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대한당뇨병학회> International Congress of Diabetes and Metabolism> S2-1 : Vascular and immune cell network in the pathogenesis of atherosclerosis

S2-1 : Vascular and immune cell network in the pathogenesis of atherosclerosis

Goo Taeg Oh
  • : 대한당뇨병학회
  • : International Congress of Diabetes and Metabolism 2019권0호
  • : 프로시딩
  • : 2019년 10월
  • : 2-2(1pages)

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Atherosclerosis is a chronic inflammatory disease that intense immunological pathways play an essential role. During the progression of atherosclerosis, large numbers of inflammatory and immune cells accumulate in intima. The accumulated immune cells, including T cells, macrophages, and dendritic cells (DCs), cross-talk each other, and affect the development of atherosclerosis. Importantly, we found DCs that were poorly phagocytic but were immune stimulatory in the steady state mouse aorta. By crossing Flt3-/- to Ldlr-/- mice, deficiency of classical CD103+ aortic DCs exacerbated atherosclerosis and fewer Foxp3+ Treg cells. These data indicate that functional DCs are dominant in normal aortic intima, and CD103+ classical DCs are associated with atherosclerosis protection. Also, we identified functional mouse and human pDCs in the aortic intima and showed that selective, inducible pDC depletion in mice exacerbates atherosclerosis. The function of CD137, a member of the tumor necrosis factor receptor superfamily, in mediating atherosclerosis plaque stability remains unknown. We found that activation of CD137 signaling decreases the stability of plaques via its combined effects on T cells, vascular smooth muscle cells, and macrophages. Recently, we show in vivo evidence that Ninjurin-1 (Nerve injury-induced protein, Ninj1) is directly cleaved by MMP9 and concomitantly its soluble form (sNinj1), which exhibits anti-atherosclerotic effects with MMP9 in mouse and human atherosclerosis.

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1PL-1 : Insulin - an unfinished story

저자 : Graeme I. Bell

발행기관 : 대한당뇨병학회 간행물 : International Congress of Diabetes and Metabolism 2019권 0호 발행 연도 : 2019 페이지 : pp. 1-1 (1 pages)

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Insulin was isolated in the period from May 17, 1921 to January 23, 1922 by Banting, Best, Collip and Macleod. The first successful clinical trial was on January 23, 1922 and insulin therapy continues to play a central role in the treatment of diabetes. Research on insulin also continues with the development of new insulin analogues and devices for delivery, as well as studies of the regulation of its secretion and how it exerts its biological actions. Insulin is the major biosynthetic and secretory of the pancreatic beta cell accounting for 10% of the total protein and 50% or more of the total protein synthesis when maximally stimulated (~1 × 106 molecules/min). Insulin biosynthesis induces ER stress that is aggravated by increasing demand or the synthesis of mutant insulin protein. We have developed a model system in the fruit fly Drosophila melanogaster that allows us to take an agnostic approach using the powerful genetic tools offered by the fruit fly to study the effects of mutant proinsulin proteins on cell function and survival. These studies could lead to new approaches for preserving beta-cell function in patients with diabetes.

2PL-2 : What can we learn from cardiovascular outcome trials in diabetes

저자 : Vivian A. Fonseca

발행기관 : 대한당뇨병학회 간행물 : International Congress of Diabetes and Metabolism 2019권 0호 발행 연도 : 2019 페이지 : pp. 1-1 (1 pages)

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Cardiovascular disease (CVD) events are a major problem in people with diabetes, contributing considerably to morbidity and mortality. However, the pattern of disease has changed with less myocardial infarction (MI) and more hospitalization for heart failure. Although glucose levels are strongly associated with CVD, reduction in glucose alone does not reduce CVD. However, it has long been hypothesized that the individual drugs used to lower glucose may have a role in reducing events. For example, metformin reduced MI and mortality in the UKPDS. The insulin sensitizer pioglitazone reduced some events, particularly recurrent stroke, in PROACTIVE - later confirmed in IRIS.
Some controversy arose with misinterpretation of data on rosiglitazone resulting in an FDA mandate to demonstrate CVD safety in all new diabetes medications. Most of these trials were designed to demonstrate safety and this was demonstrated with DPP- 4 inhibitors, including trials in high risk patients.
Trials with SGLT2 inhibitors have demonstrated a marked relative risk reduction in hospitalization for heart failure (CHF) and progression of chronic kidney disease (CKD), with some effect on other CVD events, including mortality. In contrast trials, with GLP-1 receptor agonists (GLP_1 RA) have demonstrated a reduction in a range of CVD events but not heart failure
Results of these trials have led to a significant change in guidelines for managing hyperglycemia with more precise individualization. The guidelines recommend evaluation for the presence of CVD or CKD or CHF and then starting therapy based on clinical trial results. Other considerations may still drive choice of other agents such as prevention of stroke with a TZD or avoiding hypos with a DPP-4 inhibitor or using a sulfonylurea where cost is an issue.
These recommendations are being rapidly deployed in practice allowing the development of precision medicine in diabetes.

3S1-2 : The burden of diabetes and diabetes care in Thailand

저자 : Chaicharn Deerochanawong

발행기관 : 대한당뇨병학회 간행물 : International Congress of Diabetes and Metabolism 2019권 0호 발행 연도 : 2019 페이지 : pp. 1-1 (1 pages)

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Like other countries in the Western Pacific region, Thailand is facing increasing numbers of patients with diabetes due to unhealthy diets, high obesity rates, and an aging society. Diabetes is a considerable burden for developing countries as it reduces quality of life, increases mortality, and drives up healthcare costs. The disease detection rate in Thailand has improved in recent years, but glycemic control remains suboptimal and significant numbers of patients suffer from complications. Universal healthcare coverage has increased access to care, but inequality exists between different health plans and non-medication diabetes supplies are not yet widely covered. Diabetes self-management education has not yet been standardized and a multidisciplinary team approach is not widely utilized. The Thai government recognizes the burden of diabetes and has launched nationwide programs of health promotion and disease prevention. In addition, local initiatives have targeted reductions in specific complications, including retinopathy and diabetic foot problems, which has resulted in better disease prevention and treatment. Along with strategic public health planning, increased collaboration between private and public sectors, enhanced professional training, increased use of technology and data management, and equitable distribution of care are all needed to improve outcomes of patients with diabetes in Thailand.
Cardiovascular disease (CVD) events are a major problem in people with diabetes, contributing considerably to morbidity and mortality. However, the pattern of disease has changed with less myocardial infarction (MI) and more hospitalization for heart failure. Although glucose levels are strongly associated with CVD, reduction in glucose alone does not reduce CVD. However, it has long been hypothesized that the individual drugs used to lower glucose may have a role in reducing events. For example, metformin reduced MI and mortality in the UKPDS. The insulin sensitizer pioglitazone reduced some events, particularly recurrent stroke, in PROACTIVE - later confirmed in IRIS.
Some controversy arose with misinterpretation of data on rosiglitazone resulting in an FDA mandate to demonstrate CVD safety in all new diabetes medications. Most of these trials were designed to demonstrate safety and this was demonstrated with DPP- 4 inhibitors, including trials in high risk patients.
Trials with SGLT2 inhibitors have demonstrated a marked relative risk reduction in hospitalization for heart failure (CHF) and progression of chronic kidney disease (CKD), with some effect on other CVD events, including mortality. In contrast trials, with GLP-1 receptor agonists (GLP_1 RA) have demonstrated a reduction in a range of CVD events but not heart failure
Results of these trials have led to a significant change in guidelines for managing hyperglycemia with more precise individualization. The guidelines recommend evaluation for the presence of CVD or CKD or CHF and then starting therapy based on clinical trial results. Other considerations may still drive choice of other agents such as prevention of stroke with a TZD or avoiding hypos with a DPP-4 inhibitor or using a sulfonylurea where cost is an issue.
These recommendations are being rapidly deployed in practice allowing the development of precision medicine in diabetes.

4S1-3 : The burden of diabetes and diabetes care in Malaysia

저자 : Zanariah Hussein

발행기관 : 대한당뇨병학회 간행물 : International Congress of Diabetes and Metabolism 2019권 0호 발행 연도 : 2019 페이지 : pp. 1-2 (2 pages)

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The last National Health and Morbidity Survey (NHMS) of 2015 reported a national prevalence of 17.5% among adults above 18 years, representing 3.5 million adult Malaysians, an increase from 15.2% (NHMS 2011). Current projection for prevalence in 2019 is 22.1% estimating 4.5 million adults. There were no apparent differences between gender or among urban rural population. There are almost half a million young adults < 30 years with diabetes, with majority undiagnosed. The ethnic differences in prevalence is apparent with Indians 22.1%, Malays 14.6% and Chinese 12.0%.
Majority of persons with diabetes attend government-based health care services, 60% attend primary care and 20% public hospitals. Overall glycaemic control is still poor with 30% in primary care and 20% in hospital care attaining optimal glycaemic control. In the previous Diabcare Asia studies, Malaysia was found to have the highest HbA1c and postprandial hyperglycaemia. Access to newer anti-diabetic agents in public care is restricted. Insulinisation rates are increasing, with 28.7% insulin-treated in primary care and 65% in hospital-based diabetes care. There needs to be better use of SMBG to guide insulin dose adjustment and enable better glycaemic control.
The annual national audit shows improvement in complication screening practices though not maximally covered. Malaysia has an exceptionally high rate of dialysis for diabetic nephropathy. Multidisciplinary care with diabetes educator nurses, dieticians and pharmacists is commonly practised. Group based patient education, patient support groups and community programmes to enhance overall wellbeing and quality of life of those with diabetes are not well utilised. Use of diabetes technology with insulin pumps, continuous glucose monitoring or remote glucose monitoring is still very much limited.

5S2-4 : Interactive roles of Th2 cytokines and GDF15 in glucose homeostasis

저자 : Minho Shong

발행기관 : 대한당뇨병학회 간행물 : International Congress of Diabetes and Metabolism 2019권 0호 발행 연도 : 2019 페이지 : pp. 2-3 (2 pages)

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White adipose tissue is loose connective tissue having heterogenous nature in composition of cellular components as it contains preadipocytes, adipocytes, fibroblasts, vascular endothelial cells and a variety of immune cells. Immune cells, particularly involved in innate immunity in adipose tissue play the important role in local and systemic metabolism. It has become well established that excessive obesity in mice and humans is associated with a state of chronic low-grade inflammation in adipose tissue characterized with dysregulated innate immune cells. The obesity related chronic inflammation is collectively regulated by a variety of immune cells including macrophages, Innate lymphoid cells (ILC2), T cells, natural killer cells, and eosinophils. In fact, recent studies have found that eosinophils that is upregulated by ILC2 promote alternative activation macrophage polarization by secreting Th2 type cytokines such as IL-13 and IL-4, consequently leading to reduced inflammation in adipose tissue, and meanwhile resulting in increased energy expenditure through nonshivering thermogenesis. These studies provide strong evidence demonstrating Th2 type cytokines, e.g., IL-13 and IL-4 play an unexpected role in regulating immunometabolic homeostasis in adipose tissue.
Adipose tissue macrophages (ATMs) are the most abundant immune cell in human and murine adipose tissue (Weisberg et al., 2003). ATMs show significant functional heterogeneity and actively participate in nutrient metabolism within adipose tissue under physiological conditions. Interest in the role of macrophages in shifting adipose tissue inflammation toward a pathologic state is growing. In this context, studies suggest that the STAT6 transcription factor, which is activated upon stimulation by the Th2 cytokines IL-4 and IL-13, promotes maturation of alternatively activated macrophages (Gordon, 2003; Vats et al., 2006). Recent studies show that STAT6 and its associated transcription factors play a critical role in M2-like macrophages by increasing oxidative metabolism and mitochondrial biogenesis (Kang et al., 2008; Odegaard and Chawla, 2011; Odegaard et al., 2007).
Blocking oxidative metabolism not only impairs development of an M2-like phenotype, but also drives such cells toward an M1-like state (Rodriguez-Prados et al., 2010). A recent finding shows that Irf5-deficient M2-like macrophages promote insulin sensitivity by secreting TGF-b1 (Dalmas et al., 2015). Furthermore, the failure of alternative M2 activation, which is associated with reduced oxidative function, leads to classical macrophage activation, increased weight gain, and obesity with concurrent adipose inflammation and insulin resistance (Odegaard et al., 2008). These observations indicate that a treatment modality that pushes pro-inflammatory M1-like macrophages toward an anti-inflammatory M2-like phenotype may be beneficial for those with obesity-related insulin resistance.
Here, we would like to discuss the identified a secretory factor which is required for increased oxidative metabolism in M2-like macrophages stimulated with IL-4 and the PPAR agonist, rosiglitazone (RSG). Administration of those soluble factor to obese rodents improved the oxidative function of macrophages and reversed insulin resistance. Collectively, these findings identify souble factor as a macrophageregulating paracrine signaling factor that is controlled by STAT6 and PPAR and is required for anti-inflammatory responses in white adipose tissue (WAT).

6S2-3 : SREBP-1a-stimulated lipid synthesis is required for macrophage phagocytosis

저자 : Seung Soon Im

발행기관 : 대한당뇨병학회 간행물 : International Congress of Diabetes and Metabolism 2019권 0호 발행 연도 : 2019 페이지 : pp. 2-2 (1 pages)

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There is a growing appreciation for a fundamental connection between lipid metabolism and the immune response. Macrophage phagocytosis is a signature innate immune response to pathogen exposure, and cytoplasmic membrane expansion is required to engulf the phagocytic target. The sterol regulatory element binding proteins (SREBPs) are key transcriptional regulatory proteins that sense the intracellular lipid environment and modulate expression of key genes of fatty acid and cholesterol metabolism to maintain lipid homeostasis. In this study, we show that TLR4-dependent stimulation of macrophage phagocytosis requires mTORC1-directed SREBP-1a-dependent lipid synthesis. We also show that the phagocytic defect in macrophages from SREBP-1a-deficient mice results from decreased interaction between membrane lipid rafts and the actin cytoskeleton, presumably due to reduced accumulation of newly synthesized fatty acyl chains within major membrane phospholipids. We show that mTORC1-deficient macrophages also have a phagocytic block downstream from TLR4 signaling, and, interestingly, the reduced level of phagocytosis in both SREBP-1a- and mTORC1-deficient macrophages can be restored by ectopic SREBP-1a expression. Taken together, these observations indicate SREBP-1a is a major downstream effector of TLR4-mTORC1 directed interactions between membrane lipid rafts and the actin cytoskeleton that are required for pathogen-stimulated phagocytosis in macrophages.

7S2-1 : Vascular and immune cell network in the pathogenesis of atherosclerosis

저자 : Goo Taeg Oh

발행기관 : 대한당뇨병학회 간행물 : International Congress of Diabetes and Metabolism 2019권 0호 발행 연도 : 2019 페이지 : pp. 2-2 (1 pages)

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Atherosclerosis is a chronic inflammatory disease that intense immunological pathways play an essential role. During the progression of atherosclerosis, large numbers of inflammatory and immune cells accumulate in intima. The accumulated immune cells, including T cells, macrophages, and dendritic cells (DCs), cross-talk each other, and affect the development of atherosclerosis. Importantly, we found DCs that were poorly phagocytic but were immune stimulatory in the steady state mouse aorta. By crossing Flt3-/- to Ldlr-/- mice, deficiency of classical CD103+ aortic DCs exacerbated atherosclerosis and fewer Foxp3+ Treg cells. These data indicate that functional DCs are dominant in normal aortic intima, and CD103+ classical DCs are associated with atherosclerosis protection. Also, we identified functional mouse and human pDCs in the aortic intima and showed that selective, inducible pDC depletion in mice exacerbates atherosclerosis. The function of CD137, a member of the tumor necrosis factor receptor superfamily, in mediating atherosclerosis plaque stability remains unknown. We found that activation of CD137 signaling decreases the stability of plaques via its combined effects on T cells, vascular smooth muscle cells, and macrophages. Recently, we show in vivo evidence that Ninjurin-1 (Nerve injury-induced protein, Ninj1) is directly cleaved by MMP9 and concomitantly its soluble form (sNinj1), which exhibits anti-atherosclerotic effects with MMP9 in mouse and human atherosclerosis.

8S1-4 : The burden of diabetes and diabetes care in Korea

저자 : Kun-ho Yoon

발행기관 : 대한당뇨병학회 간행물 : International Congress of Diabetes and Metabolism 2019권 0호 발행 연도 : 2019 페이지 : pp. 2-2 (1 pages)

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The proportions of people with type 2 diabetes and obesity have increased throughout Asia, and the rate of increase shows no sign of slowing. The phenotypic characteristics of patients with type 2 diabetes in Asia differs from that reported in other parts of the world: it has developed in a much shorter time, in a younger age group, and in people with much lower degree of obesity. Because of genetic predisposition and rapid industrialization, the absolute risk of diabetes and metabolic syndrome were 2~5 folds higher in Asian subjects with the same degree of obesity. Childhood obesity has also increased substantially and the prevalence of type 2 diabetes has now also increased rapidly in Asia. Furthermore the prevalence of diabetes in second generation of Asian-American immigrants include Japan, Korea and China reached more than 20% which is more than two folds higher than that of white people lived in same place in other words exposed to same environment. All of these findings strongly suggest that Asian people have a susceptibility to develop the metabolic diseases such as metabolic syndrome and type 2 diabetes with a little environmental changes comprised nutritional transit and sedentary life style. In addition to the epidemic of diabetes, only 20~40% of type 2 diabetic patients included Asian epidemiologic study IDMPS attained internationally recommended treatment targets (A1c < 7%, BP < 130/80 mm Hg and LDL-C < 2.6 mmol/L) as other regions, only 5% of patients attained all 3 targets. Therefore, we now need urgent action for prevention, early detection, and established optimal management plan for type 2 diabetic patients.

9S2-2 : Causal effects of hyperinsulinemia on insulin resistance, obesity and aging

저자 : James D. Johnson

발행기관 : 대한당뇨병학회 간행물 : International Congress of Diabetes and Metabolism 2019권 0호 발행 연도 : 2019 페이지 : pp. 2-2 (1 pages)

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Insulin plays critical roles in nutrient homeostasis. Excessive circulating insulin is associated with insulin resistance, inflammation, obesity, and accelerated aging, yet a causal role for hyperinsulinemia in these conditions has been difficult to define experimentally. Many researchers have assumed that hyperinsulinemia is simply a consequence of insulin resistance without definitive evidence. In this lecture, we will discuss evidence that specifically reducing hyperinsulinemia can prevent and reverse obesity in animal models and clinical subjects. This work questions the current dogma that hyperinsulinemia is a response to obesity and/or insulin resistance, and opens up newly appreciated possibilities for clinical translation.

10S4-1 : Clinical characteristics of older adults with diabetes - Korea

저자 : Sung Hoon Yu

발행기관 : 대한당뇨병학회 간행물 : International Congress of Diabetes and Metabolism 2019권 0호 발행 연도 : 2019 페이지 : pp. 3-4 (2 pages)

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The elderly population is continuously increasing worldwide. Diabetes mellitus is one of the most rapidly growing chronic diseases in the elderly population in Korea over the last 20 years. It has been reported that the prevalence of diabetes increased more than 50% in 2012 compared to 2002. The incidence of diabetes was more than two times higher over 65 years than that of people under 65 years and three times higher than the age of 40's. One in two elderly people aged 60 or older is reported to be prediabetes or diabetes. The prevalence of diabetes mellitus and the incidence of steady increases in the elderly population is due to the fact that the carbohydrate intake is an absolute high proportion in Korea including south-east asia, and the physiological changes due to aging are accompanied by changes in glucose metabolism, lifestyle changes. In this talk, I will discuss the clinical characteristics of Korean elderly diabetes mellitus.

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