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Although oxidative stress is the main pathophysiology of the development of diabetic neuropathy, oral administration of antioxidants has given disappointing results. Here, we hypothesized that local delivery of antioxidants would provide protective effects on Schwann cells due to the high concentration of local lesions. We prepared alpha-tocopherol (ATF)-loaded liposomes and tested their skin penetration after sonication. An in vitro study using IMS-32 cells was conducted to determine the level of reactive oxygen species (ROS) scavenging effects of ATF-liposomes. ATF reduced ROS in high-glucose-exposed IMS-32 cells in a dosedependent manner. ATF-liposomes also reduced the ROS level in vitro and ultrasound irradiation enhanced delivery to the dermis in porcine ear skin. This study showed that it is feasible to deliver ATF through the skin and can effectively reduce ROS. This model is worthy of development for clinical use.

Introduction Cardiovascular autonomic neuropathy (CAN) is a chronic complication of diabetes. As obesity is a major risk factor for CAN, we hypothesized that metabolic bariatric surgery (MBS) could improve CAN indices in Korean patients with obesity. Materials and Methods Patients who underwent bariatric surgery between February 2020 and June 2022 were prospectively recruited. CAN was conducted once before surgery and again after surgery, using the Ewing method and heart rate variability (HRV) analysis (standard deviation of the NN interval [SDNN], root mean square of successive RR interval difference [RMSSD], and spectral analysis). Results A total of 47 patients were included. The mean age was 39.8 ± 8.7 years, 15 (31.9%) were male, and 26 (55.3%) had diabetes. Resting HR before surgery was 81.0 ± 12.3 bpm, which decreased significantly to 68.0 ± 9.3 bpm after surgery (P < 0.001). Changes in HR and BP according to the Valsalva maneuver, postural changes, and handgrip were not significantly different before and after surgery. However, SDNN significantly increased from 25.2 [15.1, 33.5] to 38.0 [25.4, 45.0] ms (P < 0.001), and RMSSD also significantly increased from 17.0 [9.2, 31.8] to 28.2 [15.3, 45.6] ms (P = 0.001). Both low‐frequency power (LF) and high‐frequency power (HF) increased significantly, and the LF/HF ratio significantly decreased from 2.1 ± 1.6 to 1.3 ± 1.3 (P = 0.010). Loss of weight, fat mass, and lean body mass were independently associated with improving the HRV variables. Conclusions MBS improved HRV variables, and these changes were mainly associated with postoperative weight loss. Cardiovascular autonomic neuropathy (CAN) is a chronic complication of diabetes, and obesity is a major risk factor for CAN. CAN was evaluated before and 1 year after metabolic bariatric surgery (MBS) using the Ewing method and heart rate variability (HRV) analysis. MBS improved HRV variables, and these changes were mainly associated with postoperative weight loss.

The TGF-β signaling pathway governs key cellular processes under physiologic conditions and is deregulated in many pathologies, including cancer. TGF-β is a multifunctional cytokine that acts in a cell- and context-dependent manner as a tumor promoter or tumor suppressor. As a tumor promoter, the TGF-β pathway enhances cell proliferation, migratory invasion, metastatic spread within the tumor microenvironment and suppresses immunosurveillance. Collectively, the pleiotropic nature of TGF-β signaling contributes to drug resistance, tumor escape and undermines clinical response to therapy. Based upon a wealth of preclinical studies, the TGF-β pathway has been pharmacologically targeted using small molecule inhibitors, TGF-β-directed chimeric monoclonal antibodies, ligand traps, antisense oligonucleotides and vaccines that have been now evaluated in clinical trials. Here, we have assessed the safety and efficacy of TGF-β pathway antagonists from multiple drug classes that have been evaluated in completed and ongoing trials. We highlight Vactosertib, a highly potent small molecule TGF-β type 1 receptor kinase inhibitor that is well-tolerated with an acceptable safety profile that has shown efficacy against multiple types of cancer. The TGF-β ligand traps Bintrafusp alfa (a bifunctional conjugate that binds TGF-β and PD-L1), AVID200 (a computationally designed trap of TGF-β receptor ectodomains fused to an Fc domain) and Luspatercept (a recombinant fusion that links the activin receptor IIb to IgG) offer new ways to fight difficult-to-treat cancers. While TGF-β pathway antagonists are rapidly emerging as highly promising, safe and effective anticancer agents, significant challenges remain. Minimizing the unintentional inhibition of tumor-suppressing activity and inflammatory effects with the desired restraint on tumor-promoting activities has impeded the clinical development of TGF-β pathway antagonists. A better understanding of the mechanistic details of the TGF-β pathway should lead to more effective TGF-β antagonists and uncover biomarkers that better stratify patient selection, improve patient responses and further the clinical development of TGF-β antagonists.

Preventative Effects of Rosiglitazone on Restenosis After Coronary Stent Implantation in Patients With Type 2 Diabetes Donghoon Choi , MD, PHD 1 , Soo-Kyung Kim , MD 2 3 , Sung-Hee Choi , MD 1 , Young-Guk Ko , MD 1 , Chul-Woo Ahn , MD, PHD 1 2 , Yangsoo Jang , MD, PHD 1 2 , Sung-Kil Lim , MD, PHD 1 2 , Hyun-Chul Lee , MD, PHD 1 2 and Bong-Soo Cha , MD, PHD 1 2 1 Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea 2 Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea 3 Department of Internal Medicine, College of Medicine, Pochon CHA University, Sungnam, Kyonggi-do, Korea Address correspondence and reprint requests to Prof. Bong-Soo Cha, Department of Internal Medicine, Yonsei University College of Medicine, 134 Shinchon-Dong, Seodaemoon-Ku, Seoul 120-749, Korea. E-mail: bscha{at}yumc.yonsei.ac.kr Abstract OBJECTIVE —Despite the popularity of coronary stenting in coronary artery disease (CAD), restenosis remains a challenging clinical problem. This study evaluated the efficacy of rosiglitazone for preventing in-stent restenosis in type 2 diabetic patients. RESEARCH DESIGN AND METHODS —We conducted a prospective, randomized, case-controlled trial involving 95 diabetic patients with CAD who were randomly assigned to either the control or rosiglitazone group (48 and 47 patients, respectively). Quantitative coronary angiography (QCA) was performed at study entry and again at 6-month follow-up. The primary end point was the restenosis rate, which was determined by QCA. RESULTS —Eighty-three patients (45 patients with 55 lesions in the control group and 38 patients with 51 lesions in the rosiglitazone group) completed follow-up angiography. Rosiglitazone treatment for 6 months reduced fasting insulin concentration. The high-sensitivity C-reactive protein concentration was significantly reduced in the rosiglitazone group compared with that in the control group (from 2.92 ± 1.98 to 0.62 ± 0.44 mg/l, P < 0.001 vs. from 2.01 ± 1.33 to 1.79 ± 1.22 mg/l, P = NS). However, the baseline and follow-up glucose and lipid concentrations were not different between two groups. The rate of in-stent restenosis was significantly reduced in the rosiglitazone group compared with the control group (for stent lesions: 17.6 vs. 38.2%, P = 0.030). The rosiglitazone group had a significantly lower degree of diameter stenosis (23.0 ± 23.4% vs. 40.9 ± 31.9%, P = 0.004) compared with the control group. CONCLUSIONS —We demonstrated that treatment with rosiglitazone significantly reduces in-stent restenosis in diabetic patients with CAD who underwent coronary stent implantation. CAD, coronary artery disease hsCRP, high-sensitivity C-reactive protein MLD, minimal lumen diameter PPAR, peroxisome proliferator–activated receptor QCA, quantitative coronary angiography TZD, thiazolidinedione VSMC, vascular smooth muscle cell Footnotes D.C. and S.-K.K. contributed equally to this work. A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. See accompanying editorial, p. 2764. Accepted August 4, 2004. Received June 2, 2004. DIABETES CARE

A large body of clinical and experimental data shows that increased flux of free fatty acids from increased visceral adipose tissue can lead to hepatic steatosis and insulin resistance (5).

Aims/Introduction We developed a self‐assessable Korean Diabetes Risk score using the data of the Korean Genome and Epidemiology Study. Materials and Methods A total of 8,740 participants without diabetes at baseline were followed up biannually over a period of 10 years. We included variables that were significantly different between participants who developed diabetes mellitus and those who did not in the development cohort at baseline. We assigned a maximum score of 100 to the selected variable in each gender group. Next, the 10‐year probability of incident diabetes was calculated and validated in the validation cohort. Finally, we compared the predictive power of Korean Diabetes Risk score with models including fasting plasma glucose or glycated hemoglobin and other cohort models of Atherosclerosis Risk in Communities and Korea National Health and Nutrition Examination Survey. Results During a median follow‐up period of 9.7 years, 22.7% of the participants progressed to diabetes. The Korean Diabetes Risk score included age, living location (urban or rural area), waist circumference, hypertension, family history of diabetes and smoking history. The developed risk score yielded acceptable discrimination for incident diabetes (area under the curve 0.657) and the predictive power was improved when the model included fasting plasma glucose (area under the curve 0.690) or glycated hemoglobin (area under the curve 0.746). In addition, our model predicted incident diabetes more accurately than previous Western or Korean models. Conclusions This newly developed self‐assessable diabetes risk score is easily applicable to predict the future risk of diabetes even without the necessity for laboratory tests. This score is useful for the Korean diabetes prevention program, because high‐risk individuals can be easily screened. Age, living location (rural or urban), smoking, hypertension, family history of type 2 diabetes and waist circumference were key risk factors of new‐onset type 2 diabetes in Korean individuals. A self‐assessable Korean Diabetes Risk score composed with non‐laboratory variables provided better accurate prediction of 10‐year risk of new‐onset type 2 diabetes compared with a Western study or a previously developed Korean Diabetes Score.

Aims/hypothesis A recent large clinical study has shown that empagliflozin has a lower rate of cardiovascular and all-cause mortality when compared with placebo in patients with type 2 diabetes. We investigated the effect of empagliflozin (compared with glimepiride) on the progression of atherosclerosis, and its possible mechanisms of action. Methods Forty-eight 5-week-old male ApoE −/− mice were fed a western diet for 20 weeks and divided into four groups: control (saline, 154 mmol/l NaCl), glimepiride 0.1 mg/kg, empagliflozin 1 mg/kg and empagliflozin 3 mg/kg ( n  = 12/group). Plaque size and composition in the aortic arch/valve areas and cardiovascular risk variables in the blood and tissues were evaluated. Insulin resistance was estimated by HOMA and adiponectin levels. Body composition was determined using dual-energy x-ray absorptiometry. Results After 8 weeks of treatment, the empagliflozin and glimepiride groups exhibited decreased blood glucose levels. Atherosclerotic plaque areas in the aortic arch/valve were significantly smaller in the empagliflozin groups than in the control or glimepiride groups. Insulin resistance and circulating concentrations of TNF-α, IL-6, monocyte chemoattractant protein-1 (MCP-1), serum amyloid A and urinary microalbumin decreased after empagliflozin treatment, and this significantly correlated with plaque size. Empagliflozin treatment reduced weight and fat mass, lipid droplets in the liver, fat cell size, mRNA expression of Tnf , Il6 and Mcp-1 (also known as Ccl2 ) and the infiltration of inflammatory cells in plaque and adipose tissue compared with the control or glimepiride group. Empagliflozin treatment increased adiponectin levels. Conclusions/interpretation Improvements in inflammation and insulin resistance seem to be mechanisms involved in the mitigation of atherosclerosis by empagliflozin.

Statins are the cornerstone of the prevention and treatment of atherosclerotic cardiovascular disease (ASCVD). However, even under optimal statin therapy, a significant residual ASCVD risk remains. Therefore, there has been an unmet clinical need for novel lipid-lowering agents that can target low-density lipoprotein cholesterol (LDL-C) and other atherogenic particles. During the past decade, several drugs have been developed for the treatment of dyslipidemia. Inclisiran, a small interfering RNA that targets proprotein convertase subtilisin/kexin type 9 (PCSK9), shows comparable effects to that of PCSK9 monoclonal antibodies. Bempedoic acid, an ATP citrate lyase inhibitor, is a valuable treatment option for the patients with statin intolerance. Pemafibrate, the first selective peroxisome proliferator-activated receptor alpha modulator, showed a favorable benefit-risk balance in phase 2 trial, but the large clinical phase 3 trial (PROMINENT) was recently stopped for futility based on a late interim analysis. High dose icosapent ethyl, a modified eicosapentaenoic acid preparation, shows cardiovascular benefits. Evinacumab, an angiopoietin-like 3 (ANGPTL3) monoclonal antibody, reduces plasma LDL-C levels in patients with refractory hypercholesterolemia. Novel antisense oligonucleotides targeting apolipoprotein C3 (apoC3), ANGPTL3, and lipoprotein(a) have significantly attenuated the levels of their target molecules with beneficial effects on associated dyslipidemias. Apolipoprotein A1 (apoA1) is considered as a potential treatment to exploit the athero-protective effects of high-density lipoprotein cholesterol (HDL-C), but solid clinical evidence is necessary. In this review, we discuss the mode of action and clinical outcomes of these novel lipid-lowering agents beyond statins.

We investigated the prevalence of sarcopenic obesity (SO) and its relationship with metabolic syndrome in a community-based elderly cohort in Korea. In this study, 287 men and 278 women aged 65 or older were recruited. Sarcopenia was defined as the appendicular skeletal muscle mass (ASM) divided by height squared (Ht(2)) (kg/m(2)) or by weight (Wt) (%) of <1 SD below the sex-specific mean for young adults. Obesity was defined as a visceral fat area >or=100 cm(2). The prevalence of SO was 16.7% in men and 5.7% in women with sarcopenia defined by ASM/Ht(2); however, it was 35.1% in men and 48.1% in women by ASM/Wt. Using ASM/Wt, the homeostasis model assessment of insulin resistance of subjects with SO was higher and they were at higher risk for metabolic syndrome (odds ratio [OR] 8.28 [95% CI 4.45-15.40]) than the obese (5.51 [2.81-10.80]) or sarcopenic group (2.64 [1.08-6.44]). SO defined by ASM/Wt was more closely associated with metabolic syndrome than either sarcopenia or obesity alone.

OBJECTIVE: The number of people with metabolic syndrome is increasing worldwide, and changes in socioenvironmental factors contribute to this increase. Therefore, investigation of changes in metabolic syndrome and its components in South Korea, where rapid socioenvironmental changes have occurred in recent years, would be foundational in setting up an effective strategy for reducing this increasing trend. RESEARCH DESIGN AND METHODS: We compared the prevalence and pattern of metabolic syndrome among participants in the Korean National Health and Nutrition Examination Surveys for 1998, 2001, 2005, and 2007. In each survey, stratified, multistage, probability-sampling designs and weighting adjustments were conducted to represent the entire Korean population. The revised National Cholesterol Education Program criteria were used as the definition of metabolic syndrome. All biochemical parameters were measured in a central laboratory. RESULTS: A total of 6,907 (mean ± SE age 45.0 ± 0.2 years), 4,536 (45.5 ± 0.2), 5,373 (47.1 ± 0.2), and 2,890 (49.9 ± 0.3) Koreans over 20 years of age have participated in the studies in 1998, 2001, 2005, and 2007, respectively. The age-adjusted prevalence of metabolic syndrome increased significantly from 24.9% in 1998, 29.2% in 2001, and 30.4% in 2005 to 31.3% in 2007. Among the five components, the level of low HDL cholesterol increased the most, by 13.8% over the 10 years. Abdominal obesity and hypertriglyceridemia followed, with 8.7 and 4.9% increases, respectively. CONCLUSIONS: Because dyslipidemia and abdominal obesity were major factors in increasing the prevalence of metabolic syndrome in Koreans for the past 10 years, lifestyle interventions should be conducted at the national level to reduce the burden and consequences of metabolic syndrome.