Many factors contribute to the development of atherosclerosis. Over the past few years, understanding of the importance of inflammation during all stages of atherosclerosis, including its initiation through the progression and the complication of thrombosis, has increased greatly. Under normal conditions, the vessel wall has its own machinery to maintain vascular homeostasis. However, the balance is broken when repetitive metabolic stimuli resulting from hypertension, insulin resistance or obesity strike the vessel wall. Most of these metabolic stimuli disturb homeostasis through the initiation of inflammation, that is the recruitment of inflammatory cells, the increased adhesion molecules, secretion of chemoattractant and proinflammatory cytokines from the endothelial cells and the migration and proliferation of smooth muscle cells from media [1]. Among the top contributors of inflammatory stimuli are adipokines secreted from adipose tissue, which is now considered not as a mere mass of fat tissue, but an active organ that acts as a reservoir for energy in the energy excess state and as an active supplier of energy when the body runs short of it. Adipokines have diverse autocrine, paracrine and endocrine actions and have been implicated in the pathogenesis of metabolic syndrome and cardiovascular disease.
Chemerin, also known as tazarotene-induced gene 2 protein (TIG2) or retinoid acid receptor responder 2 (RARRES2), was a recently identified novel adipokine that has a role in adaptive and innate immunity [2]. Chemerin acts as a secreted ligand of the orphan G protein-coupled receptor chemokine-like receptor (CMKLR) 1, chemokine (C-C motif) receptor-like (CCRL) 2 and the G protein-coupled receptor (GPR) 1. Various cell types involved in innate and adaptive immunity express CMKLR1, and chemerin is known to function as a chemoattractant that promotes recruitment of immune cells to sites of injury [3,4]. Chemerin is translated as a pre-protein that is secreted as a proprotein following the proteolytic cleavage of a signal peptide [3,5]. This proprotein has low biological activity, and requires further C-terminal processing by plasmin, carboxypeptidases or serine protease of the coagulation, fibrinolytic and inflammatory cascades. This processing is suggested to be the key regulatory mechanism that affects the concentration of bioactive chemerin.
Increased chemerin expression in adipocytes was demonstrated in mice fed a high fat diet [6]. Chemerin is known to be induced during adipocyte differentiation and increases insulin-stimulated glucose uptake in adipocytes [7]. A recent study suggested that overexpression of human chemerin in low-density lipoprotein receptor knockout (LDLRKO) mice induced insulin resistance in skeletal muscle and administration of chemerin exacerbated glucose intolerance, lowered insulin levels, and decreased tissue glucose uptake in obese/diabetic mice [8]. In addition, chemerin is shown to be expressed differentially according to different fat depots [9]. In human studies, chemerin levels correlated with metabolic factors related to obesity, such as body mass index, triglyceride levels and blood pressure [10]. It has been reported that CMKLR1 is expressed in vascular endothelial cells and that its expression level is regulated by inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, or IL-6 [11]. A very recent study also shows the role for chemerin/CMKLR1 signaling in clonal expansion during adipocyte differentiation in bone marrow mesenchymal stem cells through the interaction with peroxisome proliferator-activated receptor gamma (PPARγ), a master regulator of adipocyte differentiation [12]. These data show that chemerin is correlated with adipocyte differentiation, glucose metabolism, and inflammation, suggesting its role in the pathophysiology of obesity, metabolic syndrome, and possibly type 2 diabetes mellitus.
Although accumulating data suggest a plausible role of chemerin in metabolic disorders, its role in atherosclerosis still remains elusive. Serum chemerin levels were reported to be weakly correlated with coronary plaque burden and the number of non-calcified plaques in humans, although the significance disappeared after adjustment for the cardiovascular disease risk factors [9]. Another study demonstrated that aortic and coronary atherosclerosis assessed in 41 autopsy cases was positively correlated with chemerin expression in periaortic and pericoronary adipose tissue, suggesting the paracrine effects of chemerin on atherosclerosis [13]. Overexpression of chemerin in LDLRKO mice did not affect the atherosclerotic lesion area determined by en face analysis of the entire aorta [8]. The plausible mechanisms of the relationship between chemerin and development of atherosclerosis could be as follows: 1) the accumulation of chemerin in an atherosclerotic lesion could attract immune cells which contribute to the remodeling of the vessel wall, 2) the alteration of insulin sensitivity and glucose uptake in adipocytes and skeletal muscle could contribute to development of atherosclerosis, and 3) chemerin could directly affect the inflammatory status in vascular endothelial cells by increasing the production of nitric oxide via the activation of PI3K/Akt/eNOS pathways (Fig. 1) [14].
Fig. 1
The proposed mechanism of the role of chemerin in atherosclerosis.
In this issue, Hah et al. [15] reported that subjects with multiple stenotic coronary vessels showed higher serum chemerin levels than the subjects with only one stenotic coronary artery. However, when logistic regression analysis was performed with conventional cardiovascular risk factors, such as C-reactive protein and low density lipoprotein cholesterol, chemerin was not an independent risk factor of multiple vessel disease. This study has implication in that it was the first study to assess atherosclerosis directly by coronary angiogram, although the absolute number of subjects was small. The disappearance of significance of chemerin as the determinant of coronary artery stenosis after adjustment for cardiovascular risk factors suggests that the influence of chemerin on the development of atherosclerosis might be explained more by the metabolic factors and the factors related with adipose tissues than the direct effects of chemerin on the initiation and progression of atherosclerotic plaque formation. However, there are other aspects involved in the development of atherosclerosis not yet studied in relation with chemerin expression, such as the effects of chemerin on vascular smooth muscle cell proliferation and migration, apoptosis, or plaque stability (Fig. 1). More study is needed to elucidate the role of chemerin in atherosclerosis and cardiovascular diseases.
The Committee of Clinical Practice Guidelines of the Korean Diabetes Association (KDA) updated the previous clinical practice guidelines for Korean adults with diabetes and prediabetes and published the seventh edition in May 2021. We performed a comprehensive systematic review of recent clinical trials and evidence that could be applicable in real-world practice and suitable for the Korean population. The guideline is provided for all healthcare providers including physicians, diabetes experts, and certified diabetes educators across the country who manage patients with diabetes or the individuals at the risk of developing diabetes mellitus. The recommendations for screening diabetes and glucose-lowering agents have been revised and updated. New sections for continuous glucose monitoring, insulin pump use, and non-alcoholic fatty liver disease in patients with diabetes mellitus have been added. The KDA recommends active vaccination for coronavirus disease 2019 in patients with diabetes during the pandemic. An abridgement that contains practical information for patient education and systematic management in the clinic was published separately.
Background: Glucagon-like peptide-1 receptor agonist (GLP-1RA), which is a therapeutic agent for the treatment of type 2 diabetes mellitus, has a beneficial effect on the cardiovascular system.Methods: To examine the protective effects of GLP-1RAs on proliferation and migration of vascular smooth muscle cells (VSMCs), A-10 cells exposed to angiotensin II (Ang II) were treated with either exendin-4, liraglutide, or dulaglutide. To examine the effects of GLP-1RAs on vascular calcification, cells exposed to high concentration of inorganic phosphate (Pi) were treated with exendin-4, liraglutide, or dulaglutide.Results: Ang II increased proliferation and migration of VSMCs, gene expression levels of Ang II receptors <i>AT1</i> and <i>AT2</i>, proliferation marker of proliferation Ki-67 (<i>Mki-67</i>), proliferating cell nuclear antigen (<i>Pcna</i>), and cyclin D1 (<i>Ccnd1</i>), and the protein expression levels of phospho-extracellular signal-regulated kinase (p-Erk), phospho-c-JUN N-terminal kinase (p-JNK), and phospho-phosphatidylinositol 3-kinase (p-Pi3k). Exendin-4, liraglutide, and dulaglutide significantly decreased the proliferation and migration of VSMCs, the gene expression levels of <i>Pcna</i>, and the protein expression levels of p-Erk and p-JNK in the Ang II-treated VSMCs. Erk inhibitor PD98059 and JNK inhibitor SP600125 decreased the protein expression levels of Pcna and Ccnd1 and proliferation of VSMCs. Inhibition of GLP-1R by siRNA reversed the reduction of the protein expression levels of p-Erk and p-JNK by exendin-4, liraglutide, and dulaglutide in the Ang II-treated VSMCs. Moreover, GLP-1 (9-36) amide also decreased the proliferation and migration of the Ang II-treated VSMCs. In addition, these GLP-1RAs decreased calcium deposition by inhibiting activating transcription factor 4 (Atf4) in Pi-treated VSMCs.Conclusion: These data show that GLP-1RAs ameliorate aberrant proliferation and migration in VSMCs through both GLP-1Rdependent and independent pathways and inhibit Pi-induced vascular calcification.
Adiponectin, an adipocyte-secreted protein, is known to have anti-atherogenic, anti-inflammatory and anti-diabetic properties and its serum levels are decreased in obesity, type 2 diabetes, and coronary artery disease. Several studies have been performed to investigate the association of genetic variations in the adiponectin with obesity, insulin resistance, and type 2 diabetes, but few studies were performed in association with coronary artery disease. Therefore we examined the associations between two single nucleotide polymorphisms (SNPs), +45T>G and +276G>T of the adiponectin gene, and coronary artery diseases (CAD). One hundred and fifty six subjects (mean age 57.4 yrs) were enrolled in which coronary angiograms were performed due to chest pain. Genotypings were done for two SNPs in the adiponectin gene by Taqman polymerase chain reaction (PCR) method. The presence of CAD was defined as a >50% reduction of coronary artery diameter. Among 156 subjects, the allele frequencies were 0.683 for G allele and 0.317 for T allele in SNP +276G>T and 0.705 for T allele and 0.295 for G allele in SNP +45T>G. Both genotypes were in compliance with Hardy-Weinberg equilibrium. No association with the presence of CAD was observed for adiponectin gene SNP276 and SNP45 (p = 0.954, p = 0.843). Also, no significant association was observed between the severity of CAD and either SNPs (p = 0.571, p = 0.955). Our study showed that SNP +276G>T and +45T>G in adiponectin gene were not associated with the presence of CAD. Further studies will be necessary to confirm the role of SNP 276G>T and 45T>G in the development of CAD.
Background and Objectives:It is well known that, regardless of whether a person has cardiovascular diseases, the reduction of heart rate after exercise reflects the impairment of the autonomic nervous system. It is also a predictive factor of death rate and it correlates to insulin resistance. Therefore, we assessed these correlations in normoglycemic subjects. Subjects and Methods:Exercise stress testing was performed according to the Bruce protocol. Anthropometric indices of adiposity, metabolic variables, blood pressure (BP) and several cardiovascular risk factors were measured. The HOMA index was used as the insulin resistance, and the impairment of the autonomic nervous system was assessed by measuring the reduction of heart rate for 2 minutes after the cessation of exercise. Results:The reduction of heart rate during 2 minutes after the cessation of exercise statistically correlated with the HOMA index, gender, age, body mass index, the waist circumference, heart rate during rest, the maximum heart rate, serum total cholesterol concentration, serum high density lipoprotein cholesterol concentration and serum low density lipoprotein cholesterol concentration, (p<0.05). However, on multiple regression analysis, the HOMA index, gender, heart rate during rest, and the maximum heart rate significantly correlated to the reduction of heart rate during 2 minutes after the cessation of exercise. Conclusion: In individuals with normal serum glucose levels, even after adjustment was made for other factors, the reduction of heart rate after the cessation of exercise correlated to insulin resistance. Hence, in individuals with normal serum glucose levels, efforts to improve insulin resistance have to be made, and prospective study on this subject is required. (Korean Circulation J 2005;35:228-232)
BACKGROUND The prevalence of type 1 diabetes (T1D) is increasing worldwide, with a much higher proportion of adult patients. However, achieving stable glycemic control is difficult in these patients. OBJECTIVE After periodic implementation of structured education for patients with T1D through the Home and Self-Care Program, a pilot home health care project promoted by the Korean government, we evaluated the program’s effects on glycemic control. METHODS This study was conducted from April 2020 to March 2023. We analyzed 119 participants with T1D aged >15 years. Nursing and nutrition education were provided separately up to 4 times per year, with physician consultation up to 6 times per year. A distinguishing feature of this study compared with previous ones was the provision of remote support using a general-purpose smartphone communication app offered up to 12 times annually on an as-needed basis to enhance the continuity of in-person education effects. Patients were followed up on at average intervals of 3 months for up to 24 months. The primary end point was the mean difference in glycated hemoglobin (HbA<sub>1c</sub>) at each follow-up visit from baseline. For continuous glucose monitoring (CGM) users, CGM metrics were also evaluated. RESULTS The mean HbA<sub>1c</sub> level of study participants was 8.6% at baseline (mean duration of T1D 10.02, SD 16.10 y). The HbA<sub>1c</sub> level reduction in participants who received at least 1 structured educational session went from 1.63% (SD 2.03%; <i>P</i><.001; adjustment model=1.69%, 95% CI 1.24%-2.13% at the first follow-up visit) to 1.23% (SD 1.31%; <i>P</i>=.01; adjustment model=1.28%, 95% CI 0.78%-1.79% at the eighth follow-up visit). In the adjustment model, the actual mean HbA<sub>1c</sub> values were maintained between a minimum of 7.33% (95% CI 7.20%-7.46% at the first follow-up visit) and a maximum of 7.62% (95% CI 7.41%-7.82% at the sixth follow-up visit). Among CGM users, after at least 1 session, the mean time in the target range was maintained between 61.59% (adjusted model, 95% CI 58.14%-65.03% at the second follow-up visit) and 54.7% (95% CI 50.92%-58.48% at the eighth follow-up visit), consistently staying above 54.7% (corresponding to an HbA<sub>1c</sub> level of <7.6%). The mean time below the target range (TBR) also gradually improved to the recommended range (≤4% for TBR of <70 mg/dL and ≤1% for TBR of <54 mg/dL). CONCLUSIONS The Home and Self-Care Program protocol for glycemic control in patients with T1D is effective, producing significant improvement immediately and long-term maintenance effects, including on CGM indexes.
The Key Recommendation from 2010 Dietary Guidelines to limit consumption of dietary cholesterol to 300 mg per day, is not included in the 2015 edition. Dietary Guidelines for Americans 2015~2020 released in January 2016, omitted the limit for cholesterol intake in general population; but this change does not suggest that dietary cholesterol is no longer important to consider when building healthy eating patterns. The main shift of concept in recent dietary guidelines is that limitation of intake of single macronutrient should not help to promote health; controlling and recommendation for a healthy eating pattern is important for health and for the prevention of any diseases. In Korean dietary survey, eggs are the main resources for dietary cholesterol in Koreans. However, there are recent studies regarding no association between the egg consumption and serum cholesterol level and cardiovascular disease risk. In this review, I will focus on the 2015 recommendation on dietary cholesterol and fat intake. Furthermore, I will review the literature on the evidences for the egg consumption and cardiovascular disease risk.
This article has been corrected. See "Associations among Obesity Degree, Glycemic Status, and Risk of Heart Failure in 9,720,220 Korean Adults" in Volume 44 on page 783.
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