109 results on '"Kyoungmin Park"'
Search Results
2. Human induced neural stem cells support functional recovery in spinal cord injury models
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Daryeon Son, Jie Zheng, In Yong Kim, Phil Jun Kang, Kyoungmin Park, Lia Priscilla, Wonjun Hong, Byung Sun Yoon, Gyuman Park, Jeong-Eun Yoo, Gwonhwa Song, Jang-Bo Lee, and Seungkwon You
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Medicine ,Biochemistry ,QD415-436 - Abstract
Abstract Spinal cord injury (SCI) is a clinical condition that leads to permanent and/or progressive disabilities of sensory, motor, and autonomic functions. Unfortunately, no medical standard of care for SCI exists to reverse the damage. Here, we assessed the effects of induced neural stem cells (iNSCs) directly converted from human urine cells (UCs) in SCI rat models. We successfully generated iNSCs from human UCs, commercial fibroblasts, and patient-derived fibroblasts. These iNSCs expressed various neural stem cell markers and differentiated into diverse neuronal and glial cell types. When transplanted into injured spinal cords, UC-derived iNSCs survived, engrafted, and expressed neuronal and glial markers. Large numbers of axons extended from grafts over long distances, leading to connections between host and graft neurons at 8 weeks post-transplantation with significant improvement of locomotor function. This study suggests that iNSCs have biomedical applications for disease modeling and constitute an alternative transplantation strategy as a personalized cell source for neural regeneration in several spinal cord diseases.
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- 2023
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3. Validation of the Short Physical Performance Battery via Plantar Pressure Analysis Using Commercial Smart Insoles
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Chan Woong Jang, Kyoungmin Park, Min-Chul Paek, Sanghyun Jee, and Jung Hyun Park
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aged ,foot orthoses ,frailty ,physical functional performance ,Chemical technology ,TP1-1185 - Abstract
This cross-sectional study, conducted at a tertiary care hospital’s rehabilitation clinic, aimed to validate Short Physical Performance Battery (SPPB) results obtained through plantar pressure analysis using commercial smart insoles (SPPB-SI) and to compare these results to manually acquired results by an experienced examiner (SPPB-M). This study included 40 independent-walking inpatients and outpatients aged 50 or older. SPPB-SI and SPPB-M were administered concurrently, with the smart insoles providing plantar pressure data that were converted into time–pressure curves. Two interpreters assessed the curves, determining component completion times for the SPPB-SI scores. Among the 40 participants (mean age: 72.98, SD: 9.27), the mean total SPPB-SI score was 7.72 ± 2.50, and the mean total SPPB-M score was 7.95 ± 2.63. The time recordings and measured scores of each SPPB-SI component exhibited high reliability with inter- and intra-interpreter correlation coefficients of 0.9 and 0.8 or higher, respectively. The intraclass correlation coefficient between the total SPPB-SI and SPPB-M scores was 0.831 (p < 0.001), and that between the component scores of the two measurements ranged from 0.837 to 0.901 (p < 0.001). Consistent correlations with geriatric functional parameters were observed for both SPPB-SI and SPPB-M. This study underscores the potential of commercial smart insoles as reliable tools for conducting SPPB assessments.
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- 2023
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4. Sustained therapeutic effect of an anti-inflammatory peptide encapsulated in nanoparticles on ocular vascular leakage in diabetic retinopathy
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Qiang Qu, Kyoungmin Park, Kevin Zhou, Drew Wassel, Rafal Farjo, Tracy Criswell, Jian-xing Ma, and Yuanyuan Zhang
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pigment epithelium-derived factor ,anti-inflammatory ,anti-vascular leakage ,diabetic retinopathy ,wnt signaling ,PLGA ,Biology (General) ,QH301-705.5 - Abstract
Pigment epithelium-derived factor (PEDF), an endogenous Wnt signaling inhibitor in the serine proteinase inhibitors (SERPIN) super family, is present in multiple organs, including the vitreous. Significantly low levels of PEDF in the vitreous are found to associate with pathological retinal vascular leakage and inflammation in diabetic retinopathy (DR). Intravitreal delivery of PEDF represents a promising therapeutic approach for DR. However, PEDF has a short half-life after intravitreal injection, which represents a major hurdle for the long-term treatment. Here we report the prolonged therapeutic effects of a 34-mer peptide of the PEDF N-terminus, encapsulated in poly (lactic-co-glycolic acid) (PLGA) nanoparticles (PEDF34-NP), on DR. PEDF34-NP inhibited hypoxia-induced expression of vascular endothelial growth factor and reduced levels of intercellular adhesion molecule 1 (ICAM-1) in cultured retinal cells. In addition, PEDF34-NP significantly ameliorated ischemia-induced retinal neovascularization in the oxygen-induced retinopathy rat model, and significantly reduced retinal vascular leakage and inflammation in streptozotocin-induced diabetic rats up to 4 weeks after intravitreal injection, as compared to PLGA-NP control. Intravitreal injection of PEDF34-NP did not display any detectable toxicities to retinal structure and function. Our findings suggest that PEDF34-NP can confer sustained therapeutic effects on retinal inflammation and vascular leakage, having considerable potential to provide long-term treatment options for DR.
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- 2022
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5. Regeneration of glomerular metabolism and function by podocyte pyruvate kinase M2 in diabetic nephropathy
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Jialin Fu, Takanori Shinjo, Qian Li, Ronald St-Louis, Kyoungmin Park, Marc G. Yu, Hisashi Yokomizo, Fabricio Simao, Qian Huang, I-Hsien Wu, and George L. King
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Endocrinology ,Metabolism ,Medicine - Abstract
Diabetic nephropathy (DN) arises from systemic and local changes in glucose metabolism and hemodynamics. We have reported that many glycolytic and mitochondrial enzymes, such as pyruvate kinase M2 (PKM2), were elevated in renal glomeruli of DN-protected patients with type 1 and type 2 diabetes. Here, mice with PKM2 overexpression specifically in podocytes (PPKM2Tg) were generated to uncover the renal protective function of PPKM2Tg as a potential therapeutic target that prevented elevated albumin/creatinine ratio (ACR), mesangial expansion, basement membrane thickness, and podocyte foot process effacement after 7 months of streptozotocin-induced (STZ-induced) diabetes. Furthermore, diabetes-induced impairments of glycolytic rate and mitochondrial function were normalized in diabetic PPKM2Tg glomeruli, in concordance with elevated Ppargc1a and Vegf expressions. Restored VEGF expression improved glomerular maximal mitochondrial function in diabetic PPKM2Tg and WT mice. Elevated VEGF levels were observed in the glomeruli of DN-protected patients with chronic type 1 diabetes and clinically correlated with estimated glomerular filtration (GFR) — but not glycemic control. Mechanistically, the preservations of mitochondrial function and VEGF expression were dependent on tetrameric structure and enzymatic activities of PKM2 in podocytes. These findings demonstrate that PKM2 structure and enzymatic activation in podocytes can preserve the entire glomerular mitochondrial function against toxicity of hyperglycemia via paracrine factors such as VEGF and prevent DN progression.
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- 2022
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6. Insulin's actions on vascular tissues: Physiological effects and pathophysiological contributions to vascular complications of diabetes
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Jialin Fu, Marc Gregory Yu, Qian Li, Kyoungmin Park, and George L. King
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Diabetes ,CVD ,Insulin resistance ,Cardiovascular complications ,Internal medicine ,RC31-1245 - Abstract
Background: Insulin has been demonstrated to exert direct and indirect effects on vascular tissues. Its actions in vascular cells are mediated by two major pathways: the insulin receptor substrate 1/2-phosphoinositide-3 kinase/Akt (IRS1/2/PI3K/Akt) pathway and the Src/mitogen-activated protein kinase (MAPK) pathway, both of which contribute to the expression and distribution of metabolites, hormones, and cytokines. Scope of review: In this review, we summarize the current understanding of insulin's physiological and pathophysiological actions and associated signaling pathways in vascular cells, mainly in endothelial cells (EC) and vascular smooth muscle cells (VSMC), and how these processes lead to selective insulin resistance. We also describe insulin's potential new signaling and biological effects derived from animal studies and cultured capillary and arterial EC, VSMC, and pericytes. We will not provide a detailed discussion of insulin's effects on the myocardium, insulin's structure, or its signaling pathways' various steps, since other articles in this issue discuss these areas in depth. Major conclusions: Insulin mediates many important functions on vascular cells via its receptors and signaling cascades. Its direct actions on EC and VSMC are important for transporting and communicating nutrients, cytokines, hormones, and other signaling molecules. These vascular actions are also important for regulating systemic fuel metabolism and energetics. Inhibiting or enhancing these pathways leads to selective insulin resistance, exacerbating the development of endothelial dysfunction, atherosclerosis, restenosis, poor wound healing, and even myocardial dysfunction. Targeted therapies to improve selective insulin resistance in EC and VSMC are thus needed to specifically mitigate these pathological processes.
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- 2021
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7. Homozygous receptors for insulin and not IGF-1 accelerate intimal hyperplasia in insulin resistance and diabetes
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Qian Li, Jialin Fu, Yu Xia, Weier Qi, Atsushi Ishikado, Kyoungmin Park, Hisashi Yokomizo, Qian Huang, Weikang Cai, Christian Rask-Madsen, C. Ronald Kahn, and George L. King
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Science - Abstract
Both insulin and IGF-1 signaling have been implicated in arterial intimal hyperplasia. Here the authors dissect the relative contributions of insulin and IGF-1 receptors, showing that homodimers of insulin receptors, but not IGF-1 receptor, induce proliferation of vascular smooth muscle cells.
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- 2019
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8. High density lipoprotein modulates osteocalcin expression in circulating monocytes: a potential protective mechanism for cardiovascular disease in type 1 diabetes
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Ernesto Maddaloni, Yu Xia, Kyoungmin Park, Stephanie D’Eon, Liane J. Tinsley, Ronald St-Louis, Mogher Khamaisi, Qian Li, George L. King, and Hillary A. Keenan
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Osteocalcin ,Type 1 diabetes ,Cardiovascular disease ,HDL ,Monocytes ,Calcifying monocytes ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Abstract Background Cardiovascular disease (CVD) is a major cause of mortality in type 1 diabetes (T1D). A pro-calcific drift of circulating monocytes has been linked to vascular calcification and is marked by the surface expression of osteocalcin (OCN). We studied OCN+ monocytes in a unique population with ≥50 years of T1D, the 50-Year Joslin Medalists (J50M). Methods CD45 bright/CD14+/OCN+ cells in the circulating mononuclear blood cell fraction were quantified by flow cytometry and reported as percentage of CD45 bright cells. Mechanisms were studied by inducing OCN expression in human monocytes in vitro. Results Subjects without history of CVD (n = 16) showed lower levels of OCN+ monocytes than subjects with CVD (n = 14) (13.1 ± 8.4% vs 19.9 ± 6.4%, p = 0.02). OCN+ monocytes level was inversely related to total high density lipoprotein (HDL) cholesterol levels (r = −0.424, p = 0.02), large (r = −0.413, p = 0.02) and intermediate (r = −0.445, p = 0.01) HDL sub-fractions, but not to small HDL. In vitro, incubation with OxLDL significantly increased the number of OCN+ monocytes (p
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- 2017
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9. A Novel Cell Deployment for UAM Communications in 5G-Advanced Network.
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Kyoungmin Park, Jaewon Lee, Hyunseok Ryu, and Younsun Kim
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- 2022
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10. A 32-dB SNR Readout IC With 20-Vpp Tx Using On-Chip DM-TISM in HV BCD Process for Mutual-Capacitive Fingerprint Sensor.
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Eunho Choi 0001, Seong-Mun Kim, Kyoungmin Park, Sanghyun Heo, Hyunggun Ma, Gyeongho Namgoong, Haksun Kim, and Franklin Bien
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- 2020
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11. The Effects of Organizational Culture of Early Childhood Education Institutions on Early Childhood Teachers’ Early Adaptation and Commitment to Change
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Kyoungmin Park and Hangjoon Choi
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- 2023
12. A Study on the Standard for the Safety Zone in the Domestic LNG TTS Bunkering
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Sung-In Park, Jae Seung Roh, Jaehee Park, Kyoungmin Park, and Dongkyu Shin
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- 2022
13. Research Trends on Education for Sustainable Development in Infants and Toddlers Using Keyword Network Analysis
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Kyoungmin Park
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- 2022
14. Endothelial Cells Induced Progenitors Into Brown Fat to Reduce Atherosclerosis
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Kyoungmin Park, Qian Li, Matthew D. Lynes, Hisashi Yokomizo, Ernesto Maddaloni, Takanori Shinjo, Ronald St-Louis, Qin Li, Sayaka Katagiri, Jialin Fu, Allen Clermont, Hyunseok Park, I-Hsien Wu, Marc Gregory Yu, Hetal Shah, Yu-Hua Tseng, and George L. King
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Mice, Inbred C57BL ,Mice ,Apolipoproteins E ,Adipose Tissue, Brown ,Physiology ,Animals ,Endothelial Cells ,Insulin ,Cardiology and Cardiovascular Medicine ,Atherosclerosis ,Nitric Oxide - Abstract
Background: Insulin resistance (IR) can increase atherosclerotic and cardiovascular risk by inducing endothelial dysfunction, decreasing nitric oxide (NO) production, and accelerating arterial inflammation. The aim is to determine the mechanism by which insulin action and NO production in endothelial cells can improve systemic bioenergetics and decrease atherosclerosis via differentiation of perivascular progenitor cells (PPCs) into brown adipocytes (BAT). Methods: Studies used various endothelial transgenic and deletion mutant ApoE −/− mice of insulin receptors, eNOS (endothelial NO synthase) and ETBR (endothelin receptor type B) receptors for assessments of atherosclerosis. Cells were isolated from perivascular fat and micro-vessels for studies on differentiation and signaling mechanisms in responses to NO, insulin, and lipokines from BAT. Results: Enhancing insulin’s actions on endothelial cells and NO production in ECIRS1 transgenic mice reduced body weight and increased systemic energy expenditure and BAT mass and activity by inducing differentiation of PPCs into beige/BAT even with high-fat diet. However, positive changes in bioenergetics, BAT differentiation from PPCs and weight loss were inhibited by N(gamma)-nitro-L-arginine methyl ester ( L -NAME), an inhibitor of eNOS, in ECIRS1 mice and eNOSKO mice. The mechanism mediating NO’s action on PPC differentiation into BAT was identified as the activation of solubilized guanylate cyclase/PKGIα (cGMP protein-dependent kinase Iα)/GSK3β (glycogen synthase kinase 3β) pathways. Plasma lipidomics from ECIRS1 mice with NO-induced increased BAT mass revealed elevated 12,13-diHOME production. Infusion of 12,13-diHOME improved endothelial dysfunction and decreased atherosclerosis, whereas its reduction had opposite effects in ApoE − /− mice. Conclusions: Activation of eNOS and endothelial cells by insulin enhanced the differentiation of PPC to BAT and its lipokines and improved systemic bioenergetics and atherosclerosis, suggesting that endothelial dysfunction is a major contributor of energy disequilibrium in obesity.
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- 2023
15. Elevated Retinol Binding Protein 3 Concentrations Are Associated With Decreased Vitreous Inflammatory Cytokines, VEGF, and Progression of Diabetic Retinopathy
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Ward Fickweiler, Hyunseok Park, Kyoungmin Park, Margalit G. Mitzner, Tanvi Chokshi, Tahani Boumenna, John Gautier, Yumi Zaitsu, I-Hsien Wu, Jerry Cavallerano, Lloyd P. Aiello, Jennifer K. Sun, and George L. King
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Retinol-Binding Proteins ,Vascular Endothelial Growth Factor A ,Vitreous Body ,Advanced and Specialized Nursing ,Diabetic Retinopathy ,Diabetes Mellitus, Type 2 ,Endocrinology, Diabetes and Metabolism ,Internal Medicine ,Cytokines ,Humans ,Enzyme-Linked Immunosorbent Assay ,Eye Proteins - Abstract
OBJECTIVE To correlate inflammatory cytokines and vascular endothelial growth factor (VEGF) in vitreous and plasma with vitreous retinol binding protein 3 (RBP3), diabetic retinopathy (DR) severity, and DR worsening in a population with type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS RBP3, VEGF, and inflammatory cytokines were measured in plasma and vitreous samples (n = 205) from subjects of the Joslin Medalist Study and Beetham Eye Institute. RESULTS Higher vitreous RBP3 concentrations were associated with less severe DR (P < 0.0001) and a reduced risk of developing proliferative DR (PDR) (P < 0.0001). Higher RBP3 correlated with increased photoreceptor segment thickness and lower vitreous interleukin-12 (IL-12), tumor necrosis factor-α (TNF-α), and TNF-β (P < 0.05). PDR was associated with lower vitreous interferon-γ and IL-10 and higher VEGF, IL-6, and IL-15 (P < 0.05), but was not associated with their plasma concentrations. CONCLUSIONS Higher vitreous RBP3 concentrations are associated with less severe DR and slower rates of progression to PDR, supporting its potential as a biomarker and therapeutic agent for preventing DR worsening, possibly by lowering retinal VEGF and inflammatory cytokines.
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- 2022
16. Dysregulation of CXCL1 expression and neutrophil recruitment in insulin resistance and diabetes-related periodontitis in male mice
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George L King, Fusanori Nishimura, Thomas E Van Dyke, Hatice Hasturk, Koji Mizutani, Wu I-Hsien, Jialin Fu, Ronald St-Louis, Kohei Sato, Tatsuro Zeze, Hisashi Yokomizo, Qian Li, Kyoungmin Park, Atsushi Ishikado, Yumi Zaitsu, Satoru Onizuka, and Takanori Shinjo
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Endocrinology, Diabetes and Metabolism ,Internal Medicine - Abstract
Insulin resistance and hyperglycemia are risk factors for periodontitis and poor wound healing in diabetes, which have been associated with selective loss of insulin- activation of the PI3K/Akt pathway in the gingiva. This study showed that insulin resistance in the mouse gingiva due to selective deletion of smooth muscle and fibroblast insulin receptor (SMIRKO mice) or systemic metabolic changes induced by high fat diet (HFD) in HFD-fed mice exacerbated periodontitis-induced alveolar bone loss, preceded by delayed neutrophil and monocyte recruitment and impaired bacterial clearance compared to their respective controls. The immunocytokines, CXCL1, CXCL2, MCP-1, TNFα, IL-1β and IL-17A exhibited delayed maximal expression in the gingiva of male SMIRKO and HFD-fed mice compared to controls. Targeted overexpression of CXCL1 in the gingiva by adenovirus normalized neutrophil and monocyte recruitment and prevented bone loss in both mouse models of insulin resistance. Mechanistically, insulin enhanced bacterial lipopolysaccharide-induced CXCL1 production in mouse and human gingival fibroblasts (GFs), via Akt pathway and NF-κB activation, which were reduced in GFs from SMIRKO and HFD-fed mice. These results provided the first report that insulin signaling can enhance endotoxin induced CXCL1 expression to modulate neutrophil recruitment, suggesting CXCL1 as a new therapeutic direction for periodontitis or wound healing in diabetes.
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- 2023
17. 72 dB SNR, 240 Hz Frame Rate Readout IC With Differential Continuous-Mode Parallel Architecture for Larger Touch-Screen Panel Applications.
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Sanghyun Heo, Hyunggun Ma, Joohyeb Song, Kyoungmin Park, Eun-Ho Choi 0001, Jae Joon Kim, and Franklin Bien
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- 2016
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18. A low-offset, low-noise, fully differential receiver with a differential signaling method for fingerprint mutual capacitive touch screen.
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Sanghyun Heo, Joohyeb Song, Kyoungmin Park, Eun-Ho Choi 0001, Seong-Mun Kim, and Franklin Bien
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- 2017
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19. Endothelial Cell Insulin Signaling Regulates CXCR4 (C-X-C Motif Chemokine Receptor 4) and Limits Leukocyte Adhesion to Endothelium
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Thomas Rathjen, Britta Kunkemoeller, Carly T. Cederquist, Xuanchun Wang, Sam M. Lockhart, James C. Patti, Hanni Willenbrock, Grith Skytte Olsen, Gro Klitgaard Povlsen, Hans Christian Beck, Lars Melholt Rasmussen, Qian Li, Kyoungmin Park, George L. King, and Christian Rask-Madsen
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Cardiology and Cardiovascular Medicine - Abstract
Background: An activated, proinflammatory endothelium is a key feature in the development of complications of obesity and type 2 diabetes and can be caused by insulin resistance in endothelial cells. Methods: We analyzed primary human endothelial cells by RNA sequencing to discover novel insulin-regulated genes and used endothelial cell culture and animal models to characterize signaling through CXCR4 (C-X-C motif chemokine receptor 4) in endothelial cells. Results: CXCR4 was one of the genes most potently regulated by insulin, and this was mediated by PI3K (phosphatidylinositol 3-kinase), likely through FoxO1, which bound to the CXCR4 promoter. CXCR4 mRNA in CD31+ cells was 77% higher in mice with diet-induced obesity compared with lean controls and 37% higher in db/db mice than db/+ controls, consistent with upregulation of CXCR4 in endothelial cell insulin resistance. SDF-1 (stromal cell–derived factor-1)—the ligand for CXCR4—increased leukocyte adhesion to cultured endothelial cells. This effect was lost after deletion of CXCR4 by gene editing while 80% of the increase was prevented by treatment of endothelial cells with insulin. In vivo microscopy of mesenteric venules showed an increase in leukocyte rolling after intravenous injection of SDF-1, but most of this response was prevented in transgenic mice with endothelial overexpression of IRS-1 (insulin receptor substrate-1). Conclusions: Endothelial cell insulin signaling limits leukocyte/endothelial cell interaction induced by SDF-1 through downregulation of CXCR4. Improving insulin signaling in endothelial cells or inhibiting endothelial CXCR4 may reduce immune cell recruitment to the vascular wall or tissue parenchyma in insulin resistance and thereby help prevent several vascular complications.
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- 2022
20. 24-OR: Podocyte Targeted Pyruvate Kinase M2 (PKM2) Activation Normalized Glomerular VEGF Expression, Mitochondrial Function, Fuel Metabolism, and Diabetic Nephropathy
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JIALIN FU, TAKANORI SHINJO, QIAN LI, KYOUNGMIN PARK, MARC GREGORY YU, HISASHI YOKOMIZO, QIAN HUANG, I-HSIEN WU, and GEORGE L. KING
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Endocrinology, Diabetes and Metabolism ,Internal Medicine - Abstract
Diabetic nephropathy (DN) is the result of abnormal systemic and local changes in metabolism and hemodynamics. We have reported that many glycolytic enzymes, such as pyruvate kinase M2 (PKM2) , were elevated in the renal glomeruli of type 1 and type 2 diabetic patients who were protected from DN. TEPP46, a small-molecule which activates PKM2 by inducing oligomerization, reversed glomerular pathology in diabetic mice. Here, mice with PKM2-specific overexpression in podocytes (PPKM2Tg) were generated to uncover its renal protective function as potential therapeutic target, which prevented elevated albumin-creatinine ratio (ACR) , mesangial expansion, basement membrane thickness and podocyte foot process effacement after 7-months of STZ-induced diabetes. Further, diabetes-induced impairment of glycolytic rate and mitochondrial function were normalized in diabetic PPKM2Tg glomeruli, in concordance with elevated Ppargc1a and Vegf expressions. Restored VEGF expression improved glomerular maximal mitochondrial function in diabetic PPKM2Tg and WT mice. Elevated VEGF levels were observed in the glomeruli of DN-protected patients with chronic type 1 diabetes, and clinically correlated with estimated GFR, but not glycemic control. Mechanistically, the preservations of mitochondrial function and VEGF expression were dependent on tetrameric structure and enzymatic activities of PKM2 in podocyte. Thus, these findings show that PKM2 activation in the podocyte can regulate mitochondrial metabolism of the entire glomeruli and prevent mitochondrial dysfunction induced by chronic diabetes and even reverse metabolic memory. PKM2 structures and enzymatic activities are necessary to mediate glomerular metabolism against toxicity of hyperglycemia via paracrine factors such as VEGF. Thus, PKM2 activation in podocyte is a potential therapeutic target to protect against DN. Disclosure J.Fu: None. T.Shinjo: None. Q.Li: None. K.Park: None. M.Yu: None. H.Yokomizo: None. Q.Huang: None. I.Wu: None. G.L.King: Advisory Panel; Medtronic, Research Support; Janssen Pharmaceuticals, Inc.
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- 2022
21. 43-OR: Aqueous Retinol Binding Protein 3 Is Reduced in Patients with Advanced Diabetic Retinopathy in Type 1 and Type 2 Diabetes
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TANVI CHOKSHI, WARD FICKWEILER, MARGALIT G. MITZNER, I-HSIEN WU, TAHANI BOUMENNA, DEVON B. ROBINSON, HYUNSEOK PARK, KYOUNGMIN PARK, LLOYD P. AIELLO, JENNIFER SUN, and GEORGE L. KING
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Endocrinology, Diabetes and Metabolism ,Internal Medicine - Abstract
The Joslin Medalist Study identified Retinol-binding protein 3 (RBP3) as a potential protective factor against diabetic retinopathy (DR) in the vitreous and retina of individuals with type 1 diabetes for 50 years or longer. This study evaluated the association of aqueous RBP3 concentration to vitreous RBP3 concentrations and DR severity. We measured 131 aqueous samples from patients with type 1 and 2 diabetes undergoing cataract surgery at the Joslin Beetham Eye Institute (BEI) and postmortem samples of Medalists. Aqueous RBP3 concentrations in BEI and Medalists samples were similar for eyes with proliferative DR (PDR, P=0.11) and were well correlated between fellow eyes (r=0.65, P Disclosure T.Chokshi: None. J.Sun: Consultant; American Diabetes Association, American Medical Association, Research Support; Adaptive Sensory Technology, Boehringer Ingelheim International GmbH, Genentech, Inc., Jaeb Center for Health Research, Janssen Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Optovue, Incorporated, Physical Sciences, Inc, Roche Pharmaceuticals. G.L.King: Advisory Panel; Medtronic, Research Support; Janssen Pharmaceuticals, Inc. W.Fickweiler: None. M.G.Mitzner: None. I.Wu: None. T.Boumenna: None. D.B.Robinson: None. H.Park: None. K.Park: None. L.P.Aiello: Consultant; KalVista Pharmaceuticals, Inc., Novo Nordisk, Stock/Shareholder; KalVista Pharmaceuticals, Inc. Funding American Diabetes Association (7-21-PDF-022) ; National Eye Institute (R01EYE26080-01) , the National Institute of Diabetes and Digestive and Kidney Diseases and National Institutes of Health (DP3-DK-094333-01) ; JDRF (17-2013-310) ; the Dianne Nunnally Hoppes Fund; the Beatson Pledge Fund
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- 2022
22. 46-OR: Differential Effects of RBP3 and Anti-VEGF on Retinal Dysfunctions in Diabetic Retinopathy
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QIN LI, SATORU ONIZUKA, KYOUNGMIN PARK, HYUNSEOK PARK, QIAN LI, WARD FICKWEILER, JIALIN FU, I-HSIEN WU, and GEORGE L. KING
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Endocrinology, Diabetes and Metabolism ,Internal Medicine - Abstract
Background: Anti-vascular endothelial growth factor (anti-VEGF) therapy has revolutionized the treatment of severe diabetic retinopathy (DR) , but significant subset of patients showed inadequate response to anti-VEGF. We have previously reported that retinol binding protein 3 (RBP3) prevented hyperglycemia induced retinal pathologies and progression to severe DR. Hypothesis: RBP3 and Anti-VEGF have differential protective profiles in preventing retinal dysfunctions induced by diabetes. Methods and Results: Recombinant human RBP3 (rhRBP3, 5ug/ml) and anti-VEGF (Avastin, 250mg/ml) inhibited VEGF-induced retinal vascular permeability (RVP) by 70% when intravitreal injections were given together in Lewis rats (P < 0.01) . After 2 months of diabetes induced by streptozotocin (STZ) , intravitreal injection of rhRBP3 and anti-VEGF for 3 days suppressed RVP by 64% and 53% (P < 0.01) in Lewis rats. This was accompanied by reductions of VEGF levels by both proteins. Electroretinogram (ERG) amplitudes of A wave, B wave, C wave were decreased in rats after 2 months of diabetes (P < 0.01) . rhRBP3 increased amplitudes of C wave (P < 0.01) , while anti-VEGF did not improve any waveforms. Furthermore, rhRBP3 decreased retinal mRNA expression of Cd11b and Tnfa (P =0.1) in diabetic rats. In cultured primary bovine Müller cells, rhRBP3 decreased mRNA expressions of Tnfa and Il-6 induced by high glucose (25mM) (P < 0.01) , whereas, anti-VEGF showed no effect. Metabolic function studies using Seahorse assays showed that isolated retina from intravitreal rhRBP3 treated rats exhibited reduced glycolysis rate in ECAR while anti-VEGF treatments had no effects. Conclusions: Both intravitreal anti-VEGF and RBP3 treatments normalized retinal vascular dysfunctions caused by diabetes. However, only RBP3 reversed abnormal neural-retinal dysfunctions and elevated inflammatory cytokines induced by hyperglycemia, possible by decreasing glucose uptake and glycolysis levels in retinal cells. Disclosure Q.Li: None. S.Onizuka: None. K.Park: None. H.Park: None. Q.Li: None. W.Fickweiler: None. J.Fu: None. I.Wu: None. G.L.King: Advisory Panel; Medtronic, Research Support; Janssen Pharmaceuticals, Inc.
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- 2022
23. 42-OR: Association of Vitreous Retinol Binding Protein 3 with Inflammatory Cytokines and Progression of Diabetic Retinopathy in Type 1 and Type 2 Diabetes
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WARD FICKWEILER, HYUNSEOK PARK, KYOUNGMIN PARK, MARGALIT G. MITZNER, DEVON B. ROBINSON, TANVI CHOKSHI, TAHANI BOUMENNA, JOHN GAUTHIER, I-HSIEN WU, JERRY D. CAVALLERANO, LLOYD P. AIELLO, JENNIFER SUN, and GEORGE L. KING
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Endocrinology, Diabetes and Metabolism ,Internal Medicine - Abstract
Although inflammatory cytokines and vascular endothelial growth factor (VEGF) have been proposed to underlie the progression of diabetic retinopathy (DR) , there remains an important need to identify biomarkers for early stages of DR. Findings from the Joslin Medalist Study, composed of individuals who have had insulin-dependent diabetes for 50 years or longer, showed that Retinol Binding Protein 3 (RBP3) was significantly higher both in retina and vitreous samples with no to mild DR compared to those with proliferative DR (PDR) . In this study, we examined vitreous and plasma samples from 2people with type 1 and type 2 diabetes from the Joslin Beetham Eye Institute and Medalist Study to evaluate the relationship between vitreous RBP3, inflammatory cytokines, and DR severity and progression. PDR was associated with lower levels of IL- (P=0.007) , IFN-γ (P=0.001) , and higher levels of IL-15 (P=0.01) and IL-6 (P=0.02) in vitreous. Vitreous VEGF was positively associated with increasing DR severity in surgical samples (P Disclosure W.Fickweiler: None. J.D.Cavallerano: None. L.P.Aiello: Consultant; KalVista Pharmaceuticals, Inc., Novo Nordisk, Stock/Shareholder; KalVista Pharmaceuticals, Inc. J.Sun: Consultant; American Diabetes Association, American Medical Association, Research Support; Adaptive Sensory Technology, Boehringer Ingelheim International GmbH, Genentech, Inc., Jaeb Center for Health Research, Janssen Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Optovue, Incorporated, Physical Sciences, Inc, Roche Pharmaceuticals. G.L.King: Advisory Panel; Medtronic, Research Support; Janssen Pharmaceuticals, Inc. H.Park: None. K.Park: None. M.G.Mitzner: None. D.B.Robinson: None. T.Chokshi: None. T.Boumenna: None. J.Gauthier: None. I.Wu: None. Funding American Diabetes Association (7-21-PDF-022) ; National Eye Institute (R01EYE26080-01) , the National Institute of Diabetes and Digestive and Kidney Diseases and National Institutes of Health (DP3-DK-094333-01) ; JDRF (17-2013-310) ; the Dianne Nunnally Hoppes Fund; the Beatson Pledge Fund
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- 2022
24. A 32-dB SNR Readout IC With 20-Vpp Tx Using On-Chip DM-TISM in HV BCD Process for Mutual-Capacitive Fingerprint Sensor
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Franklin Bien, Seong Mun Kim, Eunho Choi, Kyoungmin Park, Gyeongho Namgoong, Haksun Kim, Hyunggun Ma, and Sanghyun Heo
- Subjects
Physics ,business.industry ,Capacitive sensing ,020208 electrical & electronic engineering ,Transmitter ,Order (ring theory) ,02 engineering and technology ,Type (model theory) ,Signal ,Signal-to-noise ratio (imaging) ,0202 electrical engineering, electronic engineering, information engineering ,Optoelectronics ,System on a chip ,Electrical and Electronic Engineering ,business ,DC bias - Abstract
This brief presents a readout IC with a 20 V high-voltage (HV) transmitter (Tx) and On-Chip Differentially Modulated Time-Interleaved Sensing Method (DM-TISM) in a BCD process for a mutual-capacitive Transparent Fingerprint Sensor (TFPS) in order to achieve high SNR, AC & DC offset reduction, high noise immunity, and compensate for the signal loss under thick cover glass. A proposed readout IC with on-chip DM-TISM is composed of 42 identical HV Tx channels, 32 identical Rx channels, and a diamond-patterned TFPS. The performance results including those for transient noise show that the DM-TISM achieves greater SNR than conventional TISM. The measured raw data show that the proposed readout IC achieves SNR of 32 dB with current consumption of 25 mA for the Tx and 13 mA for the Rx. It can be applied to any type of mobile device that needs fingerprint recognition. The ICs for the Tx and Rx are fabricated using 0.25- $\mu \text{m}$ BCD process and 0.18- $\mu \text{m}$ CMOS process with $1.6\,\,\mathrm {mm} \times 3.5$ mm and $2.5\,\,\mathrm {mm} \times 2.5$ mm areas, respectively.
- Published
- 2020
25. 54-OR: Nucleolin Autoantibody Accelerates Atherosclerosis in Type 1 Diabetes
- Author
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Stephan Kissler, George L. King, Hyunseok Park, Kyoungmin Park, Jialin Fu, Andrew H. Lichtman, I-Hsien Wu, Ernesto Maddaloni, and Qian Li
- Subjects
Type 1 diabetes ,business.industry ,Endocrinology, Diabetes and Metabolism ,HLA-DR3 ,Autoantibody ,FOXP3 ,Context (language use) ,Nod ,medicine.disease ,medicine.disease_cause ,Autoimmunity ,Immunology ,Internal Medicine ,medicine ,business ,Insulitis - Abstract
Hyperglycemia has been evaluated extensively as risk factors for cardiovascular disease (CVD) in people with type 1 diabetes (T1DM). However, the effects of the autoantibody on atherosclerosis and immunogenic trigger are not well understood in T1D. Using the generated several mice models of atherosclerosis including NOD, congenic ApoE-/-/NOD (NDM and no- autoimmune), ApoE-/-/NOD (autoimmunity with insulitis, NDM) and ApoE-/-/NOD autoimmune DM mice, we analyzed immune cells composition of aorta and have observed the increasing numbers of CD3+(CD3+/CD25-), Th1 and Th17 subset of T cells and B cells and decreased Treg (CD3+/CD25+/Foxp3+) in the ApoE-/-/NOD and ApoE-/-/NOD-DM mice vs. control. In addition, we postulate that the identification of specific autoantibody(s) which induce dysregulaton of T-cells, resulting in enhancing its infiltration and accumulation at the plaques could aid new immunotherapies for atherosclerosis. Here we performed autoantigen microarrays to profile and identify specific autoantibodies, enhancing the severe atherosclerosis in subgroups of Medalist patients with chronic duration of T1D due to autoimmunity with positive HLA DR3/4 risk alleles and autoantibodies and compared to the people with monogenic diabetes lacking HLA DR3/4 risk alleles for T1D and autoantibodies. Autoantigen microarrays from the plasma of T1D patients with positive DR3/4 risk and CVD identified 8 autoantibodies changed in the context of atherosclerosis, compared to the people with monogenic diabetes. To confirm the autoantibody profiling data from the patients, we analyzed the autoantibody profiles in the T1D mice models of atherosclerosis described above. Autoantigen microarrays analysis of the plasma of T1D patients and mice showed several common findings that reached significance anti-Nucleolin Ab, p=0.005. These findings indicate autoimmunity may contribute to the progression of atherosclerosis in T1D. Further studies are in progress to replicate these findings in other cohorts of T1D. Disclosure K. Park: None. Q. Li: None. H. Park: None. J. Fu: None. S. Kissler: None. E. Maddaloni: Research Support; Self; European Foundation for the Study of Diabetes, Speaker's Bureau; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Merck KGaA. I. Wu: None. A. H. Lichtman: None. G. L. King: Consultant; Self; Agios, Inc., Medtronic, Other Relationship; Self; Janssen Pharmaceuticals, Inc. Funding DK036836, DK036836, EY026080
- Published
- 2021
26. 55-OR: Targeted Deletion of Insulin Receptor in Vascular Smooth Muscle Cells Promoted Atherosclerosis and Unstable Plaque
- Author
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George L. King, Qian Li, Kyoungmin Park, I-Hsien Wu, and Jialin Fu
- Subjects
medicine.medical_specialty ,Insulin receptor ,Endocrinology ,Vascular smooth muscle ,biology ,business.industry ,Endocrinology, Diabetes and Metabolism ,Internal medicine ,cardiovascular system ,Internal Medicine ,medicine ,biology.protein ,business - Abstract
Risks of unstable arterial plaques are increased in diabetes or insulin resistance. We hypothesized that insulin resistance in VSMCs contributes to reduced plaque stability since we have reported that insulin receptors (IR) on VSMCs are potent regulators of its proliferation and apoptosis. Further, insulin induced Akt phosphorylation was decreased in the aorta of diabetic mice. Lipid deposition were increased in the aortas of ApoE-/- and VSMCs IR double knockout (SMIRKO/ApoE-/-) mice vs. control mice. Pathological analysis of the atherosclerotic plaques of SMIRKO/ApoE-/- mice demonstrated features of unstable plaques, including reduced VSMCs proliferation and reduced cap thickness and collagen, but increased VSMCs apoptosis and more macrophages and necrosis area. VSMCs from SMIRKO/ApoE-/- mice exhibited less insulin induced proliferation and more apoptosis which were not inhibited by insulin compared to VSMCs from ApoE-/- mice. Artery relaxation induced by sodium nitroprusside (SNP) (NO donor) was impaired in artery from SMIRKO/ApoE-/- mice vs. control mice. Insulin and SNP induced VASP phosphorylation, a downstream signaling protein of NO in VSMCs, were reduced in SMIRKO/ApoE-/- mice vs. control mice. Expressions of MMP2, THBS1, sFRP3, and COMP were increased in the aorta of SMIRKO/ApoE-/- mice vs. ApoE-/- mice, which were also observed in the aorta of diabetic mice fed with high fat diet or diabetes induced by STZ. Insulin induced Akt and Foxo1 phosphorylation were impaired in cultured VSMCs from SMIRKO/ApoE-/- mice vs. control mice. Overexpression of constitutively activated Akt increased VASP phosphorylation and downregulated THBS1 expression in cultured VSMCs, whereas overexpression of FoxO1 increased THBS1 expression. This is the first report that selective inhibition of IR activation of pAkt in VSMCs is partially causing the elevated risk of unstable atherosclerotic plaques found in insulin resistance or diabetes. Disclosure Q. Li: None. J. Fu: None. K. Park: None. I. Wu: None. G. L. King: Consultant; Self; Agios, Inc., Medtronic, Other Relationship; Self; Janssen Pharmaceuticals, Inc. Funding National Institutes of Health (R01DK053105)
- Published
- 2021
27. 183-OR: Pyruvate Kinase M2 (PKM2) Enzymatic Activity Is Necessary to Improve Podocyte Mitochondrial Function and Glomerular Fuel Metabolism and Diabetic Nephropathy
- Author
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Kyoungmin Park, Jialin Fu, Marc Gregory Yu, Takanori Shinjo, George L. King, Hisashi Yokomizo, Hetal Shah, I-Hsien Wu, Ronald St-Louis, and Qian Li
- Subjects
medicine.medical_specialty ,biology ,Chemistry ,Endocrinology, Diabetes and Metabolism ,PKM2 ,medicine.disease ,medicine.disease_cause ,Podocyte ,Diabetic nephropathy ,medicine.anatomical_structure ,Endocrinology ,Diabetes mellitus ,Internal medicine ,Internal Medicine ,medicine ,Podocin ,biology.protein ,Glycolysis ,Pyruvate kinase ,Oxidative stress - Abstract
Diabetic nephropathy (DN) is the result of abnormal systemic and local changes in metabolism and hemodynamics. We have reported that many glycolytic enzymes, such as pyruvate kinase M2 (PKM2), were elevated in the renal glomeruli of type 1 and type 2 diabetic patients who were protected from DN. TEPP46, a small-molecule which activates PKM2 by inducing oligomerization, reversed glomerular pathology in diabetic mice. After 7 months of STZ induced diabetes, mice with PKM2 specific overexpression in podocytes (PPKM2Tg) with podocin promoter, exhibited lower albumin-creatinine ratio (ACR), kidney-body weight ratio, mesangial expansion, basement membrane thickness and podocyte foot process effacement vs. WT diabetic littermates. PPKM2Tg mice exhibited lower expression of fibrotic (FN, TGFβ1 and Col4a) and oxidative stress (p47phox, NOX2 and NOX4) genes and improvement in endothelial function with increased eNOS and VEGF expressions in the glomeruli, compared to diabetic WT mice. Glycolytic and mitochondrial metabolisms as measured by oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) using Seahorse showed striking improvement of impaired mitochondrial maximal respiration capacity and glycolytic rate in isolated glomeruli of diabetic PPKM2Tg mice, in concordance with elevated expressions of mitochondrial related-genes, such as PGC1α. Knocking-down PKM by shRNA in podocyte cell line (pPKMKD) replicated metabolic findings induced by diabetes with dramatic decline of both OCR and glycolytic rate. Re-expressing human PKM1 or PKM2 in pPKMKD cell line reversed impaired mitochondrial function and glycolysis, which were not improved in pPKMKD cells re-expressing with enzymatically inactive human PKM2 gene. These results indicate that PKM2 and its enzymatical function are both necessary in podocytes to improve glomerular mitochondrial abnormalities and delay the progression of DN. Disclosure J. Fu: None. G. L. King: Consultant; Self; Agios, Inc., Medtronic, Other Relationship; Self; Janssen Pharmaceuticals, Inc. T. Shinjo: None. Q. Li: None. R. St-louis: None. K. Park: None. H. Yokomizo: None. M. Yu: None. H. Shah: None. I. Wu: None. Funding Iacocca Family Foundation
- Published
- 2021
28. 87-OR: Vitreous Retinol Binding Protein 3 Is Increased in Patients without Advanced Diabetic Retinopathy in Type 1 and Type 2 Diabetes
- Author
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Hyunseok Park, John Gauthier, Ward Fickweiler, I-Hsien Wu, Jennifer K. Sun, Tahani Boumenna, Kyoungmin Park, George L. King, Lloyd Paul Aiello, and Jerry D. Cavallerano
- Subjects
Retinol binding protein ,medicine.medical_specialty ,Endocrinology ,business.industry ,Endocrinology, Diabetes and Metabolism ,Internal medicine ,Internal Medicine ,medicine ,In patient ,Diabetic retinopathy ,Type 2 diabetes ,medicine.disease ,business - Abstract
Retinol Binding Protein 3 (RBP3), a retinol transport protein secreted mainly by photoreceptors, may inhibit progression of diabetic retinopathy (DR) by decreasing glucose uptake and inflammation in the retina. In people with type 1 diabetes with duration of ≥50yrs (Joslin Medalist Study), >40% of Medalists exhibited no to mild non-proliferative diabetic retinopathy (NPDR) and increased expression of RBP3 compared to those with severe DR. We examined 213 vitreous samples from a larger population of Medalists and patients with type 1 and type 2 diabetes with shorter diabetes duration (mean±SD 26.5±12.7 years) from the Joslin Beetham Eye Institute to determine whether vitreous RBP3 levels are correlated with DR severity and progression in a broad population with diabetes. RBP3 was increased in vitreous from people with no diabetes compared to subjects with type 1 and type 2 diabetes (p Disclosure W. Fickweiler: None. G. L. King: Consultant; Self; Agios, Inc., Medtronic, Other Relationship; Self; Janssen Pharmaceuticals, Inc. H. Park: None. K. Park: None. T. Boumenna: None. J. Gauthier: None. I. Wu: None. J. D. Cavallerano: None. L. P. Aiello: Consultant; Self; KalVista Pharmaceuticals, Novo Nordisk, Regeneron Pharmaceuticals Inc., Stock/Shareholder; Self; KalVista Pharmaceuticals. J. Sun: Other Relationship; Self; Novo Nordisk, Roche Pharma, Research Support; Self; Adaptive Sensory Technology, Boehringer Ingelheim Pharmaceuticals, Inc., KalVista Pharmaceuticals, Optovue, Roche Pharma. Funding National Eye Institute (R01EY026080-01); National Institute of Diabetes and Digestive and Kidney Diseases (DP3DK094333-01); JDRF (17-2013-310); Beatson Foundation; Dianne Nunnally Hoppes Fund
- Published
- 2021
29. Characterization of Glycolytic Enzymes and Pyruvate Kinase M2 in Type 1 and 2 Diabetic Nephropathy
- Author
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Monika A. Niewczas, Peter S. Amenta, Thorsten Sadowski, Hetal Shah, Vanessa Bahnam, Aimo Kannt, Kyoungmin Park, Weier Qi, George L. King, Daniel Gordin, David Pober, Hillary A. Keenan, Hui Pan, Yutong Dong, Ronald St-Louis, Takanori Shinjo, Samantha M. Paniagua, Liane J. Tinsley, I-Hsien Wu, Megan J. Brissett, and Jonathan M. Dreyfuss
- Subjects
Male ,Proteomics ,Endocrinology, Diabetes and Metabolism ,Kidney Glomerulus ,Type 2 diabetes ,urologic and male genital diseases ,Kidney ,Cohort Studies ,Diabetic nephropathy ,0302 clinical medicine ,Diabetic Nephropathies ,030212 general & internal medicine ,Aged, 80 and over ,Middle Aged ,Enzymes ,Mitochondria ,medicine.anatomical_structure ,Disease Progression ,Female ,Autopsy ,Metabolic Networks and Pathways ,Glomerular Filtration Rate ,medicine.medical_specialty ,Pyruvate Kinase ,030209 endocrinology & metabolism ,PKM2 ,03 medical and health sciences ,Downregulation and upregulation ,Internal medicine ,Diabetes mellitus ,Internal Medicine ,medicine ,Humans ,Metabolomics ,Renal Insufficiency, Chronic ,Pathophysiology/Complications ,Aged ,Advanced and Specialized Nursing ,business.industry ,Kidney metabolism ,medicine.disease ,Diabetes Mellitus, Type 1 ,Glucose ,Endocrinology ,Diabetes Mellitus, Type 2 ,Mitochondrial biogenesis ,Case-Control Studies ,business ,Biomarkers - Abstract
OBJECTIVE Elevated glycolytic enzymes in renal glomeruli correlated with preservation of renal function in the Medalist Study, individuals with ≥50 years of type 1 diabetes. Specifically, pyruvate kinase M2 (PKM2) activation protected insulin-deficient diabetic mice from hyperglycemia-induced glomerular pathology. This study aims to extend these findings in a separate cohort of individuals with type 1 and type 2 diabetes and discover new circulatory biomarkers for renal protection through proteomics and metabolomics of Medalists’ plasma. We hypothesize that increased glycolytic flux and improved mitochondrial biogenesis will halt the progression of diabetic nephropathy. RESEARCH DESIGN AND METHODS Immunoblots analyzed selected glycolytic and mitochondrial enzymes in postmortem glomeruli of non-Medalists with type 1 diabetes (n = 15), type 2 diabetes (n = 19), and no diabetes (n = 5). Plasma proteomic (SOMAscan) (n = 180) and metabolomic screens (n = 214) of Medalists with and without stage 3b chronic kidney disease (CKD) were conducted and significant markers validated by ELISA. RESULTS Glycolytic (PKM1, PKM2, and ENO1) and mitochondrial (MTCO2) enzymes were significantly elevated in glomeruli of CKD− versus CKD+ individuals with type 2 diabetes. Medalists’ plasma PKM2 correlated with estimated glomerular filtration rate (r2 = 0.077; P = 0.0002). Several glucose and mitochondrial enzymes in circulation were upregulated with corresponding downregulation of toxic metabolites in CKD-protected Medalists. Amyloid precursor protein was also significantly upregulated, tumor necrosis factor receptors downregulated, and both confirmed by ELISA. CONCLUSIONS Elevation of enzymes involved in the metabolism of intracellular free glucose and its metabolites in renal glomeruli is connected to preserving kidney function in both type 1 and type 2 diabetes. The renal profile of elevated glycolytic enzymes and reduced toxic glucose metabolites is reflected in the circulation, supporting their use as biomarkers for endogenous renal protective factors in people with diabetes.
- Published
- 2019
30. Insulin's actions on vascular tissues: Physiological effects and pathophysiological contributions to vascular complications of diabetes
- Author
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George L. King, Kyoungmin Park, Jialin Fu, Qian Li, and Marc Gregory Yu
- Subjects
0301 basic medicine ,Cell signaling ,MAP Kinase Signaling System ,medicine.medical_treatment ,Myocytes, Smooth Muscle ,030209 endocrinology & metabolism ,Review ,Muscle, Smooth, Vascular ,03 medical and health sciences ,Phosphatidylinositol 3-Kinases ,0302 clinical medicine ,Insulin resistance ,Medicine ,Cardiovascular complications ,Animals ,Humans ,Insulin ,Molecular Biology ,Protein kinase B ,Internal medicine ,Vascular tissue ,PI3K/AKT/mTOR pathway ,business.industry ,Diabetes ,Endothelial Cells ,Cell Biology ,medicine.disease ,CVD ,RC31-1245 ,Cell biology ,IRS1 ,Disease Models, Animal ,030104 developmental biology ,Insulin Receptor Substrate Proteins ,Endothelium, Vascular ,Signal transduction ,business ,Proto-Oncogene Proteins c-akt ,Diabetic Angiopathies ,Signal Transduction - Abstract
Background Insulin has been demonstrated to exert direct and indirect effects on vascular tissues. Its actions in vascular cells are mediated by two major pathways: the insulin receptor substrate 1/2-phosphoinositide-3 kinase/Akt (IRS1/2/PI3K/Akt) pathway and the Src/mitogen-activated protein kinase (MAPK) pathway, both of which contribute to the expression and distribution of metabolites, hormones, and cytokines. Scope of review In this review, we summarize the current understanding of insulin's physiological and pathophysiological actions and associated signaling pathways in vascular cells, mainly in endothelial cells (EC) and vascular smooth muscle cells (VSMC), and how these processes lead to selective insulin resistance. We also describe insulin's potential new signaling and biological effects derived from animal studies and cultured capillary and arterial EC, VSMC, and pericytes. We will not provide a detailed discussion of insulin's effects on the myocardium, insulin's structure, or its signaling pathways' various steps, since other articles in this issue discuss these areas in depth. Major conclusions Insulin mediates many important functions on vascular cells via its receptors and signaling cascades. Its direct actions on EC and VSMC are important for transporting and communicating nutrients, cytokines, hormones, and other signaling molecules. These vascular actions are also important for regulating systemic fuel metabolism and energetics. Inhibiting or enhancing these pathways leads to selective insulin resistance, exacerbating the development of endothelial dysfunction, atherosclerosis, restenosis, poor wound healing, and even myocardial dysfunction. Targeted therapies to improve selective insulin resistance in EC and VSMC are thus needed to specifically mitigate these pathological processes., Highlights • Insulin's actions in vascular cells have a significant influence on systemic metabolism. • Insulin exerts its vascular effects through its receptors and signaling cascades. • Inhibition or enhancement of different insulin signaling leads to selective insulin resistance. • Loss of insulin's actions causes endothelial dysfunction and vascular complications in diabetes.
- Published
- 2021
31. Association of bone biomarkers with advanced atherosclerotic disease in people with overweight/obesity
- Author
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Ilaria Cavallari, Rossella Del Toro, Paolo Pozzilli, Mariangela De Pascalis, Raffaella Buzzetti, Nicola Napoli, Kyoungmin Park, Ernesto Maddaloni, Luciana Valente, Flavia Tramontana, Francesco Grigioni, and Rocky Strollo
- Subjects
Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Gastroenterology ,bone biomarkers ,Bone remodeling ,Pathogenesis ,chemistry.chemical_compound ,Endocrinology ,Osteoprotegerin ,cardiovascular disease ,Internal medicine ,Diabetes mellitus ,bone-vascular axis ,medicine ,Humans ,Obesity ,Osteopontin ,Klotho Proteins ,Klotho ,Adaptor Proteins, Signal Transducing ,Aged ,Glucuronidase ,biology ,Vascular disease ,business.industry ,atherosclerosis ,Middle Aged ,Overweight ,medicine.disease ,chemistry ,biology.protein ,Sclerostin ,Female ,business ,Biomarkers - Abstract
A growing body of evidence suggests a potential link between bone metabolism and cardiovascular disease. Aim of this study was to investigate the relationship between levels of circulating bone turnover biomarkers and advanced atherosclerosis. Klotho (KL), sclerostin (SOST), osteopontin (OPN) and osteoprotegerin (OPG) were measured in patients undergoing elective coronary angiography and carotid Doppler ultrasound. The primary outcome was the difference in bone biomarkers levels between participants with and without advanced atherosclerosis, defined as the presence of a critical coronary (≥70%) and/or carotid (≥50%) stenosis. A total of 80 subjects (32.5% females) with a mean age of 68 ± 10 years were included. Advanced atherosclerosis was detected in 55 (68.8%) patients. Subjects with advanced atherosclerosis showed higher serum levels of OPG (p = 0.0015) and SOST (p = 0.017) and similar levels of KL (p = 0.62) and OPN (p = 0.06) compared to patients without. After adjustment for age and sex, only elevated levels of OPG remained significantly associated with advanced atherosclerosis (p = 0.011). Higher serum levels of OPG are independently associated with advanced atherosclerosis confirming a common bond between bone metabolism and vascular disease. Further investigations on the role of selected bone biomarkers in the pathogenesis of cardiovascular disease are needed.
- Published
- 2021
32. Pigment epithelium-derived factor suppresses adipogenesis via inhibition of the MAPK/ERK pathway in 3T3-L1 preadipocytes
- Author
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Wang, Min, Wang, Joshua J., Li, Jingming, Kyoungmin, Park, Qian, Xiaoxian, Ma, Jian-xing, and Zhang, Sarah X.
- Subjects
Fat cells -- Physiological aspects ,Fat cells -- Research ,Cellular signal transduction -- Physiological aspects ,Cellular signal transduction -- Research ,Enzyme inhibitors -- Health aspects ,Enzyme inhibitors -- Research ,Protein kinases -- Physiological aspects ,Protein kinases -- Research ,Biological sciences - Abstract
Wang M, Wang JJ, Li J, Park K, Qian X, Ma J, Zhang SX. Pigment epithelium-derived factor suppresses adipogenesis via inhibition of the MAPK/ERK pathway in 3T3-L1 preadipocytes. Am J Physiol Endocrinol Metab 297: E1378-E1387, 2009. First published October 6, 2009:doi: 10.1152/ajpendo.00252.2009.--We previously reported that circulating levels of pigment epithelium-derived factor (PEDF), a newly identified adipokine, are increased in patients with type 2 diabetes, correlating with body mass index. However, the role of PEDF in adipogenesis remains elusive. In the present study, we have investigated the effects and mechanisms of PEDF on adipocyte differentiation in 3T3-L1 preadipocytes. Differentiation of 3T3-L1 preadipocytes was induced in the presence or absence of human recombinant PEDF protein. The effects of PEDF on adipogenic gene expression, mitotic clonal expansion (MCE), and MAPK activation were investigated. Physiological concentrations of human PEDF protein inhibited adipocyte differentiation, evidenced by decreased lipid accumulation, downregulation of adipocyte markers, and inhibition of master adipogenic transcription factors such as C/EBP-[alpha] and PPAR[gamma] The antiadipogenic effects of PEDF were observed only when PEDF was added to the cells on day 0 but not on day 3 during differentiation, suggesting that PEDF targets some early adipogenic events. Similarly, overexpression of PEDF by adenovirus attenuated adipocyte differentiation. Further studies revealed that PEDF, or U-0126, a specific MAPK/ERK inhibitor, sequentially inhibited the early activation of ERK and MCE. Moreover, PEDF attenuated expression and the phosphorylation of C/EBP-[beta] at [Thr.sup.188], an essential step for transcriptional activation of C/EBP-[beta]. In addition, PEDF expression was decreased significantly in the first 24 h during adipocyte differentiation, suggesting that downregulation of PEDF may be essential for the initiation of MCE and adipogenesis. We conclude that PEDF inhibits adipogenesis in 3T3-L1 preadipocytes partially because of inhibition of the MAPK/ERK signaling pathway and MCE. mitogen-activated protein kinase; extracellular signal-regulated kinase doi: 10.1152/ajpendo.00252.2009
- Published
- 2009
33. Association of the 1q25 diabetes-specific coronary heart disease locus with alterations of the γ-glutamyl cycle and increased methylglyoxal levels in endothelial cells
- Author
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Alessandro Doria, Assunta Pandolfi, Subramanian Pennathur, Vincenzo Trischitta, Kyoungmin Park, Lixia Zeng, Natalia Di Pietro, Sabrina Prudente, Hetal Shah, Caterina Pipino, and Ada Admin
- Abstract
A chromosome 1q25 variant (rs10911021) has been associated with coronary heart disease (CHD) in type 2 diabetes (T2D). In human umbilical vein endothelial cells (HUVECs), the risk allele ‘C’ is associated with lower expression of the adjacent gene GLUL encoding glutamine synthase, converting glutamic acid to glutamine. To further investigate the mechanisms through which this locus affects CHD risk, we measured 35 intracellular metabolites involved in glutamic acid metabolism and g-glutamyl cycle in 62 HUVEC strains carrying different rs10911021 genotypes. Eight metabolites were positively associated with the risk allele (17%-58% increase/allele copy, p=0.046-0.002), including five g-glutamyl amino acids, b-citryl-glutamate, N-acetyl-aspartyl-glutamate, and ophthalmate - a marker of g-glutamyl cycle malfunction. Consistent with these findings, the risk allele was also associated with decreased glutathione/glutamate ratio (-9%, p=0.012), decreased S-lactoylglutathione (-41%, p=0.019), and reduced detoxification of the atherogenic compound methylglyoxal (+54%, p=0.008). GLUL down-regulation by shRNA caused a 40% increase in methylglyoxal level, which was completely prevented by glutamine supplementation. In summary, we have identified intracellular metabolic traits associated with the 1q25 risk allele in HUVECs, including impairments of the g-glutamyl cycle and methylglyoxal detoxification. Glutamine supplementation abolishes the latter abnormality, suggesting that such treatment may prevent CHD in 1q25 risk allele carriers.
- Published
- 2020
34. 327-OR: Association of Retinol Binding Protein 3 with Retinal Neural Structure and Clinical Parameters in Diabetic Retinopathy
- Author
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Kyoungmin Park, Lloyd Paul Aiello, Hyunseok Park, George L. King, Per-Henrik Groop, Emily Wolfson, Valma Harjutsalo, Jennifer K. Sun, Hisashi Yokomizo, Daniel Gordin, Ward Fickweiler, and I-Hsien Wu
- Subjects
Type 1 diabetes ,education.field_of_study ,medicine.medical_specialty ,Protective capacity ,business.industry ,Endocrinology, Diabetes and Metabolism ,Population ,Retinal ,Type 2 diabetes ,Diabetic retinopathy ,medicine.disease ,chemistry.chemical_compound ,Retinol binding protein ,chemistry ,Ophthalmology ,Diabetes mellitus ,Internal Medicine ,medicine ,education ,business - Abstract
The Joslin Medalist Study, which characterizes people with type 1 diabetes duration of 50 years or more, reported that the levels of Retinol Binding Protein 3 (RBP3) are increased in the retina and vitreous of Medalists who are protected from the development of severe diabetic retinopathy (DR). This protective capacity of RBP3 is potentially mediated by its ability to delay the uptake of glucose into the cells of the retinal vasculature and neural retina in hyperglycemia. This study correlated the relationship between DR severity and neural retinal layer thickness with vitreous and serum RBP3 levels in a broad population of people with diabetes. Optical coherence tomography (OCT) was performed to obtain neural retinal layer thicknesses and structure. Specific ELISA assays were developed to measure vitreous and serum RBP3 concentrations in individuals with type 1 and type 2 diabetes recruited from the Joslin Beetham Eye Institute, Medalist Study, and the FinnDiane study. Vitreous RBP3 concentration was associated with DR severity (p Disclosure W. Fickweiler: None. K. Park: None. E. Wolfson: None. H. Park: None. H. Yokomizo: None. I. Wu: None. D. Gordin: Consultant; Self; GE Healthcare. Speaker’s Bureau; Self; AstraZeneca, Fresenius Medical Care, Novo Nordisk A/S. Other Relationship; Self; CVRx, Sanofi-Aventis. V. Harjutsalo: None. P. Groop: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Sanofi, Sanofi. Speaker’s Bureau; Self; Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medscape, Merck Sharp & Dohme Corp., Mundipharma International. L.P. Aiello: Advisory Panel; Self; Novo Nordisk Inc. Consultant; Self; KalVista Pharmaceuticals, Inc., Novo Nordisk Inc. Stock/Shareholder; Self; KalVista Pharmaceuticals, Inc. Other Relationship; Self; Optos. J. Sun: Research Support; Self; Adaptive Sensory Technology, Boehringer Ingelheim Pharmaceuticals, Inc., KalVista Pharmaceuticals, Inc., Novo Nordisk Inc., Optovue, Inc., Roche Pharma. Other Relationship; Self; Merck Foundation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Roche Pharma. G.L. King: Research Support; Self; Janssen Pharmaceuticals, Inc. Funding National Eye Institute (R01EY026080-01); National Institute of Diabetes and Digestive and Kidney Diseases (DP3DK094333-01); JDRF (17-2013-310); Thomas J. Beatson, Jr. Foundation; Dianne Nunnally Hoppes Scholarship Fund
- Published
- 2020
35. 456-P: Targeted Deletion of Insulin Receptor in Vascular Smooth Muscle Cells Accelerated Thinning of Plaque Cap and Apoptosis and Atherosclerosis
- Author
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George L. King, Ronald St-Louis, Kyoungmin Park, Jialin Fu, Qian Li, Christian Rask-Madsen, and Yumi Zaitsu
- Subjects
Apolipoprotein E ,medicine.medical_specialty ,Aorta ,Vascular smooth muscle ,Intimal hyperplasia ,biology ,business.industry ,Endocrinology, Diabetes and Metabolism ,Femoral artery ,medicine.disease ,Insulin receptor ,Endocrinology ,Apoptosis ,Internal medicine ,medicine.artery ,cardiovascular system ,Internal Medicine ,biology.protein ,Medicine ,business ,Receptor - Abstract
Vascular smooth muscle cells (VSMCs) play an important role in the development of the stability of atherosclerotic plaque. We reported that knockout of insulin receptor (IR), but not IGF1 receptor, in VSMCs reduced intimal hyperplasia of femoral artery after wire injury. To investigate the role of IR in VSMCs on atherosclerotic plaque, ApoE and smooth muscle cells IR double knockout (SMIRKO/ApoE-/-) mice were generated. Extent of lipid deposition and atherosclerosis were increased in the aorta of SMIRKO/ApoE-/- mice compared to control mice (p Disclosure Q. Li: None. J. Fu: None. K. Park: None. Y. Zaitsu: Employee; Self; Sunstar Group. R. St-Louis: None. C. Rask-Madsen: None. G.L. King: Research Support; Self; Janssen Pharmaceuticals, Inc. Funding National Institutes of Health (R01DK053105)
- Published
- 2020
36. 309-OR: IGF-1 Receptors, Not Insulin Receptors, on Mesangial Cells Are Accelerating Mesangial Expansion and Albuminuria in Streptozotocin-Induced Diabetic Mice
- Author
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Yasutaka Maeda, Hisashi Yokomizo, Takanori Shinjo, Ronald St-Louis, Atsushi Ishikado, Kyoungmin Park, George L. King, Weier Qi, and Qian Li
- Subjects
MAPK/ERK pathway ,medicine.medical_specialty ,biology ,Chemistry ,Kinase ,Endocrinology, Diabetes and Metabolism ,Insulin ,medicine.medical_treatment ,Streptozotocin ,medicine.disease ,Insulin receptor ,Endocrinology ,Internal medicine ,Diabetes mellitus ,Internal Medicine ,medicine ,biology.protein ,Receptor ,Protein kinase B ,medicine.drug - Abstract
Clinical studies have suggested that loss of insulin’s action and excessive IGF-1 levels in the glomeruli elevate the risk for diabetic kidney disease (DKD). To define the potential pathogenic role of IGF-1 and insulin signaling in DKD, we generated mice with selective loss of insulin receptor (IR) or IGF-1 receptor (IGF-1R) in the mesangial cells (MCs) by cross breeding IRflox/flox mice with Sm22α-Cre mice (SMIRKO) or IGF-1Rflox/flox mice with Myh11-Cre mice (SMIGF1RKO), and examined urinary albumin excretion (ACR) and mesangial expansion with 6 month duration of streptozotocin (STZ)-induced diabetes. IGF-1 levels were significantly increased by 1.5 fold in the renal cortex, but not in the plasma of all three types of diabetic mice. Diabetes induced elevation of ACR (2.0 fold), glomerular size and mesangial expansion (2.1 fold), in parallel with increased glomerular expressions of fibrosis-related (Tgfβ1, fibronectin and Col3a) and matrix (Has2) genes by 2-3 fold, significantly, in Wt and SMIRKO mice, but were prevented in diabetic SMIGF1RKO mice. In cultured MCs, IGF-1, at physiological levels, and insulin, only at supra-physiological levels, induced the expressions of Has2 (3.8 fold) and Tgfβ1 (1.7 fold). Deletion of IGF-1R, but not IR, in MCs inhibited both IGF-1 and insulin-induced expressions of Has2. Inhibitor of MAP kinase pathway, but not inhibitor of PI3 kinase reduced insulin or IGF-1-induced expressions of Has2 in MCs. IGF-1-induced phosphorylations of IGF-1R (39 fold), Akt (34 fold) and Erk/MAPK (8 fold) were significantly inhibited in both IR or IGF-1R-deleted MCs. Insulin-induced phosphorylations of IR-β (11 fold) and Akt (27 fold) were also decreased in IR-deleted MCs, but surprisingly increased in IGF-1R-deleted MCs. Thus, MAPK activation by elevated glomerular IGF-1 levels via IGF-1R, but not IR, on MCs, may contribute to the pathogenesis of DKD through induction of Has2 and fibrotic genes. Disclosure A. Ishikado: Employee; Self; Sunstar Group. Employee; Spouse/Partner; Sunstar Group. T. Shinjo: None. H. Yokomizo: None. Y. Maeda: None. K. Park: None. W. Qi: None. R. St-Louis: None. Q. Li: None. G.L. King: Research Support; Self; Janssen Pharmaceuticals, Inc.
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- 2020
37. 1867-P: White and Brown Rice Supplementation Changes High-Fat Diet–Induced Dysbiosis of Gut Microbiome and Improves Energy and Glucose Metabolism
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Hisashi Yokomizo, Suzanne Devkota, Yasutaka Maeda, Atsushi Ishikado, Aleksandar Kostic, Takanori Shinjo, George L. King, Kyoungmin Park, Motonobu Matsumoto, Qian Li, and I-Hsien Wu
- Subjects
medicine.medical_specialty ,biology ,Chemistry ,Endocrinology, Diabetes and Metabolism ,digestive, oral, and skin physiology ,Lachnospiraceae ,food and beverages ,Type 2 diabetes ,Gut flora ,Carbohydrate metabolism ,medicine.disease ,Streptococcaceae ,biology.organism_classification ,medicine.anatomical_structure ,Endocrinology ,Internal medicine ,Brown adipose tissue ,Internal Medicine ,medicine ,Brown rice ,Composition (visual arts) - Abstract
Increased white rice (WR) with parallel decreased brown rice (BR) consumption has been associated with increased prevalence of type 2 diabetes (T2DM). To test whether WR and BR have differential effects on energy and glucose metabolism, C57BL/6 mice were fed 6 different diets: control diet (CD, 10% Fat), high-fat diet (HFD, 46% Fat) with either no rice, WR or BR. BR and, surprisingly, WR activated PGC1α and UCP-1 expressions in brown adipose tissue (BAT) and increased energy expenditure as measured by oxygen consumption, CO2 release and heat production, resulting in reduced body weight (36%, 23%) and improvements of glucose tolerance and insulin sensitivity while on HFD after 18 weeks. To investigate the underlying mechanism, gut microbial analysis was performed. Gut microbiota composition showed clear differences between HFD vs. CD or vs. the addition of BR or WR. Ratio of Firmicutes to Bacteroidetes was 3.7-fold increased in HFD vs.CD, but decreased by the WR (46%) or BR (59%). Increased alpha diversity was observed by WR and BR on HFD. Heat map binary showed that several genera are different in HFD+BR vs. HFD or HFD+WR vs. HFD. Analysis of family abundance revealed that Lachnospiraceae, Ruminococcaceae and Streptococcaceae are 2.5, 1.2 and 2.6-fold increased in HFD, which were reduced by WR or BR. Analysis of genus abundance showed that Lactococcus, Dorea, Peptococcus, Clostridium XIVb, Johnsonella, Anaerovorax are 2.6, 3.7, 2.9, 2.7, 4.7 and 1.7-fold respectively, increased in HFD, which were reduced by WR or BR on HFD. In addition, mice on BR+HFD showed greater reductions than mice on WR+HFD in family and genus levels. Our results demonstrated that supplementation with BR or WR, to a lesser degree, changed HFD-induced gut microbial composition at family and genus levels, in parallel with improved systemic energy and glucose metabolism via activation of BAT and increased energy expenditure, resulting in reduced body weight and improved insulin sensitivity. Disclosure H. Yokomizo: None. A. Ishikado: Employee; Self; Sunstar Group. Employee; Spouse/Partner; Sunstar Group. T. Shinjo: None. K. Park: None. Y. Maeda: None. Q. Li: None. I. Wu: None. M. Matsumoto: Employee; Self; Sunstar Group. S. Devkota: None. A. Kostic: None. G.L. King: Research Support; Self; Janssen Pharmaceuticals, Inc.
- Published
- 2020
38. 480-P: Reversal of Diabetic Nephropathy in T2D db/db Mouse Model by Systemic Pyruvate Kinase M2 (PKM2) Activation
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Emily Wolfson, Ronald St-Louis, Johanna Ludeke, Hisashi Yokomizo, Kyoungmin Park, Jialin Fu, Qian Li, George L. King, and Takanori Shinjo
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medicine.medical_specialty ,Creatinine ,business.industry ,Endocrinology, Diabetes and Metabolism ,Insulin ,medicine.medical_treatment ,Type 2 diabetes ,PKM2 ,medicine.disease ,Nephropathy ,Diabetic nephropathy ,Db/db Mouse ,chemistry.chemical_compound ,Endocrinology ,chemistry ,Diabetes mellitus ,Internal medicine ,Internal Medicine ,medicine ,business - Abstract
Mitochondrial abnormalities induced by diabetes have been postulated to cause several complications including nephropathy. Elevated expressions of enzymes for glycolysis and mitochondrial functions in the glomeruli have been associated with protection against the development of diabetic nephropathy of chronic duration. Activation of a glycolytic enzyme, pyruvate kinase M2 (PKM2), by a small molecule selective activator (TEPP-46) or its targeted overexpression to the podocytes in mice reversed glomerular mitochondrial dysfunction and pathology in insulin deficient diabetic mice. However, the effects of PKM2 activation to stop glomerular dysfunction and pathology have not been studied in animal models of type 2 diabetes (T2D). Thus, we studied the effect of activating glycolysis and mitochondrial metabolism with PKM2 activator, TEPP-46, in db/db mice (with obesity and hyperglycemia) and BLKS mice on regular diet (RD) or high fat diet (HFD). HFD feeding induced obesity in BLKS but did not cause changes in glomerular PKM activities or functions as measured by urinary albumin to creatinine ratio (ACR). Oral feeding with TEPP-46 did not affect body weight (BW), glucose tolerance, lipids, ACR, glomerular pathology in BLKS mice on RD or HFD. In contrast, db/db mice on RD had elevated BW and hyperglycemia that were significantly increased by HFD, which also induced loss of glomerular PKM2 protein expression and activities, elevations of gene expression for fibrosis (fibronectin, TGF-b), mesangial expansion and ACR after 3 months. Intervention with oral TEPP-46 treatment for 3 months, but not 1 month, after 3 months of diabetes and HFD, (total of 6 months of diabetes), improved significantly both glomerular PK activities and ACR, without lowering hyperglycemia and hyperlipidemia of the db/db mice. These findings support the idea that systemic activation of PKM2 can improve renal functions in both T1D and T2D. Disclosure R. St-Louis: None. J. Fu: None. K. Park: None. T. Shinjo: None. J. Ludeke: None. H. Yokomizo: None. Q. Li: None. E. Wolfson: None. G.L. King: Research Support; Self; Janssen Pharmaceuticals, Inc.
- Published
- 2020
39. 307-OR: Activation of Mitochondrial Activities by Pyruvate Kinase M2 (PKM2) in Podocytes Improved Glomerular Metabolism and Diabetic Nephropathy
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Kyoungmin Park, Marc Gregory Yu, Jialin Fu, Ronald St-Louis, Qian Li, George L. King, I-Hsien Wu, Takanori Shinjo, Hisashi Yokomizo, Hetal Shah, and Yumi Zaitsu
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Kidney ,medicine.medical_specialty ,business.industry ,Endocrinology, Diabetes and Metabolism ,Type 2 diabetes ,PKM2 ,medicine.disease_cause ,medicine.disease ,Streptozotocin ,Diabetic nephropathy ,medicine.anatomical_structure ,Endocrinology ,Diabetes mellitus ,Internal medicine ,Internal Medicine ,medicine ,business ,Oxidative stress ,Pyruvate kinase ,medicine.drug - Abstract
Diabetic nephropathy (DN) is the result of systemic and local changes in metabolism and hemodynamics. We have found that the elevation of glycolytic enzymes, such as pyruvate kinase M2 (PKM2) in the renal glomeruli is correlated with preservation of renal function in human type 1 and type 2 diabetes. A small-molecule PKM2 activator, TEPP46, prevented or reversed glomerular pathology in diabetic mice of chronic duration. Mice with PKM2 overexpression specifically in podocytes (PPKM2Tg) were generated, which after 7 months of diabetes induced by streptozotocin, exhibited significantly lower albumin-creatinine ratio (ACR), kidney weight-body weight ratio, and glomeruli pathology such as reduced glomeruli size, mesangial expansion, and basement membrane thickness compared to diabetic WT mice. Furthermore, the glomeruli of diabetic PPKM2Tg mice exhibited lower expressions of fibrotic (FN, TGFβ1 and Col4a) and oxidative stress (p47phox, NOX2 and NOX4) genes compared to WT diabetic mice. Interestingly, the decreased expression of endothelial-trophic genes and mitochondrial-related genes were improved in the whole glomeruli of diabetic PPKM2Tg mice. Oxygen consumption rate (OCR) of glomeruli as measured by Seahorse showed significant improvement in diabetic PPKM2Tg mice versus WT mice (p < 0.05). In vitro studies showed that the activation of PKM2 in mouse podocyte cell line by TEPP-46 decreased high glucose-induced ROS production, improved mitochondrial membrane potential (MMP) by increased the level of mitochondrial OCR and enhanced glycolytic rate. Furthermore, PKM-knockdown stable podocyte cell line, mimicking diabetic conditions, showed dramatical decline of OCR and glycolytic rate. These results showed that PKM2 specific overexpression in podocytes can significantly reduce diabetes-induced mitochondrial abnormalities and oxidative stress in the whole glomeruli, and delay the progression of diabetic nephropathy. Disclosure J. Fu: None. T. Shinjo: None. R. St-Louis: None. Q. Li: None. K. Park: None. H. Yokomizo: None. Y. Zaitsu: Employee; Self; Sunstar Group. M. Yu: None. I. Wu: None. H. Shah: None. G.L. King: Research Support; Self; Janssen Pharmaceuticals, Inc.
- Published
- 2020
40. 436-P: Characterization of Autoimmunity in the Acceleration of Atherosclerosis in Type 1 Diabetes
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Ernesto Maddaloni, Hyunseok Park, Kyoungmin Park, Christian Rask-Madsen, Stephan Kissler, Jialin Fu, Qian Li, Hisashi Yokomizo, George L. King, Ronald St-Louis, and Andrew H. Lichtman
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Type 1 diabetes ,business.industry ,Endocrinology, Diabetes and Metabolism ,Autoantibody ,Nod ,medicine.disease ,medicine.disease_cause ,Autoimmunity ,Diabetes mellitus ,Immunology ,Hyperlipidemia ,Internal Medicine ,Medicine ,business ,Insulitis ,NOD mice - Abstract
Hyperglycemia, hyperlipidemia and hypertension have been evaluated extensively as risk factors for cardiovascular disease (CVD) in people with type 1 diabetes (T1DM). However, the impact of autoimmunity in T1DM on CVD has not been determined. We have generated several mice models of atherosclerosis including ApoE-/-/NOD, ApoE-/-/NOD (congenic non diabetes and non-autoimmune), ApoE-/-/NOD (autoimmunity with insulitis, nondiabetes) and ApoE-/-/NOD autoimmune diabetic mice. All groups of mice have high plasma lipids but only ApoE-/-/NOD diabetic mice had hyperglycemia. However, ApoE-/-/NOD (insulitis and nondiabetes) and ApoE-/-/NOD (insulitis and diabetes) had high titers of autoantibodies to IA2 compared to control CongApoE-/-/NOD mice or nondiabetic ApoE-/-/NOD mice (P Disclosure K. Park: None. Q. Li: None. H. Park: None. R. St-Louis: None. J. Fu: None. C. Rask-Madsen: None. E. Maddaloni: Consultant; Self; Merck KGaA. Speaker’s Bureau; Self; Abbott, AstraZeneca, Pikdare. H. Yokomizo: None. S. Kissler: None. A.H. Lichtman: None. G.L. King: Research Support; Self; Janssen Pharmaceuticals, Inc. Funding National Institutes of Health (R01DK053105); Thomas J. Beatson, Jr. Foundation
- Published
- 2020
41. 570-P: Osteoprotegerin Induces Endothelial Dysfunction and Is Associated with Vascular Complications In Type 2 Diabetes
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Maria Gisella Cavallo, Susanna Morano, Sabrina Prudente, Salvatore De Cosmo, Paolo Pozzilli, Rury R. Holman, Lucia Coraggio, Paola D'Angelo, Kyoungmin Park, Luca D'Onofrio, Marco Giorgio Baroni, Frida Leonetti, Vincenzo Trischitta, L. Morviducci, George L. King, Cecilia Luordi, Raffaella Buzzetti, Michela Di Guida, Giuseppe Pugliese, and Ernesto Maddaloni
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education.field_of_study ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Endocrinology, Diabetes and Metabolism ,Population ,Type 2 diabetes ,medicine.disease ,Osteoprotegerin ,Internal medicine ,Diabetes mellitus ,Internal Medicine ,medicine ,Endothelial dysfunction ,Diabetic Vascular Complications ,Lipid profile ,education ,business ,Vascular calcification - Abstract
Novel markers of vascular disease in diabetes could help identify new disease pathways and enhance risk stratification. Osteoprotegerin (OPG) and osteopontin (OPN) are key molecules involved in bone and vascular calcification processes, both compromised in diabetes. To evaluate whether OPG and/or OPN are associated with diabetic vascular complications, we measured their serum concentrations in 995 type 2 diabetes subjects enrolled in the Sapienza University Mortality and Morbidity Event Rate (SUMMER) Study. Any association with history of cardiovascular disease (CVD), diabetic retinopathy (DR) and reduced eGFR were examined with ANOVA, correcting for age, gender, HbA1c and lipid profile. Among the population, 15.7% had CVD, 18.4% had DR, 12.0% had an eGFR between 45-59 ml/min/1.73m2 and 7.5% had an eGFR Disclosure E. Maddaloni: Consultant; Self; Merck KGaA. Speaker’s Bureau; Self; Abbott, AstraZeneca, Pikdare. K. Park: None. M. Di Guida: None. L. Coraggio: None. C. Luordi: None. L. D’Onofrio: None. M.G. Baroni: None. M.G. Cavallo: None. P. D’Angelo: None. S. De Cosmo: None. F. Leonetti: None. S. Morano: None. L. Morviducci: None. P. Pozzilli: Advisory Panel; Self; Abbott, AstraZeneca, Eli Lilly and Company. Research Support; Self; Medtronic, Sanofi. S. Prudente: None. G. Pugliese: Advisory Panel; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mundipharma International, Sanofi-Aventis, Sigma-tau, Takeda Pharmaceutical Company Limited. Other Relationship; Self; Laboratori Guidotti. V. Trischitta: None. R.R. Holman: Advisory Panel; Self; Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Bayer AG, Merck Sharp & Dohme Corp. G.L. King: Research Support; Self; Janssen Pharmaceuticals, Inc. R. Buzzetti: Advisory Panel; Self; Sanofi. Speaker’s Bureau; Self; AstraZeneca, Lilly Diabetes, Merck Sharp & Dohme Corp. Funding European Foundation for the Study of Diabetes; AstraZeneca (MS 2017_2); Società Italiana di Diabetologia
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- 2020
42. Association of the 1q25 Diabetes-Specific Coronary Heart Disease Locus With Alterations of the γ-Glutamyl Cycle and Increased Methylglyoxal Levels in Endothelial Cells
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Kyoungmin Park, Caterina Pipino, Hetal Shah, Assunta Pandolfi, Lixia Zeng, Vincenzo Trischitta, Natalia Di Pietro, Subramanian Pennathur, Sabrina Prudente, and Alessandro Doria
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Glutamine ,030209 endocrinology & metabolism ,Locus (genetics) ,Coronary Disease ,Type 2 diabetes ,Biology ,γ-glutamyl cycle ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Downregulation and upregulation ,Glutamates ,Glutamate-Ammonia Ligase ,Internal medicine ,Diabetes mellitus ,Internal Medicine ,medicine ,Human Umbilical Vein Endothelial Cells ,Humans ,coronary heart disease ,Allele ,RNA, Small Interfering ,Endophthalmitis ,Methylglyoxal ,Endothelial Cells ,Genetics/Genomes/Proteomics/Metabolomics ,Glutamic acid ,Dipeptides ,medicine.disease ,Pyruvaldehyde ,030104 developmental biology ,Endocrinology ,type 2 diabetes ,chemistry ,Chromosomes, Human, Pair 1 - Abstract
A chromosome 1q25 variant (rs10911021) has been associated with coronary heart disease (CHD) in type 2 diabetes. In human umbilical vein endothelial cells (HUVECs), the risk allele “C” is associated with lower expression of the adjacent gene GLUL encoding glutamine synthase, converting glutamic acid to glutamine. To further investigate the mechanisms through which this locus affects CHD risk, we measured 35 intracellular metabolites involved in glutamic acid metabolism and the γ-glutamyl cycle in 62 HUVEC strains carrying different rs10911021 genotypes. Eight metabolites were positively associated with the risk allele (17–58% increase/allele copy, P = 0.046–0.002), including five γ-glutamyl amino acids, β-citryl-glutamate, N-acetyl-aspartyl-glutamate, and ophthalmate—a marker of γ-glutamyl cycle malfunction. Consistent with these findings, the risk allele was also associated with decreased glutathione-to-glutamate ratio (−9%, P = 0.012), decreased S-lactoylglutathione (−41%, P = 0.019), and reduced detoxification of the atherogenic compound methylglyoxal (+54%, P = 0.008). GLUL downregulation by shRNA caused a 40% increase in the methylglyoxal level, which was completely prevented by glutamine supplementation. In summary, we have identified intracellular metabolic traits associated with the 1q25 risk allele in HUVECs, including impairments of the γ-glutamyl cycle and methylglyoxal detoxification. Glutamine supplementation abolishes the latter abnormality, suggesting that such treatment may prevent CHD in 1q25 risk allele carriers.
- Published
- 2020
43. Pathogenesis of Microvascular Complications
- Author
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Mogher Khamaisi, Qian Li, Kyoungmin Park, and George L. King
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Pathogenesis ,Pathology ,medicine.medical_specialty ,business.industry ,medicine ,business - Published
- 2020
44. Pigment epithelium-derived factor, a noninhibitory serine protease inhibitor, is renoprotective by inhibiting the Wnt pathway
- Author
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Chengyi Sun, Jian Xing Ma, Siribhinya Benyajati, Kai Lau, Gennadiy Moiseyev, Rui Cheng, Kyoungmin Park, Bonnie Eby, Xuemin He, Lorin E. Olson, and Yanhui Yang
- Subjects
0301 basic medicine ,Time Factors ,Apoptosis ,030204 cardiovascular system & hematology ,urologic and male genital diseases ,Kidney Tubules, Proximal ,0302 clinical medicine ,Fibrosis ,Diabetic Nephropathies ,Wnt Signaling Pathway ,Mice, Knockout ,Kidney ,Chemistry ,Wnt signaling pathway ,3. Good health ,Phenotype ,medicine.anatomical_structure ,Nephrology ,Knockout mouse ,PEDF ,Kidney Diseases ,Inflammation Mediators ,medicine.symptom ,Ureteral Obstruction ,kidney ,medicine.medical_specialty ,Wnt pathway ,Inflammation ,Transfection ,Article ,Cell Line ,03 medical and health sciences ,Axin Protein ,Internal medicine ,Genetic model ,medicine ,Renal fibrosis ,Animals ,Humans ,Genetic Predisposition to Disease ,Nerve Growth Factors ,Eye Proteins ,Serpins ,renal tubule epithelial cells ,Epithelial Cells ,β-catenin ,medicine.disease ,Mice, Inbred C57BL ,Disease Models, Animal ,Oxidative Stress ,Diabetes Mellitus, Type 1 ,030104 developmental biology ,Endocrinology ,Diabetes Mellitus, Type 2 ,Gene Expression Regulation ,inflammation ,renoprotective - Abstract
Pigment epithelium-derived factor (PEDF) expression is down- regulated in the kidneys of diabetic rats and delivery of PEDF suppressed renal fibrotic factors in these animals. PEDF has multiple functions including anti-angiogenic, anti-inflammatory and anti-fibrotic activities. Since the mechanism underlying its anti-fibrotic effect remains unclear, we studied this in several murine models of renal disease. Renal PEDF levels were significantly reduced in genetic models of type 1 and type 2 diabetes (Akita and db/db, respectively), negatively correlating with Wnt signaling activity in the kidneys. In unilateral ureteral obstruction, an acute renal injury model, there were significant decreases of renal PEDF levels. The kidneys of PEDF knock-out mice with ureteral obstruction displayed exacerbated expression of fibrotic and inflammatory factors, oxidative stress, tubulointerstitial fibrosis and tubule epithelial cell apoptosis, compared to the kidneys of wild-type mice with obstruction. PEDF knock-out enhanced Wnt signaling activation induced by obstruction, while PEDF inhibited the Wnt pathway-mediated fibrosis in primary renal proximal tubule epithelial cells. Additionally, oxidative stress was aggravated in renal proximal tubule epithelial cells isolated from knock-out mice, and suppressed by PEDF treatment of renal proximal tubule epithelial cells. PEDF also reduced oxidation-induced apoptosis in renal proximal tubule epithelial cells. Thus, the renoprotective effects of PEDF are mediated, at least partially, by inhibition of the Wnt pathway. Hence, restoration of renal PEDF levels may have therapeutic potential for renal fibrosis.
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- 2017
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45. Homozygous receptors for insulin and not IGF-1 accelerate intimal hyperplasia in insulin resistance and diabetes
- Author
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Weier Qi, Hisashi Yokomizo, Yu Xia, Atsushi Ishikado, Weikang Cai, Qian Huang, Kyoungmin Park, Jialin Fu, Qian Li, George L. King, Christian Rask-Madsen, and C. Ronald Kahn
- Subjects
Male ,0301 basic medicine ,Intimal hyperplasia ,medicine.medical_treatment ,General Physics and Astronomy ,Muscle, Smooth, Vascular ,Receptor, IGF Type 1 ,Mice ,0302 clinical medicine ,Insulin ,Insulin-Like Growth Factor I ,lcsh:Science ,Receptor ,Vascular diseases ,Multidisciplinary ,biology ,Chemistry ,Homozygote ,Hyperplasia ,Femoral Artery ,Signal transduction ,Signal Transduction ,medicine.medical_specialty ,Science ,030209 endocrinology & metabolism ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Insulin resistance ,Internal medicine ,Diabetes Mellitus ,medicine ,Animals ,Insulin-like growth factor 1 receptor ,Insulin signalling ,General Chemistry ,medicine.disease ,Receptor, Insulin ,Mice, Inbred C57BL ,Disease Models, Animal ,Insulin receptor ,030104 developmental biology ,Endocrinology ,biology.protein ,lcsh:Q ,Insulin Resistance ,Hyaluronan Synthases - Abstract
Insulin and IGF-1 actions in vascular smooth muscle cells (VSMC) are associated with accelerated arterial intima hyperplasia and restenosis after angioplasty, especially in diabetes. To distinguish their relative roles, we delete insulin receptor (SMIRKO) or IGF-1 receptor (SMIGF1RKO) in VSMC and in mice. Here we report that intima hyperplasia is attenuated in SMIRKO mice, but not in SMIGF1RKO mice. In VSMC, deleting IGF1R increases homodimers of IR, enhances insulin binding, stimulates p-Akt and proliferation, but deleting IR decreases responses to insulin and IGF-1. Studies using chimeras of IR(extracellular domain)/IGF1R(intracellular-domain) or IGF1R(extracellular domain)/IR(intracellular-domain) demonstrate homodimer IRα enhances insulin binding and signaling which is inhibited by IGF1Rα. RNA-seq identifies hyaluronan synthase2 as a target of homo-IR, with its expression increases by IR activation in SMIGF1RKO mice and decreases in SMIRKO mice. Enhanced intima hyperplasia in diabetes is mainly due to insulin signaling via homo-IR, associated with increased Has2 expression., Both insulin and IGF-1 signaling have been implicated in arterial intimal hyperplasia. Here the authors dissect the relative contributions of insulin and IGF-1 receptors, showing that homodimers of insulin receptors, but not IGF-1 receptor, induce proliferation of vascular smooth muscle cells.
- Published
- 2019
46. Retinol binding protein 3 is increased in the retina of patients with diabetes resistant to diabetic retinopathy
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Hisashi Yokomizo, Yasutaka Maeda, Hillary A. Keenan, Atsushi Ishikado, Allen C. Clermont, Chih-Hao Wang, David M. Pober, Bei Sun, Edward P. Feener, Liane J. Tinsley, Sayaka Katagiri, Robert L. Avery, Jennifer K. Sun, Timothy S. Kern, Samantha M. Paniagua, Sonia L. Hernandez, Lloyd Paul Aiello, Kyoungmin Park, Qian Li, Fabrício Simão, George L. King, Ward Fickweiler, and I-Hsien Wu
- Subjects
Vascular Endothelial Growth Factor A ,0301 basic medicine ,Glucose uptake ,Inbred C57BL ,Eye ,Medical and Health Sciences ,Transgenic ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Cell Movement ,2.1 Biological and endogenous factors ,Aetiology ,Inbred Lew ,biology ,Diabetes ,General Medicine ,Diabetic retinopathy ,Biological Sciences ,Recombinant Proteins ,Vascular endothelial growth factor ,Intravitreal Injections ,Glycolysis ,Signal Transduction ,medicine.medical_specialty ,Ependymoglial Cells ,Retinol transport ,Deoxyglucose ,Protective Agents ,Retina ,Article ,Proinflammatory cytokine ,03 medical and health sciences ,Protein Domains ,Internal medicine ,Diabetes Mellitus ,medicine ,Animals ,Humans ,Photoreceptor Cells ,Eye Proteins ,Eye Disease and Disorders of Vision ,Metabolic and endocrine ,Diabetic Retinopathy ,Vertebrate ,business.industry ,Glucose transporter ,Endothelial Cells ,Reproducibility of Results ,medicine.disease ,Vascular Endothelial Growth Factor Receptor-2 ,Rats ,Vitreous Body ,Retinol-Binding Proteins ,Retinol binding protein ,030104 developmental biology ,Endocrinology ,chemistry ,biology.protein ,3-O-Methylglucose ,GLUT1 ,business ,Acids ,030217 neurology & neurosurgery - Abstract
The Joslin Medalist Study characterized people affected with type 1 diabetes for 50 years or longer. More than 35% of these individuals exhibit no to mild diabetic retinopathy (DR), independent of glycemic control, suggesting the presence of endogenous protective factors against DR in a subpopulation of patients. Proteomic analysis of retina and vitreous identified retinol binding protein 3 (RBP3), a retinol transport protein secreted mainly by the photoreceptors, as elevated in Medalist patients protected from advanced DR. Mass spectrometry and protein expression analysis identified an inverse association between vitreous RBP3 concentration and DR severity. Intravitreal injection and photoreceptor-specific overexpression of RBP3 in rodents inhibited the detrimental effects of vascular endothelial growth factor (VEGF). Mechanistically, our results showed that recombinant RBP3 exerted the therapeutic effects by binding and inhibiting VEGF receptor tyrosine phosphorylation. In addition, by binding to glucose transporter 1 (GLUT1) and decreasing glucose uptake, RBP3 blocked the detrimental effects of hyperglycemia in inducing inflammatory cytokines in retinal endothelial and Müller cells. Elevated expression of photoreceptor-secreted RBP3 may have a role in protection against the progression of DR due to hyperglycemia by inhibiting glucose uptake via GLUT1 and decreasing the expression of inflammatory cytokines and VEGF.
- Published
- 2019
47. 628-P: Insulin's Regulation of CXCL1 Expression Is Critical for Neutrophil Recruitments and the Development of Periodontitis and Poor Wound Healing in Diabetes
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Haiyan Wang, George L. King, Hisashi Yokomizo, Thomas E. Van Dyke, Atsushi Ishikado, Kyoungmin Park, Takanori Shinjo, Jialin Fu, Marc Gregory Yu, Ronald St-Louis, Qian Li, and Hatice Hasturk
- Subjects
CXCL1 ,Periodontitis ,business.industry ,Endocrinology, Diabetes and Metabolism ,Insulin ,medicine.medical_treatment ,Diabetes mellitus ,Immunology ,Internal Medicine ,medicine ,Poor wound healing ,business ,medicine.disease - Abstract
A major cause of poor wound healing and periodontitis in diabetes is defective immune response to infections. Insulin signaling via the PI3K/Akt pathway is selectively inhibited in the gingival and wound fibroblasts of diabetic rodents and patients. To determine how loss of insulin actions in gingival fibroblasts can affect periodontitis development, myofibroblast insulin receptors (IR) were deleted by crossbreeding IRβ-flox/flox mice with SM22-Cre C57BL/6 (SMIRKO) mice, which were fed with regular diet (RD), while wild type (WT) littermates were fed with high-fat diet (HFD) for 10 weeks. To induce periodontitis, 7-0 silk ligatures were tied around maxillary molars for 4, 7 or 14 days. When mice were sacrificed to assess alveolar bone loss, immune cell populations and inflammatory cytokine expression in the gingiva was assessed. Gingival IRβ expression in SMIRKO and HFD-fed mice was decreased by 70% and 50%, respectively, with comparable reductions in insulin-induced (100nM) phosphorylation of Akt (pAkt). Ligature-induced alveolar bone loss in SMIRKO and HFD-fed mice was greater by 70% and 40%, respectively, as compared to RD-fed WT mice. Post-ligature time course analysis showed that while neutrophil recruitment was delayed significantly, macrophages and lymphocyte numbers were elevated in both SMIRKO and HFD-fed mice. Similarly, neutrophil-recruiting factors CXCL1 and 2 expression were decreased in the gingiva, whereas TNFα and IL-1β expression were elevated. Gingival myofibroblasts from SMIRKO and HFD-fed mice showed dramatic reductions of IRβ expression and insulin-induced pAkt with parallel lowering of E.coli LPS-induced CXCL1 expression via downregulation of TLR2, compared to RD-fed mice. These data provided the first evidence that insulin action is critical for neutrophil recruitment during infection by enabling CXCL1 expression in gingival myofibroblasts, which is inhibited in diabetes. Disclosure T. Shinjo: None. Q. Li: None. A. Ishikado: Employee; Self; SunStar Inc. Employee; Spouse/Partner; SunStar Inc. K. Park: None. R. St-Louis: None. H. Yokomizo: None. J. Fu: None. M. Yu: None. H. Wang: None. H. Hasturk: None. T.E. Van Dyke: None. G.L. King: Research Support; Self; Sanofi. Funding Sunstar Foundation; Iacocca Family Foundation
- Published
- 2019
48. 586-P: Vitreous and Serum Measurements of Retinol Binding Protein 3 in the Clinical Evaluation of Diabetic Retinopathy
- Author
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George L. King, David M. Pober, Allen C. Clermont, Ward Fickweiler, Lloyd Paul Aiello, I-Hsien Wu, Kyoungmin Park, Samantha M. Paniagua, Jennifer K. Sun, Vanessa Bahnam, and Hisashi Yokomizo
- Subjects
Type 1 diabetes ,medicine.medical_specialty ,business.industry ,Endocrinology, Diabetes and Metabolism ,Diabetic retinopathy ,Elisa assay ,medicine.disease ,Retinol binding protein ,Diabetes mellitus ,Ophthalmology ,Internal Medicine ,Medicine ,business ,No detection ,Clinical evaluation ,Glycemic - Abstract
The Joslin 50-Year Medalist Study discovered that elevated photoreceptor-secreted Retinol Binding Protein 3 (RBP3) in the retina and vitreous of individuals with extreme duration of type 1 diabetes is associated with long-term protection from advanced diabetic retinopathy (DR), independent of glycemic control. This represents the first neuroretinal protein identified with potential protective activity against the toxic effects of hyperglycemia on the retinal vasculature, a major cause of DR onset and worsening. We extended these findings by correlating vitreous and serum RBP3 concentrations and examining associated clinical characteristics. We developed a novel RBP3 ELISA assay with high sensitivity (0.1-1 nM), specificity (no detection of immunoglobulin G, albumin, or RBP4), and intra-and inter-assay correlations (p Disclosure W. Fickweiler: None. H. Yokomizo: None. K. Park: None. S.M. Paniagua: None. I. Wu: None. D.M. Pober: None. V. Bahnam: None. A. Clermont: Consultant; Self; KalVista Pharmaceuticals, Inc. L.P. Aiello: Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Decision Resources Group, KalVista Pharmaceuticals, Inc., Mingsight, Retinal Solutions. Stock/Shareholder; Self; KalVista Pharmaceuticals, Inc. Other Relationship; Self; Optos. J.K. Sun: Research Support; Self; Adaptive Sensory Technology, Boston Micromachines Corporation, Genentech, Inc., KalVista Pharmaceuticals, Inc., Optovue, Incorporated. Other Relationship; Self; Genentech, Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc. G.L. King: Research Support; Self; Sanofi. Funding National Eye Institute (R01EY026080-01); National Institute of Diabetes and Digestive and Kidney Diseases (DP3DK094333-01); JDRF (17-2013-310); Thomas J. Beatson, Jr. Foundation Inc.; Dianne Nunnally Hoppes Scholarship Fund
- Published
- 2019
49. 20-LB: Endothelial Cell Metabolomics Identifies ?-glutamyl Cycle Alterations Associated with the 1q25 T2D-Specific Cardiovascular Locus
- Author
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Kyoungmin Park, Christine Mendonca, George L. King, Caterina Pipino, Stefano Monti, Assunta Pandolfi, Hetal Shah, and Alessandro Doria
- Subjects
medicine.medical_specialty ,business.industry ,Endocrinology, Diabetes and Metabolism ,Locus (genetics) ,medicine.disease_cause ,Umbilical vein ,Endothelial stem cell ,Glutamine ,Endocrinology ,Downregulation and upregulation ,Internal medicine ,Internal Medicine ,medicine ,Metabolon ,business ,Gene ,Oxidative stress - Abstract
A variant on chromosome 1q25 (rs10911021) has been previously associated with coronary artery disease (CAD) in individuals with T2D. In human umbilical vein endothelial cells (HUVECs), the 1q25 risk allele (‘C’) was found to be associated with decreased expression of the adjacent gene GLUL encoding the enzyme glutamine synthase converting glutamate to glutamine. To further investigate the mechanisms through which the 1q25 locus modulates CAD risk in T2D, we performed a global metabolomics study (LC-MS, Metabolon) in 62 HUVECs (TT=11, CT=21, CC=30). Among 597 metabolites detected in HUVEC lysates, 23 attained p In summary, we have identified several metabolic pathways potentially mediating the 1q25 locus effect on CAD risk in T2D. These include impairment of the γ-glutamyl cycle, possibly increasing susceptibility to oxidative stress, and downregulation of PUFA derivatives and sphingomyelins. Further studies of these pathways may lead to the identification of novel therapeutic targets to reduce CAD risk in T2D. Disclosure C. Pipino: None. H. Shah: None. K. Park: None. S. Monti: None. C. Mendonca: None. G.L. King: Research Support; Self; Sanofi. A. Pandolfi: None. A. Doria: Research Support; Self; Sanofi-Aventis. Funding Sanofi-Aventis
- Published
- 2019
50. 597-P: Retinol Binding Protein 3 in Diabetic Retinopathy: Mechanisms of Protective Activity
- Author
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Allen C. Clermont, Ward Fickweiler, Hisashi Yokomizo, Atsushi Ishikado, I-Hsien Wu, Kyoungmin Park, Qian Li, Yasutaka Maeda, David M. Pober, Lloyd Paul Aiello, Hillary A. Keenan, Chih-Hao Wang, Jennifer K. Sun, and George L. King
- Subjects
medicine.medical_specialty ,Type 1 diabetes ,Retina ,business.industry ,Endocrinology, Diabetes and Metabolism ,Glucose uptake ,Retinal ,Diabetic retinopathy ,medicine.disease ,Retinol binding protein ,chemistry.chemical_compound ,Endocrinology ,medicine.anatomical_structure ,Retinal dysfunction ,chemistry ,Internal medicine ,Diabetes mellitus ,Internal Medicine ,medicine ,business - Abstract
The Joslin Medalist study reported that after having type 1 diabetes (T1D) for > 50 years, over 35% of Medalists exhibit no to mild diabetic retinopathy (DR) independent of glycemic control, suggesting presence of endogenous protective factors against DR. Proteomic analysis of Medalist retina and vitreous found that Retinol Binding Protein 3 (RBP3), secreted by photoreceptors, is elevated in individuals protected from DR. This finding was confirmed by RBP3 ELISA of replicate vitreous samples from Medalists and other T1D and T2D individuals. In contrast, vitreous VEGF concentrations increased with DR severity. Thus, elevated ratios of intravitreous RBP3/VEGF correlated with lack of progression to advanced DR. Intervention and prevention studies overexpressing RBP3 in retina/photoreceptors of nondiabetic and diabetic animals inhibited VEGF actions and normalized diabetes-induced retinal capillary permeability, neuro-retinal dysfunctions, expressions of VEGF and IL-6, and formation of acellular capillaries. Mechanistically, physiological levels of recombinant RBP3 (10-100nM), but not RBP4 or FGF, inhibited the increased in VEGFR2 tyrosine phosphorylation, hyperglycemia-induced expression of pro-inflammatory cytokines (VEGF and IL-6), and migration of retinal endothelial cells and Müller cells. RBP3, but not RBP4, physically bound to VEGFR2 in cross linkage studies. At physiological levels, RBP3 significantly inhibited glucose uptake into retinal endothelial and Müller cells, and subsequently decreased expression of VEGF and IL-6. These results suggest novel actions for RBP3 to slow glucose uptake in retinal cells and inhibit VEGF actions, thereby preventing, delaying and even arresting diabetes-induced neuro- and vascular retinal dysfunction, inflammatory abnormalities and DR pathologies. These findings strongly support therapeutic potential of RBP3 in DR. Disclosure H. Yokomizo: None. K. Park: None. A. Clermont: Consultant; Self; KalVista Pharmaceuticals, Inc. Y. Maeda: Research Support; Self; Abbott, Arkray, Inc. Speaker's Bureau; Self; Abbott, Arkray, Inc., Astellas Pharma Inc., AstraZeneca, Daiichi Sankyo Company, Limited, Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Terumo Medical Corporation. W. Fickweiler: None. A. Ishikado: Employee; Self; SunStar Inc. Employee; Spouse/Partner; SunStar Inc. Q. Li: None. C. Wang: None. D.M. Pober: None. I. Wu: None. H.A. Keenan: Employee; Self; Sanofi Genzyme. L.P. Aiello: Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Decision Resources Group, KalVista Pharmaceuticals, Inc., Mingsight, Retinal Solutions. Stock/Shareholder; Self; KalVista Pharmaceuticals, Inc. Other Relationship; Self; Optos. J.K. Sun: Research Support; Self; Adaptive Sensory Technology, Boston Micromachines Corporation, Genentech, Inc., KalVista Pharmaceuticals, Inc., Optovue, Incorporated. Other Relationship; Self; Genentech, Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc. G.L. King: Research Support; Self; Sanofi. Funding National Eye Institute; National Institute of Diabetes and Digestive and Kidney Diseases; JDRF; Thomas J. Beatson, Jr. Foundation Inc.; Dianne Nunnally Hoppes Scholarship Fund
- Published
- 2019
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