapeutic strategy to prevent diet-induced NASH. LAY SUMMARY: Western diets, containing high fat and high fructose, often induce non-alcoholic steatohepatitis (NASH). Mitochondrial dysfunction is considered pathogenically linked to diet-induced NASH. We observed that the mitochondrial protease ClpP decreased in the livers of mice fed a western diet and supplementation of ClpP ameliorated western diet-induced NASH.

Hepatoprotective effects of gemigliptin and empagliflozin in a murine model of diet-induced non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) includes a broad spectrum of liver diseases characterized by steatosis, inflammation, and fibrosis. This study aimed to investigate the potential of dipeptidyl peptidase-4 inhibitors and sodium-glucose cotransporter 2 inhibitors in alleviating the progression of NAFLD. The NAFLD model was generated by feeding male C57BL/6J mice a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) for 7 weeks. After 2 weeks of CDAHFD feeding, the NAFLD model mice were assigned to four groups, namely (ⅰ) VEHICLE, (ⅱ) gemigliptin (GEMI), (ⅲ) empagliflozin (EMPA), and (ⅳ) GEMI + EMPA. For the next 5 weeks, mice received the vehicle or the drug based upon the group to which they belonged. Thereafter, the triglyceride concentration, extent of fibrosis, and the expression of genes encoding inflammatory cytokines, chemokines, and antioxidant enzymes were analyzed in the livers of mice. The NAFLD activity score and hepatic fibrosis grade were assessed via hematoxylin and eosin and Sirius Red staining of the liver tissue samples. All mice belonging to the GEMI, EMPA, and GEMI + EMPA groups showed improvements in the accumulation of liver triglycerides and the expression of inflammatory cytokines and chemokines. Additionally, the oxidative stress was reduced due to inhibition of the c-Jun N-terminal kinase pathway and upregulation of the antioxidant enzymes. Furthermore, in these three groups, the galectin-3 and interleukin 33-induced activity of tumor necrosis factor-α was inhibited, thereby preventing the progression of liver fibrosis. These findings suggest that the GEMI, EMPA, and GEMI + EMPA treatments ameliorate hepatic steatosis, inflammation, oxidative stress, and fibrosis in CDAHFD-induced NAFLD mouse models.

Coenzyme Q10 ameliorates the quality of mouse oocytes during in vitro culture.

Oxidative stress causes several diseases and dysfunctions in cells, including oocytes. Clearly, oxidative stress influences oocyte quality during in vitro maturation and fertilization. Here we tested the ability of coenzyme Q10 (CoQ10) to reduce reactive oxygen species (ROS) and improve mouse oocyte quality during in vitro culture. Treatment with 50 µM CoQ10 efficiently reduced ROS levels in oocytes cultured in vitro. The fertilizable form of an oocyte usually contains a cortical granule-free domain (CGFD). CoQ10 enhanced the ratio of CGFD-oocytes from 35% to 45%. However, the hardening of the zona pellucida in oocytes was not affected by CoQ10 treatment. The in vitro maturation capacity of oocytes, which was determined by the first polar body extrusion, was enhanced from 48.9% to 75.7% by the addition of CoQ10 to the culture medium. During the parthenogenesis process, the number of two-cell embryos was increased by CoQ10 from 43.5% to 67.3%. Additionally, treatment with CoQ10 increased the expression of Bcl2 and Sirt1 in cumulus cells. These results suggested that CoQ10 had a positive effect on ROS reduction, maturation rate and two-cell embryo formation in mouse oocyte culture.

Effectiveness and safety of sodium-glucose co-transporter-2 inhibitors compared with dipeptidyl peptidase-4 inhibitors in older adults with type 2 diabetes: A nationwide population-based study.

AIM: To examine the real-world cardiovascular effectiveness and safety associated with sodium-glucose co-transporter-2 (SGLT2) inhibitor compared with dipeptidyl peptidase-4 (DPP-4) inhibitor treatment in older adults with type 2 diabetes. MATERIALS AND METHODS: In this retrospective cohort study, older adults with type 2 diabetes (aged ≥65 years) were identified in the Korean National Health Insurance Service database from September 2014 to December 2016. In total, 408 506 new users of an SGLT2 inhibitor or DPP-4 inhibitor were propensity score matched. Cox regression was used to estimate the hazard ratios (HR) and 95% confidence interval (CI) for outcomes of interest: hospitalization for heart failure (HHF), all-cause death, myocardial infarction, stroke, diabetic ketoacidosis (DKA), bone fracture, severe hypoglycaemia, genital infection and urinary tract infection (UTI). RESULTS: Compared with DPP-4 inhibitors, new users of SGLT2 inhibitors had a lower risk of HHF (HR 0.86; 95% CI 0.76-0.97), all-cause death (HR 0.85; 95% CI 0.75-0.98) and stroke (HR 0.86; 95% CI 0.77-0.97), but a similar risk of myocardial infarction (HR 0.95; 95% CI 0.77-1.19). The risks of DKA, bone fracture and severe hypoglycaemia were similar between both groups, although genital infection (HR 2.44; 95% CI 2.22-2.67) and UTI (HR 1.05; 95% CI 1.00-21.11) were more frequent among new users of SGLT2 inhibitors compared with DPP-4 inhibitors. CONCLUSION: Our findings suggest that initiation of SGLT2 inhibitors offers cardiovascular disease protection and can be used safely in older adults with type 2 diabetes.

Visfatin exacerbates hepatic inflammation and fibrosis in a methionine-choline-deficient diet mouse model.

BACKGROUND AND AIM: Non-alcoholic fatty liver disease (NAFLD) ranges from simple steatosis to non-alcoholic steatohepatitis, which is characterized by hepatic inflammation that can progress to fibrosis, cirrhosis, and hepatocellular carcinoma. Visfatin, an adipocytokine, was reported to induce pro-inflammatory cytokines and can be associated with liver fibrosis. We investigated the role of visfatin on hepatic inflammation and fibrosis in a methionine-choline-deficient (MCD)-diet-induced steatohepatitis mouse model. METHODS: Eight-week-old male C57BL/6 J mice were randomly assigned into one of three groups: (1) saline-injected control diet group; (2) saline-injected MCD diet group; and (3) visfatin-injected MCD diet group (n = 8 per group). Mice were administered intravenous saline or 10 µg/kg of recombinant murine visfatin for 2 weeks. Histologic assessment of liver and biochemical and molecular measurements of endoplasmic reticulum (ER) stress, reactive oxidative stress (ROS), inflammation, and fibrosis were performed in livers from these animals. RESULTS: Visfatin injection aggravated hepatic steatosis and increased plasma alanine aminotransferase and aspartate aminotransferase concentrations. Visfatin increased inflammatory cell infiltration (as indicated by F4/80, CD68, ly6G, and CD3 mRNA expression) and expression of chemokines in the liver. Visfatin also increased the expression of pro-inflammatory cytokines (IL-1ß, TNF-α, and IL-6) and activated fibrosis markers (CTGF, TIMP1, collagen 1α2, collagen 3α2, αSMA, fibronectin, and vimentin) in liver. Livers of visfatin-injected mice showed upregulation of ER stress and ROS and activation of JNK signaling. CONCLUSIONS: These results suggest that visfatin aggravates hepatic inflammation together with induction of ER and oxidative stress and exacerbates fibrosis in an MCD-diet-fed mouse model of NAFLD.

Acute Glucose Shift Induces the Activation of the NLRP3 Inflammasome in THP-1 Cells.

We aimed to investigate the effect of acute glucose shift on the activation of the NLRP3 inflammasome, IL-1ß secretion, and underlying signaling pathways in THP-1 cells. THP-1 cells were divided into four groups and exposed to the following glucose concentrations for 24 h: constant normal glucose (NG, 5.5 mM), constant high glucose (HG, 25 mM), normal to high glucose shift (NG-to-HG, 5.5 to 25 mM), and high to normal glucose shift (HG-to-NG, 25 to 5.5 mM). Cell viability, oxidative stress, and the levels of NLRP3 inflammasome components were assessed. Both directions of the acute glucose shift increased the activation of the NLRP3 inflammasome, generation of reactive oxygen species (ROS), and expression of phosphorylated p38 MAPK, JNK, and NF-κB compared with either constant NG or HG. Treatment with N-acetylcysteine, a pharmacological antioxidant, inhibited the acute glucose shift-induced generation of ROS, activation of NLRP3 inflammasome, and upregulation of MAPK-NF-κB. Further analysis using inhibitors of p38 MAPK, JNK, and NF-κB indicated that acute glucose shifts promoted IL-1ß secretion by activating the signaling pathway in a ROS-MAPK-NF-κB-NLRP3 inflammasome in THP-1 cells. These findings suggested that acute changes in glucose concentration might cause monocyte inflammation, which is associated with diabetic complications.

5'-UTR and ORF elements, as well as the 3'-UTR regulate the translation of Cyclin.

Mammalian oocyte maturation is wholly dependent on the translation of accumulated maternal transcripts. Therefore, measuring the translation of specific genes, especially Ccnb1 and Ccnb2, which are key regulators of the oocyte cell cycle in mice, is essential to monitor oocyte cell cycle progression. For this purpose, almost all previous research has used a reporter construct containing the 3'-untranslated region (UTR) of Ccnb. It is based on the concept that the 3'-UTR is the main modulator of translation. Here, we investigated the expression pattern of Renilla luciferase (RL) reporters combining the 5'-UTR and/or open reading frame (ORF) as well as the 3'-UTR (RL-3', 5'-RL-3', RL-ORF-3', and 5'-RL-ORF-3') of Ccnb1 and Ccnb2 in somatic cells and mouse oocytes. The addition of the 5'-UTR and/or ORF of Ccnb altered the expression of the RL-3' reporter in HEK293T cells and mouse oocytes. The ORF tended to suppress RL expression, whereas the 5'-UTR enhanced the expression in most cases. The increased rate in expression was the highest when only the 3'-UTR of Ccnb1 (RL-3') was used, whereas the 5'-RL-ORF-3' reporter showed a relatively lower increase during oocyte maturation. For Ccnb2, the RL-ORF-3' reporter showed the largest increase, and other reporters exhibited a similar increase in expression during oocyte maturation. Results show that the expression of these genes is modulated not only by the 3'-UTR but also by the 5'-UTR and ORF. Therefore, special caution should be taken when using only the 3'-UTR to monitor the expression of specific genes.

CCL20 induced by visfatin in macrophages via the NF-κB and MKK3/6-p38 signaling pathways contributes to hepatic stellate cell activation.

Chemokines interact with hepatic resident cells during inflammation and fibrosis. CC chemokine ligand (CCL) 20 has been reported to be important in inflammation and fibrosis in the liver. We hypothesized that visfatin, an adipocytokine, could play a role in hepatic fibrosis via CCL20. We investigated the effect of visfatin on CCL20 in THP-1 human promonocytic cells and examined the molecular mechanisms involved. Following treatment of THP-1 cells with visfatin, CCL20 expression and secretion were assessed. We assessed the intracellular signaling molecules IKK/NF-κB, JAK2/STAT3, MAPKs, and MKK3/6 by western blotting. We treated THP-1 cells with visfatin and signaling inhibitors, and examined CCL20 mRNA and protein levels. To investigate the effect of visfatin-induced CCL20 expression in hepatic stellate cells (HSCs), LX-2 cells were co-cultured with the culture supernatant of THP-1 cells with or without anti-CCL20 neutralizing antibodies, and fibrosis markers were examined by RT-PCR and immunoblotting. In THP-1 cells, visfatin increased the CCL20 mRNA and protein levels. visfatin increased the activities of the NF-κB, p38, and MLK3/6 signaling pathways but not those of the JAK2/STAT3 and ERK pathways. Visfatin treatment together with an NF-κB, p38, or MLK3 inhibitor reduced the mRNA and protein levels of CCL20. The visfatin-induced CCL20 increased the expression of fibrosis markers and CCR6 in HSCs. Following neutralization of CCL20, the levels of fibrosis markers and CCR6 were decreased. Visfatin increases the expression of CCL20 via the NF-κB and MKK3/6-p38 signaling pathways in macrophages, and visfatin-induced CCL20 expression promotes the fibrosis markers in HSCs.

The Association of Adiponectin and Visceral Fat with Insulin Resistance and ß-Cell Dysfunction.

BACKGROUND: Obesity is a risk factor for metabolic abnormalities. We investigated the relationship of adiponectin levels and visceral adiposity with insulin resistance and ß-cell dysfunction. METHODS: This cross-sectional study enrolled 1,347 participants (501 men and 846 women aged 30-64 years) at the Cardiovascular and Metabolic Diseases Etiology Research Center. Serum adiponectin levels and visceral fat were measured using enzyme-linked immunosorbent assay kits and dual-energy X-ray absorptiometry, respectively. Insulin resistance was evaluated using the homeostatic model assessment of insulin resistance (HOMA-IR) and Matsuda insulin sensitivity index. ß-cell dysfunction was evaluated using the homeostatic model assessment of ß-cell function (HOMA-ß), insulinogenic index, and disposition index. RESULTS: Regarding insulin resistance, compared with individuals with the highest adiponectin levels and visceral fat mass < 75th percentile, the fully adjusted odds ratios (ORs) for HOMA-IR ≥ 2.5 and Matsuda index < 25th percentile were 13.79 (95% confidence interval, 7.65-24.83) and 8.34 (4.66-14.93), respectively, for individuals with the lowest adiponectin levels and visceral fat ≥ 75th percentile. Regarding ß-cell dysfunction, the corresponding ORs for HOMA-ß < 25th percentile, insulinogenic index < 25th percentile, and disposition index < 25th percentile were 1.20 (0.71-2.02), 1.01 (0.61-1.66), and 1.87 (1.15-3.04), respectively. CONCLUSION: Low adiponectin levels and high visceral adiposity might affect insulin resistance and ß-cell dysfunction.

The association of diabetes duration and glycemic control with depression in elderly men with type 2 diabetes mellitus.

BACKGROUND: The prevalence of depression and type 2 diabetes mellitus (T2DM) are increasing in the elderly and are reportedly related to each other. We evaluated the relationship between T2DM-related factors and the degree of depression in elderly patients with T2DM based on gender. MATERIALS AND METHODS: A total of 155 patients with T2DM (56 males and 99 females aged ≥ 65 years) from seven hospitals were included in the study. To assess the status of depressive symptoms, the short form of the Geriatric Depression Scale-Korean version (SGDS-K) was used. We evaluated DM-related factors, such as T2DM duration, hemoglobin A1c (HbA1c) levels, and T2DM complications, as well as other possible factors that could affect depression, such as cognitive function, physical function, education level, and other personal factors. RESULTS: Mean age of the participants was 71.3 years with a mean HbA1c level of 7.6%. Males in the good glycemic control group (HbA1c <7%) showed lower SGDS-K scores compared to those in the poor glycemic control group, and the mean SGDS-K score was higher in the group with a longer duration of DM (M10 years); however, no difference was observed in females. Males and females with microvascular and macrovascular complications tended to have higher SGDS-K scores than participants with no microvascular or macrovascular complications. A multiple linear regression analysis revealed that DM duration and HbA1c level were independently associated with SGDS-K scores in males. CONCLUSION: Greater depression was associated with poorer glycemic control and a longer duration of DM in elderly males with T2DM.

Association between sodium glucose co-transporter 2 inhibitors and a reduced risk of heart failure in patients with type 2 diabetes mellitus: a real-world nationwide population-based cohort study.

BACKGROUND: Recently, two large randomized controlled trials which only included patients with underlying cardiovascular disease (CVD) or patients at high risk for CVD showed that two sodium glucose co-transporter 2 inhibitors (SGLT-2is) significantly reduced hospitalization for heart failure (hHF), with an early separation in the survival curves for hHF. There were concerns whether SGLT-2i use could protect hHF in patients without CVD and how soon SGLT-2i-treated patients show a lower risk of hHF. Thus, we aimed to evaluate whether the heart failure protective effect of SGLT-2i differs depending on the underlying CVD and the prescription period compared with dipeptidyl peptidase-4 inhibitors (DPP-4i). METHODS: We performed a nationwide retrospective observational study to estimate the effect of SGLT-2i on HF. The 59,479 SGLT-2i new-users were matched with same number of DPP-4i new-users through propensity score matching using 53 confounding variables. Kaplan-Meier (K-M) curves and Cox proportional hazards regression analyses were used to estimate the risk of hospitalization for hHF. RESULTS: The incidence rates of hHF were 0.83 and 1.13 per 100 person-years in SGLT-2i-treated patients and DPP-4i-treated patients, respectively. The hazard ratios of hHF were 0.66 (95% confidence interval 0.58-0.75) in SGLT-2i-treated patients compared with the DPP-4i-treated patients. Among the patients with underlying CVD, SGLT-2i-treated patients were associated with a lower risk of hHF from 30 days to 3 years after initiating drugs compared with DPP-4i. However, SGLT-2i use only showed a lower risk of hHF with a significant difference 3 years after drug initiation among patients without underlying CVD. CONCLUSIONS: Our findings suggest that SGLT-2i reduced hHF compared with DPP-4i. A heart failure protective effect of SGLT-2i use vs. DPP-4i use was shown 30 days after initiating the SGLT-2i among patients with established CVD, but this effect appeared later in patients without established CVD.

Sodium-glucose co-transporter-2 inhibitors and the risk of ketoacidosis in patients with type 2 diabetes mellitus: A nationwide population-based cohort study.

AIMS: To estimate the risk of diabetic ketoacidosis (DKA) associated with sodium-glucose co-transporter-2 (SGLT2) inhibitor treatment compared with the risk associated with dipeptidyl-peptidase-4 (DPP-4) inhibitor treatment. METHODS: A nationwide population-based cohort study using claims data from the Korean Health Insurance Review and Assessment Service from January 1, 2013 to June 30, 2017 was performed. A total of 56 325 patients who were started on SGLT2 inhibitors were included in this study and were matched with same number of patients who were started on DPP-4 inhibitors using propensity score matching. Kaplan-Meier curves and Cox proportional hazards regression analyses were used to estimate the risk of hospitalization for DKA. RESULTS: The risk of hospitalization for DKA was not increased in SGLT2 inhibitor users vs DPP-4 inhibitor users (hazard ratio [HR] 0.956, 95% confidence interval [CI] 0.581-1.572; P = .996). The incidence rate of hospitalization for DKA during the first 30 days after initiation of the SGLT2 inhibitor was 2.501 cases per 1000 person-years, which was higher than the rate during 3 years (0.614 cases per 1000 person-years). SGLT2 inhibitor use was associated with a higher HR in patients with diabetic microvascular complications (HR 2.044, 95% CI 0.900-4.640; P = .088) and in patients taking diuretics (HR 3.648, 95% CI 0.720-18.480; P = .118), although these associations were not statistically significant. CONCLUSION: We found that SGLT2 inhibitor treatment did not increase the risk of DKA compared with DPP-4 inhibitor treatment. Our findings suggest that patients prescribed diuretics or those with microvascular complications may have a greater tendency to be hospitalized for DKA.

Precise Targeting of Liver Tumor Using Glycol Chitosan Nanoparticles: Mechanisms, Key Factors, and Their Implications.

Herein, we elucidated the mechanisms and key factors for the tumor-targeting ability of nanoparticles that presented high targeting efficiency for liver tumor. We used several different nanoparticles with sizes of 200-300 nm, including liposome nanoparticles (LNPs), polystyrene nanoparticles (PNPs) and glycol chitosan-5ß-cholanic acid nanoparticles (CNPs). Their sizes are suitable for the enhanced permeation and retention (EPR) effect in literature. Different in vitro characteristics, such as the particle structure, stability, and bioinertness, were carefully analyzed with and without serum proteins. Also, pH-dependent tumor cell uptakes of nanoparticles were studied using fluorescence microscopy. Importantly, CNPs had sufficient stability and bioinertness to maintain their nanoparticle structure in the bloodstream, and they also presented prolonged circulation time in the body (blood circulation half-life T1/2 = about 12.2 h), compared to the control nanoparticles. Finally, employing liver tumor bearing mice, we also observed that CNPs had excellent liver tumor targeting ability in vivo, while LNPs and PNPs demonstrated lower tumor-targeting efficiency due to the nonspecific accumulation in normal liver tissue. Liver tumor models were produced by laparotomy and direct injection of HT29 tumor cells into the left lobe of the liver of athymic nude mice. This study provides valuable information concerning the key factors for the tumor-targeting ability of nanoparticles such as stability, bioinertness, and rapid cellular uptake at targeted tumor tissues.

The impact of Value Incentive Program (VIP) on the quality of hospital care for acute stroke in Korea.

OBJECTIVES: This study aims to analyze the impact of Value Incentive Program (VIP) on the quality improvement of acute stroke care, and to determine the difference of effect by the size of hospitals. INTERVENTIONS: Adopting the VIP on the fifth acute stroke quality assessment. DESIGN/SETTING/PARTICIPANTS: Using paired t-test and student t-test, we compared the quality assessment results of the third assessment, which was publicly reported without the VIP implementation and the fifth assessment, on which the VIP was applied. The subjects of the third assessment were acute stroke admissions in 201 hospitals (44 tertiary and 157 general hospitals) from January to March 2010. The fifth assessment included 201 hospitals (42 tertiary and 159 general hospitals) from March to May 2013. MAIN OUTCOME MEASURES: Seven process indicators of acute stroke quality assessment and in-hospital mortality rate. RESULT: In comparison to the third assessment, five of the seven process indicators showed statistically significant improvement in the fifth assessment. Also, there were significant decreases in the interquartile ranges of five process indicators. This phenomenon was more notable in general hospitals. The in-hospital mortality rate of hemorrhagic stroke in general hospitals showed a statistically significant decrease from 20.8% in the third assessment to 11.6% (P < 0.05) in the fifth assessment. CONCLUSION: This study demonstrated that the VIP was effective in improving quality of acute stroke care. The improvement was more prominent in general hospitals, and led to reduced quality gaps among hospitals.