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Du G, Zhang Q, Huang X, Wang Y. Molecular mechanism of ferroptosis and its role in the occurrence and treatment of diabetes. Front Genet 2022; 13:1018829. [PMID: 36160012 PMCID: PMC9500181 DOI: 10.3389/fgene.2022.1018829] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Accepted: 08/29/2022] [Indexed: 12/17/2022] Open
Abstract
Ferroptosis is an iron-dependent programmed cell death, which is different from apoptosis, necrosis, and autophagy. Specifically, under the action of divalent iron or ester oxygenase, unsaturated fatty acids that are highly expressed on the cell membrane are catalyzed to produce lipid peroxidation, which induces cell death. In addition, the expression of the antioxidant system [glutathione (GSH) and glutathione peroxidase 4 (GPX4)] is decreased. Ferroptosis plays an important role in the development of diabetes mellitus and its complications. In this article, we review the molecular mechanism of ferroptosis in the development of diabetes mellitus and its complications. We also summarize the emerging questions in this particular area of research, some of which remain unanswered. Overall, this is a comprehensive review focusing on ferroptosis-mediated diabetes and providing novel insights in the treatment of diabetes from the perspective of ferroptosis.
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Affiliation(s)
- Guanghui Du
- Department of Outpatient, Sichuan Academy of Medical Science and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Qi Zhang
- School of Medicine, University of Electronics and Technology of China, Chengdu, China
| | - Xiaobo Huang
- Department of Critical Care Medicine, Sichuan Academy of Medical Science and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- *Correspondence: Xiaobo Huang, ; Yi Wang,
| | - Yi Wang
- Department of Critical Care Medicine, Sichuan Academy of Medical Science and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- *Correspondence: Xiaobo Huang, ; Yi Wang,
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Martin Vázquez E, Cobo-Vuilleumier N, Araujo Legido R, Marín-Cañas S, Nola E, Dorronsoro A, López Bermudo L, Crespo A, Romero-Zerbo SY, García-Fernández M, Martin Montalvo A, Rojas A, Comaills V, Bérmudez-Silva FJ, Gannon M, Martin F, Eizirik D, Lorenzo PI, Gauthier BR. NR5A2/LRH-1 regulates the PTGS2-PGE 2-PTGER1 pathway contributing to pancreatic islet survival and function. iScience 2022; 25:104345. [PMID: 35602948 PMCID: PMC9117883 DOI: 10.1016/j.isci.2022.104345] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 03/30/2022] [Accepted: 04/28/2022] [Indexed: 11/29/2022] Open
Abstract
LRH-1/NR5A2 is implicated in islet morphogenesis postnatally, and its activation using the agonist BL001 protects islets against apoptosis, reverting hyperglycemia in mouse models of Type 1 Diabetes Mellitus. Islet transcriptome profiling revealed that the expression of PTGS2/COX2 is increased by BL001. Herein, we sought to define the role of LRH-1 in postnatal islet morphogenesis and chart the BL001 mode of action conferring beta cell protection. LRH-1 ablation within developing beta cells impeded beta cell proliferation, correlating with mouse growth retardation, weight loss, and hypoglycemia leading to lethality. LRH-1 deletion in adult beta cells abolished the BL001 antidiabetic action, correlating with beta cell destruction and blunted Ptgs2 induction. Islet PTGS2 inactivation led to reduced PGE2 levels and loss of BL001 protection against cytokines as evidenced by increased cytochrome c release and cleaved-PARP. The PTGER1 antagonist-ONO-8130-negated BL001-mediated islet survival. Our results define the LRH-1/PTGS2/PGE2/PTGER1 signaling axis as a key pathway mediating BL001 survival properties.
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Affiliation(s)
- Eugenia Martin Vázquez
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - Nadia Cobo-Vuilleumier
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - Raquel Araujo Legido
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - Sandra Marín-Cañas
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Emanuele Nola
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - Akaitz Dorronsoro
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - Lucia López Bermudo
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
| | - Alejandra Crespo
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - Silvana Y. Romero-Zerbo
- Instituto de Investigación Biomédica de Málaga-IBIMA, UGC Endocrinología y Nutrición. Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain
- Facultad de Medicina, Departamento de Fisiología Humana, Anatomía Patológica y Educación Físico Deportiva, Universidad de Málaga, Málaga, Spain
| | - Maria García-Fernández
- Facultad de Medicina, Departamento de Fisiología Humana, Anatomía Patológica y Educación Físico Deportiva, Universidad de Málaga, Málaga, Spain
| | - Alejandro Martin Montalvo
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
| | - Anabel Rojas
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
| | - Valentine Comaills
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - Francisco J. Bérmudez-Silva
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
- Instituto de Investigación Biomédica de Málaga-IBIMA, UGC Endocrinología y Nutrición. Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain
| | - Maureen Gannon
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville USA
| | - Franz Martin
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
| | - Decio Eizirik
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Petra I. Lorenzo
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - Benoit R. Gauthier
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
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Fry JL, Munson BD, Thompson KL, Fry CS, Paddon-Jones D, Arentson-Lantz EJ. The T allele of TCF7L2 rs7903146 is associated with decreased glucose tolerance after bed rest in healthy older adults. Sci Rep 2022; 12:6897. [PMID: 35477971 PMCID: PMC9046412 DOI: 10.1038/s41598-022-10683-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 04/11/2022] [Indexed: 12/19/2022] Open
Abstract
Inpatient populations are at increased risk of hyperglycemia due to factors such as medications, physical inactivity and underlying illness, which increases morbidity and mortality. Unfortunately, clinicians have limited tools available to prospectively identify those at greatest risk. We evaluated the ability of 10 common genetic variants associated with development of type 2 diabetes to predict impaired glucose metabolism. Our research model was a simulated inpatient hospital stay (7 day bed rest protocol, standardized diet, and physical inactivity) in a cohort of healthy older adults (n = 31, 65 ± 8 years) with baseline fasting blood glucose < 100 mg/dL. Participants completed a standard 75 g oral glucose tolerance test (OGTT) at baseline and post-bed rest. Bed rest increased 2-h OGTT blood glucose and insulin independent of genetic variant. In multiple regression modeling, the transcription factor 7-like 2 (TCF7L2) rs7903146 T allele predicted increases in 2-h OGTT blood glucose (p = 0.039). We showed that the TCF7L2 rs7903146 T allele confers risk for loss of glucose tolerance in nondiabetic older adults following 7 days of bed rest.
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Affiliation(s)
- Jean L Fry
- Department of Athletic Training and Clinical Nutrition, University of Kentucky, Lexington, KY, 40536-0200, USA.
| | - Brooke D Munson
- Department of Athletic Training and Clinical Nutrition, University of Kentucky, Lexington, KY, 40536-0200, USA
| | - Katherine L Thompson
- Dr. Bing Zhang Department of Statistics, University of Kentucky, Lexington, KY, 40536-0082, USA
| | - Christopher S Fry
- Department of Athletic Training and Clinical Nutrition, University of Kentucky, Lexington, KY, 40536-0200, USA
| | - Douglas Paddon-Jones
- Department of Nutrition & Metabolism, Center for Rehabilitation, Physical Activity and Nutrition, University of Texas Medical Branch, Galveston, TX, 77555-1028, USA
| | - Emily J Arentson-Lantz
- Department of Nutrition & Metabolism, Center for Rehabilitation, Physical Activity and Nutrition, University of Texas Medical Branch, Galveston, TX, 77555-1028, USA
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Li J, Zhou L, Ouyang X, He P. Transcription Factor-7-Like-2 (TCF7L2) in Atherosclerosis: A Potential Biomarker and Therapeutic Target. Front Cardiovasc Med 2021; 8:701279. [PMID: 34568447 PMCID: PMC8459927 DOI: 10.3389/fcvm.2021.701279] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 08/09/2021] [Indexed: 01/07/2023] Open
Abstract
Transcription factor-7-like-2 (TCF7L2), a vital member of the T-cell factor/lymphoid enhancer factor (TCF/LEF) family, plays an important role in normal human physiological and pathological processes. TCF7L2 exhibits multiple anti-atherosclerotic effects through the activation of specific molecular mechanisms, including regulation of metabolic homeostasis, macrophage polarization, and neointimal hyperplasia. A single-nucleotide substitution of TCF7L2, rs7903146, is a genetic high-risk factor for type 2 diabetes and indicates susceptibility to cardiovascular disease as a link between metabolic disorders and atherosclerosis. In this review, we summarize the anti-atherosclerosis effect and novel mechanisms underlying the function of TCF7L2 to elucidate its potential as an anti-atherosclerosis biomarker and provide a novel therapeutic target for cardiovascular diseases.
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Affiliation(s)
- Junyi Li
- School of Nursing, Hengyang Medical College, University of South China, Hengyang, China
| | - Li Zhou
- Department of Pathology, Chongqing Public Health Medical Center, Southwest University Public Health Hospital, Chongqing, China
| | - Xinping Ouyang
- Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Department of Physiology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical College, The Neuroscience Institute, University of South China, Hengyang, China
| | - Pingping He
- School of Nursing, Hengyang Medical College, University of South China, Hengyang, China
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Regulatory variants in TCF7L2 are associated with thoracic aortic aneurysm. Am J Hum Genet 2021; 108:1578-1589. [PMID: 34265237 DOI: 10.1016/j.ajhg.2021.06.016] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 06/18/2021] [Indexed: 02/08/2023] Open
Abstract
Thoracic aortic aneurysm (TAA) is characterized by dilation of the aortic root or ascending/descending aorta. TAA is a heritable disease that can be potentially life threatening. While 10%-20% of TAA cases are caused by rare, pathogenic variants in single genes, the origin of the majority of TAA cases remains unknown. A previous study implicated common variants in FBN1 with TAA disease risk. Here, we report a genome-wide scan of 1,351 TAA-affected individuals and 18,295 control individuals from the Cardiovascular Health Improvement Project and Michigan Genomics Initiative at the University of Michigan. We identified a genome-wide significant association with TAA for variants within the third intron of TCF7L2 following replication with meta-analysis of four additional independent cohorts. Common variants in this locus are the strongest known genetic risk factor for type 2 diabetes. Although evidence indicates the presence of different causal variants for TAA and type 2 diabetes at this locus, we observed an opposite direction of effect. The genetic association for TAA colocalizes with an aortic eQTL of TCF7L2, suggesting a functional relationship. These analyses predict an association of higher expression of TCF7L2 with TAA disease risk. In vitro, we show that upregulation of TCF7L2 is associated with BCL2 repression promoting vascular smooth muscle cell apoptosis, a key driver of TAA disease.
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Ramzy A, Kieffer TJ. Altered islet prohormone processing: A cause or consequence of diabetes? Physiol Rev 2021; 102:155-208. [PMID: 34280055 DOI: 10.1152/physrev.00008.2021] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Peptide hormones are first produced as larger precursor prohormones that require endoproteolytic cleavage to liberate the mature hormones. A structurally conserved but functionally distinct family of nine prohormone convertase enzymes (PCs) are responsible for cleavage of protein precursors of which PC1/3 and PC2 are known to be exclusive to neuroendocrine cells and responsible for prohormone cleavage. Differential expression of PCs within tissues define prohormone processing; whereas glucagon is the major product liberated from proglucagon via PC2 in pancreatic α-cells, proglucagon is preferentially processed by PC1/3 in intestinal L cells to produce glucagon-like peptides 1 and 2 (GLP-1, GLP-2). Beyond our understanding of processing of islet prohormones in healthy islets, there is convincing evidence that proinsulin, proIAPP, and proglucagon processing is altered during prediabetes and diabetes. There is predictive value of elevated circulating proinsulin or proinsulin : C-peptide ratio for progression to type 2 diabetes and elevated proinsulin or proinsulin : C-peptide is predictive for development of type 1 diabetes in at risk groups. After onset of diabetes, patients have elevated circulating proinsulin and proIAPP and proinsulin may be an autoantigen in type 1 diabetes. Further, preclinical studies reveal that α-cells have altered proglucagon processing during diabetes leading to increased GLP-1 production. We conclude that despite strong associative data, current evidence is inconclusive on the potential causal role of impaired prohormone processing in diabetes, and suggest that future work should focus on resolving the question of whether altered prohormone processing is a causal driver or merely a consequence of diabetes pathology.
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Affiliation(s)
- Adam Ramzy
- Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
| | - Timothy J Kieffer
- Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.,Department of Surgery, University of British Columbia, Vancouver, BC, Canada.,School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada
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Ye Y, Barghouth M, Luan C, Kazim A, Zhou Y, Eliasson L, Zhang E, Hansson O, Thevenin T, Renström E. The TCF7L2-dependent high-voltage activated calcium channel subunit α2δ-1 controls calcium signaling in rodent pancreatic beta-cells. Mol Cell Endocrinol 2020; 502:110673. [PMID: 31805307 DOI: 10.1016/j.mce.2019.110673] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 11/19/2019] [Accepted: 11/30/2019] [Indexed: 12/16/2022]
Abstract
The transcription factor TCF7L2 remains the most important diabetes gene identified to date and genetic risk carriers exhibit lower insulin secretion. We show that Tcf7l2 regulates the auxiliary subunit of voltage-gated Ca2+ channels, Cacna2d1 gene/α2δ-1 protein levels. Furthermore, suppression of α2δ-1 decreased voltage-gated Ca2+ currents and high glucose/depolarization-evoked Ca2+ signaling which mimicked the effect of silencing of Tcf7l2. This appears to be the result of impaired voltage-gated Ca2+ channel trafficking to the plasma membrane, as Cav1.2 channels accumulated in the recycling endosomes after α2δ-1 suppression, in clonal as well as primary rodent beta-cells. This impaired the capacity for glucose-induced insulin secretion in Cacna2d1-silenced cells. Overexpression of α2δ-1 increased high-glucose/K+-stimulated insulin secretion. Furthermore, overexpression of α2δ-1 in Tcf7l2-silenced cells rescued the Tcf7l2-dependent impairment of Ca2+ signaling, but not the reduced insulin secretion. Taken together, these data clarify the connection between Tcf7l2, α2δ-1 in Ca2+-dependent insulin secretion.
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Affiliation(s)
- Yingying Ye
- Lund University, Department of Clinical Sciences, Islet Pathophysiology Group, Sweden
| | - Mohammad Barghouth
- Lund University, Department of Clinical Sciences, Islet Pathophysiology Group, Sweden
| | - Cheng Luan
- Lund University, Department of Clinical Sciences, Islet Pathophysiology Group, Sweden
| | - Abdulla Kazim
- Lund University, Department of Clinical Sciences, Islet Pathophysiology Group, Sweden
| | - Yuedan Zhou
- Lund University, Department of Clinical Sciences, Diabetes and Endocrinology Group, Sweden
| | - Lena Eliasson
- Lund University, Department of Clinical Sciences, Islet Pathophysiology Group, Sweden
| | - Enming Zhang
- Lund University, Department of Clinical Sciences, Islet Pathophysiology Group, Sweden
| | - Ola Hansson
- Lund University, Department of Clinical Sciences, Diabetes and Endocrinology Group, Sweden
| | - Thomas Thevenin
- Lund University, Department of Clinical Sciences, Islet Pathophysiology Group, Sweden
| | - Erik Renström
- Lund University, Department of Clinical Sciences, Islet Pathophysiology Group, Sweden.
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Kong X, Xing X, Zhang X, Hong J, Yang W. Early-onset type 2 diabetes is associated with genetic variants of β-cell function in the Chinese Han population. Diabetes Metab Res Rev 2020; 36:e3214. [PMID: 31465628 DOI: 10.1002/dmrr.3214] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Revised: 06/24/2019] [Accepted: 08/16/2019] [Indexed: 02/06/2023]
Abstract
AIMS To investigate the genetic factors contributing to early-onset type 2 diabetes (EOD) in the Chinese Hans populations. MATERIALS AND METHODS For 2734 newly diagnosed type 2 diabetes patients and 4041 normal glycemic controls, 25 single nucleotide polymorphisms from 24 genomic loci linked to diabetes were successfully genotyped. Three genetic risk scores (GRSs) were constructed, including the weighted type 2 diabetes-related GRS (wT-GRS), the weighted β-cell function-related GRS (wB-GRS), and the weighted GRS constructed by risk alleles not related to β-cell function (wNB-GRS). For patients with diabetes, EOD, middle-age-onset type 2 diabetes (MOD), and late-onset type 2 diabetes (LOD) were defined by onset ages ≤40, 40 to 60, and ≥60 years, respectively. RESULTS From single marker analysis, different gene profiles were identified between EOD and LOD patients. EOD patients had greater wT-GRS and wB-GRS values than LOD patients. After adjustment for sex, elevated wT-GRS and wB-GRS values were significantly associated with an increased risk for EOD by 1.11- and 1.21-fold per allele (P = 1.69 × 10-7 ; 6.07 × 10-8 ). The wT-GRS and wNB-GRS were nominally related to an increased risk of LOD by 1.03-fold per allele (P = 1.03 × 10-2 , 1.78 × 10-2 ). In patients with diabetes, higher wT-GRS and wB-GRS were associated with younger onset age [wT-GRS: β (SE) = -0.0033(0.0016), P = 3.74 × 10-2 ; wB-GRS: -0.0076(0.0028), 7.45 × 10-3 ] and decreased insulinogenic index [wT-GRS: -0.0384(0.0098), 9.39 × 10-5 ; wB-GRS: -0.0722(0.0176), 4.21 × 10-5 ]. CONCLUSION Our findings indicate a strong genetic predisposition for EOD, which can be mainly attributed to genetic variants linked to β-cell function, suggesting the β-cell dysfunction plays a key role in the pathogenesis of EOD in Chinese Han individuals.
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Affiliation(s)
- Xiaomu Kong
- Department of Endocrinology, China-Japan Friendship Hospital, Beijing, China
| | - Xiaoyan Xing
- Department of Endocrinology, China-Japan Friendship Hospital, Beijing, China
| | - Xuelian Zhang
- Department of Endocrinology, China-Japan Friendship Hospital, Beijing, China
| | - Jing Hong
- Department of Endocrinology, China-Japan Friendship Hospital, Beijing, China
| | - Wenying Yang
- Department of Endocrinology, China-Japan Friendship Hospital, Beijing, China
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Srivastava R, Rolyan H, Xie Y, Li N, Bhat N, Hong L, Esteghamat F, Adeniran A, Geirsson A, Zhang J, Ge G, Nobrega M, Martin KA, Mani A. TCF7L2 (Transcription Factor 7-Like 2) Regulation of GATA6 (GATA-Binding Protein 6)-Dependent and -Independent Vascular Smooth Muscle Cell Plasticity and Intimal Hyperplasia. Arterioscler Thromb Vasc Biol 2019; 39:250-262. [PMID: 30567484 PMCID: PMC6365015 DOI: 10.1161/atvbaha.118.311830] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Supplemental Digital Content is available in the text. Objective— TCF7L2 (transcription factor 7-like 2) is a Wnt-regulated transcription factor that maintains stemness and promotes proliferation in embryonic tissues and adult stem cells. Mice with a coronary artery disease–linked mutation in Wnt-coreceptor LRP6 (LDL receptor-related protein 6) exhibit vascular smooth muscle cell dedifferentiation and obstructive coronary artery disease, which are paradoxically associated with reduced TCF7L2 expression. We conducted a comprehensive study to explore the role of TCF7L2 in vascular smooth muscle cell differentiation and protection against intimal hyperplasia. Approach and Results— Using multiple mouse models, we demonstrate here that TCF7L2 promotes differentiation and inhibits proliferation of vascular smooth muscle cells. TCF7L2 accomplishes these effects by stabilization of GATA6 (GATA-binding protein 6) and upregulation of SM-MHC (smooth muscle cell myosin heavy chain) and cell cycle inhibitors. Accordingly, TCF7L2 haploinsufficient mice exhibited increased susceptibility to injury-induced hyperplasia, while mice overexpressing TCF7L2 were protected against injury-induced intimal hyperplasia compared with wild-type littermates. Consequently, the overexpression of TCF7L2 in LRP6 mutant mice rescued the injury-induced intimal hyperplasia. Conclusions— Our novel findings imply cell type-specific functional role of TCF7L2 and provide critical insight into mechanisms underlying the pathogenesis of intimal hyperplasia.
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Affiliation(s)
- Roshni Srivastava
- From the Yale Cardiovascular Research Center (R.S., H.R., Y.X., N.L., N,B., L.H., F.E., J.Z., G.G., K.A.M., A.M.), Yale School of Medicine, New Haven, CT
| | - Harshvardhan Rolyan
- From the Yale Cardiovascular Research Center (R.S., H.R., Y.X., N.L., N,B., L.H., F.E., J.Z., G.G., K.A.M., A.M.), Yale School of Medicine, New Haven, CT
| | - Yi Xie
- From the Yale Cardiovascular Research Center (R.S., H.R., Y.X., N.L., N,B., L.H., F.E., J.Z., G.G., K.A.M., A.M.), Yale School of Medicine, New Haven, CT
| | - Na Li
- From the Yale Cardiovascular Research Center (R.S., H.R., Y.X., N.L., N,B., L.H., F.E., J.Z., G.G., K.A.M., A.M.), Yale School of Medicine, New Haven, CT
| | - Neha Bhat
- From the Yale Cardiovascular Research Center (R.S., H.R., Y.X., N.L., N,B., L.H., F.E., J.Z., G.G., K.A.M., A.M.), Yale School of Medicine, New Haven, CT
| | - Lingjuan Hong
- From the Yale Cardiovascular Research Center (R.S., H.R., Y.X., N.L., N,B., L.H., F.E., J.Z., G.G., K.A.M., A.M.), Yale School of Medicine, New Haven, CT
| | - Fatemehsadat Esteghamat
- From the Yale Cardiovascular Research Center (R.S., H.R., Y.X., N.L., N,B., L.H., F.E., J.Z., G.G., K.A.M., A.M.), Yale School of Medicine, New Haven, CT
| | | | - Arnar Geirsson
- Department of Surgery (A.G.), Yale School of Medicine, New Haven, CT
| | - Jiasheng Zhang
- From the Yale Cardiovascular Research Center (R.S., H.R., Y.X., N.L., N,B., L.H., F.E., J.Z., G.G., K.A.M., A.M.), Yale School of Medicine, New Haven, CT
| | - Guanghao Ge
- From the Yale Cardiovascular Research Center (R.S., H.R., Y.X., N.L., N,B., L.H., F.E., J.Z., G.G., K.A.M., A.M.), Yale School of Medicine, New Haven, CT
| | - Marcelo Nobrega
- Department of Human Genetics, University of Chicago, IL (M.N.)
| | - Kathleen A Martin
- From the Yale Cardiovascular Research Center (R.S., H.R., Y.X., N.L., N,B., L.H., F.E., J.Z., G.G., K.A.M., A.M.), Yale School of Medicine, New Haven, CT
| | - Arya Mani
- From the Yale Cardiovascular Research Center (R.S., H.R., Y.X., N.L., N,B., L.H., F.E., J.Z., G.G., K.A.M., A.M.), Yale School of Medicine, New Haven, CT.,Department of Genetics (A.M.), Yale School of Medicine, New Haven, CT
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10
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Hall E, Jönsson J, Ofori JK, Volkov P, Perfilyev A, Dekker Nitert M, Eliasson L, Ling C, Bacos K. Glucolipotoxicity Alters Insulin Secretion via Epigenetic Changes in Human Islets. Diabetes 2019; 68:1965-1974. [PMID: 31420409 DOI: 10.2337/db18-0900] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Accepted: 07/24/2019] [Indexed: 11/13/2022]
Abstract
Type 2 diabetes (T2D) is characterized by insufficient insulin secretion and elevated glucose levels, often in combination with high levels of circulating fatty acids. Long-term exposure to high levels of glucose or fatty acids impair insulin secretion in pancreatic islets, which could partly be due to epigenetic alterations. We studied the effects of high concentrations of glucose and palmitate combined for 48 h (glucolipotoxicity) on the transcriptome, the epigenome, and cell function in human islets. Glucolipotoxicity impaired insulin secretion, increased apoptosis, and significantly (false discovery rate <5%) altered the expression of 1,855 genes, including 35 genes previously implicated in T2D by genome-wide association studies (e.g., TCF7L2 and CDKN2B). Additionally, metabolic pathways were enriched for downregulated genes. Of the differentially expressed genes, 1,469 also exhibited altered DNA methylation (e.g., CDK1, FICD, TPX2, and TYMS). A luciferase assay showed that increased methylation of CDK1 directly reduces its transcription in pancreatic β-cells, supporting the idea that DNA methylation underlies altered expression after glucolipotoxicity. Follow-up experiments in clonal β-cells showed that knockdown of FICD and TPX2 alters insulin secretion. Together, our novel data demonstrate that glucolipotoxicity changes the epigenome in human islets, thereby altering gene expression and possibly exacerbating the secretory defect in T2D.
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Affiliation(s)
- Elin Hall
- Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Scania University Hospital, Malmö, Sweden
| | - Josefine Jönsson
- Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Scania University Hospital, Malmö, Sweden
| | - Jones K Ofori
- Islet Cell Exocytosis Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Scania University Hospital, Malmö, Sweden
| | - Petr Volkov
- Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Scania University Hospital, Malmö, Sweden
| | - Alexander Perfilyev
- Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Scania University Hospital, Malmö, Sweden
| | - Marloes Dekker Nitert
- Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Scania University Hospital, Malmö, Sweden
| | - Lena Eliasson
- Islet Cell Exocytosis Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Scania University Hospital, Malmö, Sweden
| | - Charlotte Ling
- Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Scania University Hospital, Malmö, Sweden
| | - Karl Bacos
- Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Scania University Hospital, Malmö, Sweden
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11
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Xue A, Wu Y, Zhu Z, Zhang F, Kemper KE, Zheng Z, Yengo L, Lloyd-Jones LR, Sidorenko J, Wu Y, McRae AF, Visscher PM, Zeng J, Yang J. Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes. Nat Commun 2018; 9:2941. [PMID: 30054458 PMCID: PMC6063971 DOI: 10.1038/s41467-018-04951-w] [Citation(s) in RCA: 546] [Impact Index Per Article: 78.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2018] [Accepted: 06/05/2018] [Indexed: 02/06/2023] Open
Abstract
Type 2 diabetes (T2D) is a very common disease in humans. Here we conduct a meta-analysis of genome-wide association studies (GWAS) with ~16 million genetic variants in 62,892 T2D cases and 596,424 controls of European ancestry. We identify 139 common and 4 rare variants associated with T2D, 42 of which (39 common and 3 rare variants) are independent of the known variants. Integration of the gene expression data from blood (n = 14,115 and 2765) with the GWAS results identifies 33 putative functional genes for T2D, 3 of which were targeted by approved drugs. A further integration of DNA methylation (n = 1980) and epigenomic annotation data highlight 3 genes (CAMK1D, TP53INP1, and ATP5G1) with plausible regulatory mechanisms, whereby a genetic variant exerts an effect on T2D through epigenetic regulation of gene expression. Our study uncovers additional loci, proposes putative genetic regulatory mechanisms for T2D, and provides evidence of purifying selection for T2D-associated variants.
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Affiliation(s)
- Angli Xue
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia
| | - Yang Wu
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia
| | - Zhihong Zhu
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia
| | - Futao Zhang
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia
| | - Kathryn E Kemper
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia
| | - Zhili Zheng
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia
- The Eye Hospital, School of Ophthalmology & Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China
| | - Loic Yengo
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia
| | - Luke R Lloyd-Jones
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia
| | - Julia Sidorenko
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia
- Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, 51010, Estonia
| | - Yeda Wu
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia
| | - Allan F McRae
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia
- Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, 4072, Australia
| | - Peter M Visscher
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia
- Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, 4072, Australia
| | - Jian Zeng
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia.
| | - Jian Yang
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia.
- The Eye Hospital, School of Ophthalmology & Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China.
- Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, 4072, Australia.
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12
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Huang ZQ, Liao YQ, Huang RZ, Chen JP, Sun HL. Possible role of TCF7L2 in the pathogenesis of type 2 diabetes mellitus. BIOTECHNOL BIOTEC EQ 2018; 32:830-834. [DOI: 10.1080/13102818.2018.1438211] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Accepted: 02/05/2018] [Indexed: 01/17/2023] Open
Affiliation(s)
- Zhi-qiu Huang
- Department of Endocrinology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, PR China
| | - Yao-qi Liao
- Department of Endocrinology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, PR China
| | - Run-ze Huang
- Department of Endocrinology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, PR China
| | - Jin-peng Chen
- Department of Endocrinology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, PR China
| | - Hui-lin Sun
- Department of Endocrinology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, PR China
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13
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Barna B, Badaruddoza, Kaur M, Bhanwer A. A multifactor dimensionality reduction model of gene polymorphisms and an environmental interaction analysis in type 2 diabetes mellitus study among Punjabi, a North India population. Meta Gene 2018. [DOI: 10.1016/j.mgene.2018.01.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
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14
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Abstract
Glucose is the key source for most organisms to provide energy, as well as the key source for metabolites to generate building blocks in cells. The deregulation of glucose homeostasis occurs in various diseases, including the enhanced aerobic glycolysis that is observed in cancers, and insulin resistance in diabetes. Although p53 is thought to suppress tumorigenesis primarily by inducing cell cycle arrest, apoptosis, and senescence in response to stress, the non-canonical functions of p53 in cellular energy homeostasis and metabolism are also emerging as critical factors for tumor suppression. Increasing evidence suggests that p53 plays a significant role in regulating glucose homeostasis. Furthermore, the p53 family members p63 and p73, as well as gain-of-function p53 mutants, are also involved in glucose metabolism. Indeed, how this protein family regulates cellular energy levels is complicated and difficult to disentangle. This review discusses the roles of the p53 family in multiple metabolic processes, such as glycolysis, gluconeogenesis, aerobic respiration, and autophagy. We also discuss how the dysregulation of the p53 family in these processes leads to diseases such as cancer and diabetes. Elucidating the complexities of the p53 family members in glucose homeostasis will improve our understanding of these diseases.
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15
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Cropano C, Santoro N, Groop L, Dalla Man C, Cobelli C, Galderisi A, Kursawe R, Pierpont B, Goffredo M, Caprio S. The rs7903146 Variant in the TCF7L2 Gene Increases the Risk of Prediabetes/Type 2 Diabetes in Obese Adolescents by Impairing β-Cell Function and Hepatic Insulin Sensitivity. Diabetes Care 2017; 40:1082-1089. [PMID: 28611053 PMCID: PMC5521977 DOI: 10.2337/dc17-0290] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Accepted: 05/06/2017] [Indexed: 02/03/2023]
Abstract
OBJECTIVE In this study, we aimed to explore the mechanism by which TCF7L2 rs7903146 risk allele confers susceptibility to impaired glucose tolerance (IGT) or type 2 diabetes (T2D) in obese adolescents. RESEARCH DESIGN AND METHODS The rs7903146 variant in the TCF7L2 gene was genotyped in a multiethnic cohort of 955 youths. All subjects underwent an oral glucose tolerance test with the use of the Oral Minimal Model to assess insulin secretion, and 33 subjects underwent a hyperinsulinemic-euglycemic clamp. In 307 subjects, a follow-up oral glucose tolerance test was repeated after 3.11 ± 2.36 years. RESULTS The TCF7L2 rs7903146 risk allele was associated with higher 2-h glucose levels in Caucasians (P = 0.006) and African Americans (P = 0.009), and a trend was seen also in Hispanics (P = 0.072). Also, the T allele was associated with decreased β-cell responsivity and IGT (P < 0.05). Suppression of endogenous hepatic glucose production was lower in subjects with the risk variant (P = 0.006). Finally, the odds of showing IGT/T2D at follow-up were higher in subjects carrying the minor allele (odds ratio 2.224; 95% CI 1.370-3.612; P = 0.0012). CONCLUSIONS The rs7903146 variant in the TCF7L2 gene increases the risk of IGT/T2D in obese adolescents by impairing β-cell function, and hepatic insulin sensitivity predicts the development of IGT/T2D over time.
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Affiliation(s)
- Catrina Cropano
- Division of Pediatric Endocrinology, Department of Pediatrics, Yale University School of Medicine, New Haven, CT
| | - Nicola Santoro
- Division of Pediatric Endocrinology, Department of Pediatrics, Yale University School of Medicine, New Haven, CT
| | - Leif Groop
- Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, Malmo, Sweden.,Lund University Diabetes Center, Lund University, Malmo, Sweden
| | - Chiara Dalla Man
- Department of Information Engineering, University of Padua, Padua, Italy
| | - Claudio Cobelli
- Department of Information Engineering, University of Padua, Padua, Italy
| | - Alfonso Galderisi
- Division of Pediatric Endocrinology, Department of Pediatrics, Yale University School of Medicine, New Haven, CT
| | | | - Bridget Pierpont
- Division of Pediatric Endocrinology, Department of Pediatrics, Yale University School of Medicine, New Haven, CT
| | - Martina Goffredo
- Division of Pediatric Endocrinology, Department of Pediatrics, Yale University School of Medicine, New Haven, CT
| | - Sonia Caprio
- Division of Pediatric Endocrinology, Department of Pediatrics, Yale University School of Medicine, New Haven, CT
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16
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da Silva Xavier G, Mondragon A, Mourougavelou V, Cruciani-Guglielmacci C, Denom J, Herrera PL, Magnan C, Rutter GA. Pancreatic alpha cell-selective deletion of Tcf7l2 impairs glucagon secretion and counter-regulatory responses to hypoglycaemia in mice. Diabetologia 2017; 60:1043-1050. [PMID: 28343277 PMCID: PMC5423960 DOI: 10.1007/s00125-017-4242-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2017] [Accepted: 02/15/2017] [Indexed: 01/19/2023]
Abstract
AIMS/HYPOTHESIS Transcription factor 7-like 2 (TCF7L2) is a high mobility group (HMG) box-containing transcription factor and downstream effector of the Wnt signalling pathway. SNPs in the TCF7L2 gene have previously been associated with an increased risk of type 2 diabetes in genome-wide association studies. In animal studies, loss of Tcf7l2 function is associated with defective islet beta cell function and survival. Here, we explore the role of TCF7L2 in the control of the counter-regulatory response to hypoglycaemia by generating mice with selective deletion of the Tcf7l2 gene in pancreatic alpha cells. METHODS Alpha cell-selective deletion of Tcf7l2 was achieved by crossing mice with floxed Tcf7l2 alleles to mice bearing a Cre recombinase transgene driven by the preproglucagon promoter (PPGCre), resulting in Tcf7l2AKO mice. Glucose homeostasis and hormone secretion in vivo and in vitro, and islet cell mass were measured using standard techniques. RESULTS While glucose tolerance was unaffected in Tcf7l2AKO mice, glucose infusion rates were increased (AUC for glucose during the first 60 min period of hyperinsulinaemic-hypoglycaemic clamp test was increased by 1.98 ± 0.26-fold [p < 0.05; n = 6] in Tcf7l2AKO mice vs wild-type mice) and glucagon secretion tended to be lower (plasma glucagon: 0.40 ± 0.03-fold vs wild-type littermate controls [p < 0.01; n = 6]). Tcf7l2AKO mice displayed reduced fasted plasma glucose concentration. Glucagon release at low glucose was impaired in islets isolated from Tcf7l2AKO mice (0.37 ± 0.02-fold vs islets from wild-type littermate control mice [p < 0.01; n = 6). Alpha cell mass was also reduced (72.3 ± 20.3% [p < 0.05; n = 7) in Tcf7l2AKO mice compared with wild-type mice. CONCLUSIONS/INTERPRETATION The present findings demonstrate an alpha cell-autonomous role for Tcf7l2 in the control of pancreatic glucagon secretion and the maintenance of alpha cell mass and function.
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Affiliation(s)
- Gabriela da Silva Xavier
- Section of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, London, W12 0NN, UK.
| | - Angeles Mondragon
- Section of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, London, W12 0NN, UK
| | - Vishnou Mourougavelou
- Section of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, London, W12 0NN, UK
| | | | - Jessica Denom
- Université Paris Diderot Paris 7 - CNRS UMR 8251, Paris, France
| | - Pedro Luis Herrera
- Department of Genetic Medicine & Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | | | - Guy A Rutter
- Section of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, London, W12 0NN, UK
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17
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Strycharz J, Drzewoski J, Szemraj J, Sliwinska A. Is p53 Involved in Tissue-Specific Insulin Resistance Formation? OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:9270549. [PMID: 28194257 PMCID: PMC5282448 DOI: 10.1155/2017/9270549] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 12/19/2016] [Indexed: 02/06/2023]
Abstract
p53 constitutes an extremely versatile molecule, primarily involved in sensing the variety of cellular stresses. Functional p53 utilizes a plethora of mechanisms to protect cell from deleterious repercussions of genotoxic insults, where senescence deserves special attention. While the impressive amount of p53 roles has been perceived solely by the prism of antioncogenic effect, its presence seems to be vastly connected with metabolic abnormalities underlain by cellular aging, obesity, and inflammation. p53 has been found to regulate multiple biochemical processes such as glycolysis, oxidative phosphorylation, lipolysis, lipogenesis, β-oxidation, gluconeogenesis, and glycogen synthesis. Notably, p53-mediated metabolic effects are totally up to results of insulin action. Accumulating amount of data identifies p53 to be a factor activated upon hyperglycemia or excessive calorie intake, thus contributing to low-grade chronic inflammation and systemic insulin resistance. Prominent signs of its actions have been observed in muscles, liver, pancreas, and adipose tissue being associated with attenuation of insulin signalling. p53 is of crucial importance for the regulation of white and brown adipogenesis simultaneously being a repressor for preadipocyte differentiation. This review provides a profound insight into p53-dependent metabolic actions directed towards promotion of insulin resistance as well as presenting experimental data regarding obesity-induced p53-mediated metabolic abnormalities.
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Affiliation(s)
- Justyna Strycharz
- Diabetes Student Scientific Society at the Department of Internal Diseases, Diabetology and Clinical Pharmacology, Medical University of Lodz, Lodz, Poland
| | - Jozef Drzewoski
- Department of Internal Diseases, Diabetology and Clinical Pharmacology, Medical University of Lodz, Lodz, Poland
| | - Janusz Szemraj
- Department of Medical Biochemistry, Medical University of Lodz, Lodz, Poland
| | - Agnieszka Sliwinska
- Department of Nucleic Acid Biochemistry, Medical University of Lodz, Lodz, Poland
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18
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Katoh I, Fukunishi N, Fujimuro M, Kasai H, Moriishi K, Hata RI, Kurata SI. Repression of Wnt/β-catenin response elements by p63 (TP63). Cell Cycle 2016; 15:699-710. [PMID: 26890356 PMCID: PMC4845946 DOI: 10.1080/15384101.2016.1148837] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022] Open
Abstract
Submitted: TP63 (p63), a member of the tumor suppressor TP53 (p53) gene family, is expressed in keratinocyte stem cells and well-differentiated squamous cell carcinomas to maintain cellular potential for growth and differentiation. Controversially, activation of the Wnt/β-catenin signaling by p63 (Patturajan M. et al., 2002, Cancer Cells) and inhibition of the target gene expression (Drewelus I. et al., 2010, Cell Cycle) have been reported. Upon p63 RNA-silencing in squamous cell carcinoma (SCC) lines, a few Wnt target gene expression substantially increased, while several target genes moderately decreased. Although ΔNp63α, the most abundant isoform of p63, appeared to interact with protein phosphatase PP2A, neither GSK-3β phosphorylation nor β-catenin nuclear localization was altered by the loss of p63. As reported earlier, ΔNp63α enhanced β-catenin-dependent luc gene expression from pGL3-OT having 3 artificial Wnt response elements (WREs). However, this activation was detectable only in HEK293 cells examined so far, and involved a p53 family-related sequence 5' to the WREs. In Wnt3-expressing SAOS-2 cells, ΔNp63α rather strongly inhibited transcription of pGL3-OT. Importantly, ΔNp63α repressed WREs isolated from the regulatory regions of MMP7. ΔNp63α-TCF4 association occurred in their soluble forms in the nucleus. Furthermore, p63 and TCF4 coexisted at a WRE of MMP7 on the chromatin, where β-catenin recruitment was attenuated. The combined results indicate that ΔNp63α serves as a repressor that regulates β-catenin-mediated gene expression.
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Affiliation(s)
- Iyoko Katoh
- a Center for Medical Education and Sciences, Faculty of Medicine, University of Yamanashi , Chuo , Yamanashi , Japan.,b Oral Health Science Research Center, Kanagawa Dental University , Yokosuka , Japan
| | - Nahoko Fukunishi
- c Medical Research Institute, Tokyo Medical and Dental University , Tokyo , Japan
| | - Masahiro Fujimuro
- d Department of Cell Biology , Kyoto Pharmaceutical University , Yamashina , Kyoto , Japan
| | - Hirotake Kasai
- e Department of Microbiology , Faculty of Medicine, University of Yamanashi , Chuo , Yamanashi , Japan
| | - Kohji Moriishi
- e Department of Microbiology , Faculty of Medicine, University of Yamanashi , Chuo , Yamanashi , Japan
| | - Ryu-Ichiro Hata
- b Oral Health Science Research Center, Kanagawa Dental University , Yokosuka , Japan
| | - Shun-Ichi Kurata
- b Oral Health Science Research Center, Kanagawa Dental University , Yokosuka , Japan.,c Medical Research Institute, Tokyo Medical and Dental University , Tokyo , Japan
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19
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Wu H, Gao L, Kasabov NK. Network-Based Method for Inferring Cancer Progression at the Pathway Level from Cross-Sectional Mutation Data. IEEE/ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS 2016; 13:1036-1044. [PMID: 26915128 DOI: 10.1109/tcbb.2016.2520934] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
Large-scale cancer genomics projects are providing a wealth of somatic mutation data from a large number of cancer patients. However, it is difficult to obtain several samples with a temporal order from one patient in evaluating the cancer progression. Therefore, one of the most challenging problems arising from the data is to infer the temporal order of mutations across many patients. To solve the problem efficiently, we present a Network-based method (NetInf) to Infer cancer progression at the pathway level from cross-sectional data across many patients, leveraging on the exclusive property of driver mutations within a pathway and the property of linear progression between pathways. To assess the robustness of NetInf, we apply it on simulated data with the addition of different levels of noise. To verify the performance of NetInf, we apply it to analyze somatic mutation data from three real cancer studies with large number of samples. Experimental results reveal that the pathways detected by NetInf show significant enrichment. Our method reduces computational complexity by constructing gene networks without assigning the number of pathways, which also provides new insights on the temporal order of somatic mutations at the pathway level rather than at the gene level.
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20
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Kung CP, Murphy ME. The role of the p53 tumor suppressor in metabolism and diabetes. J Endocrinol 2016; 231:R61-R75. [PMID: 27613337 PMCID: PMC5148674 DOI: 10.1530/joe-16-0324] [Citation(s) in RCA: 111] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 09/08/2016] [Indexed: 12/12/2022]
Abstract
In the context of tumor suppression, p53 is an undisputedly critical protein. Functioning primarily as a transcription factor, p53 helps fend off the initiation and progression of tumors by inducing cell cycle arrest, senescence or programmed cell death (apoptosis) in cells at the earliest stages of precancerous development. Compelling evidence, however, suggests that p53 is involved in other aspects of human physiology, including metabolism. Indeed, recent studies suggest that p53 plays a significant role in the development of metabolic diseases, including diabetes, and further that p53's role in metabolism may also be consequential to tumor suppression. Here, we present a review of the literature on the role of p53 in metabolism, diabetes, pancreatic function, glucose homeostasis and insulin resistance. Additionally, we discuss the emerging role of genetic variation in the p53 pathway (single-nucleotide polymorphisms) on the impact of p53 in metabolic disease and diabetes. A better understanding of the relationship between p53, metabolism and diabetes may one day better inform the existing and prospective therapeutic strategies to combat this rapidly growing epidemic.
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Affiliation(s)
- Che-Pei Kung
- Department of Internal MedicineWashington University School of Medicine, St Louis, Missouri, USA
| | - Maureen E Murphy
- Department of Internal MedicineWashington University School of Medicine, St Louis, Missouri, USA
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21
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Zhou Y, Oskolkov N, Shcherbina L, Ratti J, Kock KH, Su J, Martin B, Oskolkova MZ, Göransson O, Bacon J, Li W, Bucciarelli S, Cilio C, Brazma A, Thatcher B, Rung J, Wierup N, Renström E, Groop L, Hansson O. HMGB1 binds to the rs7903146 locus in TCF7L2 in human pancreatic islets. Mol Cell Endocrinol 2016; 430:138-45. [PMID: 26845344 DOI: 10.1016/j.mce.2016.01.027] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Revised: 01/19/2016] [Accepted: 01/28/2016] [Indexed: 02/03/2023]
Abstract
The intronic SNP rs7903146 in the T-cell factor 7-like 2 gene (TCF7L2) is the common genetic variant most highly associated with Type 2 diabetes known to date. The risk T-allele is located in an open chromatin region specific to human pancreatic islets of Langerhans, thereby accessible for binding of regulatory proteins. The risk T-allele locus exhibits stronger enhancer activity compared to the non-risk C-allele. The aim of this study was to identify transcriptional regulators that bind the open chromatin region in the rs7903146 locus and thereby potentially regulate TCF7L2 expression and activity. Using affinity chromatography followed by Edman sequencing, we identified one candidate regulatory protein, i.e. high-mobility group protein B1 (HMGB1). The binding of HMGB1 to the rs7903146 locus was confirmed in pancreatic islets from human deceased donors, in HCT116 and in HEK293 cell lines using: (i) protein purification on affinity columns followed by Western blot, (ii) chromatin immunoprecipitation followed by qPCR and (iii) electrophoretic mobility shift assay. The results also suggested that HMGB1 might have higher binding affinity to the C-allele of rs7903146 compared to the T-allele, which was supported in vitro using Dynamic Light Scattering, possibly in a tissue-specific manner. The functional consequence of HMGB1 depletion in HCT116 and INS1 cells was reduced insulin and TCF7L2 mRNA expression, TCF7L2 transcriptional activity and glucose stimulated insulin secretion. These findings suggest that the rs7903146 locus might exert its enhancer function by interacting with HMGB1 in an allele dependent manner.
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Affiliation(s)
- Yuedan Zhou
- Department of Clinical Sciences, CRC, Lund University, Malmö, 20502, Sweden
| | - Nikolay Oskolkov
- Department of Clinical Sciences, CRC, Lund University, Malmö, 20502, Sweden
| | - Liliya Shcherbina
- Department of Clinical Sciences, CRC, Lund University, Malmö, 20502, Sweden
| | - Joyce Ratti
- Department of Biochemistry, University of Cambridge, CB2 1GA, Cambridge, UK
| | - Kian-Hong Kock
- Department of Biochemistry, University of Cambridge, CB2 1GA, Cambridge, UK
| | - Jing Su
- European Bioinformatics Institute, Functional Genomics, Hinxton, Cambridge CB10 1SD, UK
| | - Brian Martin
- National Institute of Mental Health NIMH, National Institutes of Health, Bethesda, MD 20892, USA
| | | | - Olga Göransson
- Department of Clinical Sciences, CRC, Lund University, Malmö, 20502, Sweden
| | - Julie Bacon
- Department of Clinical Sciences, CRC, Lund University, Malmö, 20502, Sweden
| | - Weimin Li
- Department of Physical Chemistry, Lund University, Lund, 22100, Sweden
| | | | - Corrado Cilio
- Department of Clinical Sciences, CRC, Lund University, Malmö, 20502, Sweden
| | - Alvis Brazma
- European Bioinformatics Institute, Functional Genomics, Hinxton, Cambridge CB10 1SD, UK
| | - Bradley Thatcher
- Department of Clinical Sciences, CRC, Lund University, Malmö, 20502, Sweden
| | - Johan Rung
- European Bioinformatics Institute, Functional Genomics, Hinxton, Cambridge CB10 1SD, UK
| | - Nils Wierup
- Department of Clinical Sciences, CRC, Lund University, Malmö, 20502, Sweden
| | - Erik Renström
- Department of Clinical Sciences, CRC, Lund University, Malmö, 20502, Sweden
| | - Leif Groop
- Department of Clinical Sciences, CRC, Lund University, Malmö, 20502, Sweden
| | - Ola Hansson
- Department of Clinical Sciences, CRC, Lund University, Malmö, 20502, Sweden.
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22
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The MDM2-p53-pyruvate carboxylase signalling axis couples mitochondrial metabolism to glucose-stimulated insulin secretion in pancreatic β-cells. Nat Commun 2016; 7:11740. [PMID: 27265727 PMCID: PMC4897763 DOI: 10.1038/ncomms11740] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Accepted: 04/26/2016] [Indexed: 02/06/2023] Open
Abstract
Mitochondrial metabolism is pivotal for glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells. However, little is known about the molecular machinery that controls the homeostasis of intermediary metabolites in mitochondria. Here we show that the activation of p53 in β-cells, by genetic deletion or pharmacological inhibition of its negative regulator MDM2, impairs GSIS, leading to glucose intolerance in mice. Mechanistically, p53 activation represses the expression of the mitochondrial enzyme pyruvate carboxylase (PC), resulting in diminished production of the TCA cycle intermediates oxaloacetate and NADPH, and impaired oxygen consumption. The defective GSIS and mitochondrial metabolism in MDM2-null islets can be rescued by restoring PC expression. Under diabetogenic conditions, MDM2 and p53 are upregulated, whereas PC is reduced in mouse β-cells. Pharmacological inhibition of p53 alleviates defective GSIS in diabetic islets by restoring PC expression. Thus, the MDM2-p53-PC signalling axis links mitochondrial metabolism to insulin secretion and glucose homeostasis, and could represent a therapeutic target in diabetes.
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23
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Ma Y, Yang Q, Chen X, Liang W, Ren Z, Ding G. c-Abl contributes to glucose-promoted apoptosis via p53 signaling pathway in podocytes. Diabetes Res Clin Pract 2016; 113:171-8. [PMID: 26810274 DOI: 10.1016/j.diabres.2015.12.013] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Revised: 11/05/2015] [Accepted: 12/26/2015] [Indexed: 02/07/2023]
Abstract
AIM To investigate the role of the non-receptor tyrosine kinase c-Abl in high glucose-induced podocyte injury and its possible signal transduction pathway. METHODS Sixteen C57BL/6 mice were randomly assigned to a group with diabetes and a normal control group. Subsequently, differentiated mouse podocytes were exposed to high-glucose conditions, and podocyte apoptosis was then assessed by flow cytometry and Hoechst 33258 staining. Western blot and immunofluorescence assay were used to measure c-Abl expression. Co-immunoprecipitation assay was used and c-Abl siRNA was applied to evaluate the interaction between c-Abl and p53. RESULTS High glucose promotes podocyte apoptosis. The c-Abl expression in podocytes was increased after exposure to high glucose, stimulating the p53 signaling pathway. Conversely, treatment with c-Abl siRNA restored high glucose-promoted podocyte apoptosis and resulted in the reduction of p53 expression. CONCLUSION c-Abl contributes to high glucose-induced podocyte apoptosis via p53 signaling pathway.
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Affiliation(s)
- Yiqiong Ma
- Division of Nephrology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan 430060, Hubei, China
| | - Qian Yang
- Division of Nephrology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan 430060, Hubei, China
| | - Xinghua Chen
- Division of Nephrology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan 430060, Hubei, China
| | - Wei Liang
- Division of Nephrology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan 430060, Hubei, China
| | - Zhilong Ren
- Division of Nephrology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan 430060, Hubei, China
| | - Guohua Ding
- Division of Nephrology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan 430060, Hubei, China.
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24
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Wnt9a deficiency discloses a repressive role of Tcf7l2 on endocrine differentiation in the embryonic pancreas. Sci Rep 2016; 6:19223. [PMID: 26771085 PMCID: PMC4725895 DOI: 10.1038/srep19223] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Accepted: 12/09/2015] [Indexed: 12/16/2022] Open
Abstract
Transcriptional and signaling networks establish complex cross-regulatory interactions that drive cellular differentiation during development. Using microarrays we identified the gene encoding the ligand Wnt9a as a candidate target of Neurogenin3, a basic helix-loop-helix transcription factor that functions as a master regulator of pancreatic endocrine differentiation. Here we show that Wnt9a is expressed in the embryonic pancreas and that its deficiency enhances activation of the endocrine transcriptional program and increases the number of endocrine cells at birth. We identify the gene encoding the endocrine transcription factor Nkx2-2 as one of the most upregulated genes in Wnt9a-ablated pancreases and associate its activation to reduced expression of the Wnt effector Tcf7l2. Accordingly, in vitro studies confirm that Tcf7l2 represses activation of Nkx2-2 by Neurogenin3 and inhibits Nkx2-2 expression in differentiated β-cells. Further, we report that Tcf7l2 protein levels decline upon initiation of endocrine differentiation in vivo, disclosing the downregulation of this factor in the developing endocrine compartment. These findings highlight the notion that modulation of signalling cues by lineage-promoting factors is pivotal for controlling differentiation programs.
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25
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Saadi H, Seillier M, Carrier A. The stress protein TP53INP1 plays a tumor suppressive role by regulating metabolic homeostasis. Biochimie 2015. [PMID: 26225460 DOI: 10.1016/j.biochi.2015.07.024] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
In the recent years, we have provided evidence that Tumor Protein 53-Induced Nuclear Protein 1 (TP53INP1) is a key stress protein with antioxidant-associated tumor suppressive function. The TP53INP1 gene, which is highly conserved in mammals, is over-expressed during stress responses including inflammation. This gene encodes two protein isoforms with nuclear or cytoplasmic subcellular localization depending on the context. TP53INP1 contributes to stress responses, thus preventing stress-induced dysfunctions leading to pathologies such as cancer. Two major mechanisms by which TP53INP1 functions have been unveiled. First, in the nucleus, TP53INP1 was shown to regulate the transcriptional activity of p53 and p73 by direct interaction, and to mediate the antioxidant activity of p53. Second, independently of p53, TP53INP1 contributes to autophagy and more particularly mitophagy through direct interaction with molecular actors of autophagy. TP53INP1 is thus required for the homeostasis of the mitochondrial compartment, and is therefore involved in the regulation of energetic metabolism. Finally, the antioxidant function of TP53INP1 stems from the control of mitochondrial reactive oxygen species production. In conclusion, TP53INP1 is a multifaceted protein endowed with multiple functions, including metabolic regulation, as is its main functional partner p53.
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Affiliation(s)
- Houda Saadi
- Inserm, U1068, CRCM, Marseille, F-13009, France; Institut Paoli-Calmettes, Marseille, F-13009, France; Aix-Marseille Université, UM 105, Marseille, F-13284, France; CNRS, UMR7258, CRCM, Marseille, F-13009, France
| | - Marion Seillier
- Inserm, U1068, CRCM, Marseille, F-13009, France; Institut Paoli-Calmettes, Marseille, F-13009, France; Aix-Marseille Université, UM 105, Marseille, F-13284, France; CNRS, UMR7258, CRCM, Marseille, F-13009, France
| | - Alice Carrier
- Inserm, U1068, CRCM, Marseille, F-13009, France; Institut Paoli-Calmettes, Marseille, F-13009, France; Aix-Marseille Université, UM 105, Marseille, F-13284, France; CNRS, UMR7258, CRCM, Marseille, F-13009, France.
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Lamikanra AA, Merryweather-Clarke AT, Tipping AJ, Roberts DJ. Distinct mechanisms of inadequate erythropoiesis induced by tumor necrosis factor alpha or malarial pigment. PLoS One 2015; 10:e0119836. [PMID: 25781011 PMCID: PMC4363658 DOI: 10.1371/journal.pone.0119836] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Accepted: 12/19/2014] [Indexed: 12/18/2022] Open
Abstract
The role of infection in erythropoietic dysfunction is poorly understood. In children with P. falciparum malaria, the by-product of hemoglobin digestion in infected red cells (hemozoin) is associated with the severity of anemia which is independent of circulating levels of the inflammatory cytokine tumor necrosis alpha (TNF-α). To gain insight into the common and specific effects of TNF-α and hemozoin on erythropoiesis, we studied the gene expression profile of purified primary erythroid cultures exposed to either TNF-α (10ng/ml) or to hemozoin (12.5μg/ml heme units) for 24 hours. Perturbed gene function was assessed using co-annotation of associated gene ontologies and expression of selected genes representative of the profile observed was confirmed by real time PCR (rtPCR). The changes in gene expression induced by each agent were largely distinct; many of the genes significantly modulated by TNF-α were not affected by hemozoin. The genes modulated by TNF-α were significantly enriched for those encoding proteins involved in the control of type 1 interferon signalling and the immune response to viral infection. In contrast, genes induced by hemozoin were significantly enriched for functional roles in regulation of transcription and apoptosis. Further analyses by rtPCR revealed that hemozoin increases expression of transcription factors that form part of the integrated stress response which is accompanied by reduced expression of genes involved in DNA repair. This study confirms that hemozoin induces cellular stress on erythroblasts that is additional to and distinct from responses to inflammatory cytokines and identifies new genes that may be involved in the pathogenesis of severe malarial anemia. More generally the respective transcription profiles highlight the varied mechanisms through which erythropoiesis may be disrupted during infectious disease.
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Affiliation(s)
- Abigail A. Lamikanra
- Nuffield Division of Clinical Laboratory Sciences, University of Oxford, Oxford OX3 9BQ, United Kingdom
- National Health Service Blood and Transplant, John Radcliffe Hospital, Headington, Oxford OX3 9BQ, United Kingdom
- * E-mail:
| | - Alison T. Merryweather-Clarke
- Nuffield Division of Clinical Laboratory Sciences, University of Oxford, Oxford OX3 9BQ, United Kingdom
- National Health Service Blood and Transplant, John Radcliffe Hospital, Headington, Oxford OX3 9BQ, United Kingdom
| | - Alex J. Tipping
- Nuffield Division of Clinical Laboratory Sciences, University of Oxford, Oxford OX3 9BQ, United Kingdom
- National Health Service Blood and Transplant, John Radcliffe Hospital, Headington, Oxford OX3 9BQ, United Kingdom
| | - David J. Roberts
- Nuffield Division of Clinical Laboratory Sciences, University of Oxford, Oxford OX3 9BQ, United Kingdom
- National Health Service Blood and Transplant, John Radcliffe Hospital, Headington, Oxford OX3 9BQ, United Kingdom
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27
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Rulifson IC, Majeti JZ, Xiong Y, Hamburger A, Lee KJ, Miao L, Lu M, Gardner J, Gong Y, Wu H, Case R, Yeh WC, Richards WG, Baribault H, Li Y. Inhibition of secreted frizzled-related protein 5 improves glucose metabolism. Am J Physiol Endocrinol Metab 2014; 307:E1144-52. [PMID: 25370851 DOI: 10.1152/ajpendo.00283.2014] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Elucidating the role of secreted frizzled-related protein 5 (SFRP5) in metabolism and obesity has been complicated by contradictory findings when knockout mice were used to determine metabolic phenotypes. By overexpressing SFRP5 in obese, prediabetic mice we consistently observed elevated hyperglycemia and glucose intolerance, supporting SFRP5 as a negative regulator of glucose metabolism. Accordingly, Sfrp5 mRNA expression analysis of both epididymal and subcutaneous adipose depots of mice indicated a correlation with obesity. Thus, we generated a monoclonal antibody (mAb) against SFRP5 to ascertain the effect of SFRP5 inhibition in vivo. Congruent with SFRP5 overexpression worsening blood glucose levels and glucose intolerance, anti-SFRP5 mAb therapy improved these phenotypes in vivo. The results from both the overexpression and mAb inhibition studies suggest a role for SFRP5 in glucose metabolism and pancreatic β-cell function and thus establish the use of an anti-SFRP5 mAb as a potential approach to treat type 2 diabetes.
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Affiliation(s)
| | | | - Yumei Xiong
- Amgen Incorporated, South San Francisco, California; and
| | | | | | - Li Miao
- Amgen Incorporated, South San Francisco, California; and
| | - Mei Lu
- Amgen Incorporated, South San Francisco, California; and
| | | | - Yan Gong
- Amgen Incorporated, South San Francisco, California; and
| | - Hai Wu
- Amgen Incorporated, South San Francisco, California; and
| | - Ryan Case
- Amgen Incorporated, South San Francisco, California; and
| | - Wen-Chen Yeh
- Amgen Incorporated, South San Francisco, California; and
| | | | | | - Yang Li
- Amgen Incorporated, South San Francisco, California; and
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Global genomic and transcriptomic analysis of human pancreatic islets reveals novel genes influencing glucose metabolism. Proc Natl Acad Sci U S A 2014; 111:13924-9. [PMID: 25201977 DOI: 10.1073/pnas.1402665111] [Citation(s) in RCA: 351] [Impact Index Per Article: 31.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Genetic variation can modulate gene expression, and thereby phenotypic variation and susceptibility to complex diseases such as type 2 diabetes (T2D). Here we harnessed the potential of DNA and RNA sequencing in human pancreatic islets from 89 deceased donors to identify genes of potential importance in the pathogenesis of T2D. We present a catalog of genetic variants regulating gene expression (eQTL) and exon use (sQTL), including many long noncoding RNAs, which are enriched in known T2D-associated loci. Of 35 eQTL genes, whose expression differed between normoglycemic and hyperglycemic individuals, siRNA of tetraspanin 33 (TSPAN33), 5'-nucleotidase, ecto (NT5E), transmembrane emp24 protein transport domain containing 6 (TMED6), and p21 protein activated kinase 7 (PAK7) in INS1 cells resulted in reduced glucose-stimulated insulin secretion. In addition, we provide a genome-wide catalog of allelic expression imbalance, which is also enriched in known T2D-associated loci. Notably, allelic imbalance in paternally expressed gene 3 (PEG3) was associated with its promoter methylation and T2D status. Finally, RNA editing events were less common in islets than previously suggested in other tissues. Taken together, this study provides new insights into the complexity of gene regulation in human pancreatic islets and better understanding of how genetic variation can influence glucose metabolism.
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29
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Andersen MK, Sterner M, Forsén T, Käräjämäki A, Rolandsson O, Forsblom C, Groop PH, Lahti K, Nilsson PM, Groop L, Tuomi T. Type 2 diabetes susceptibility gene variants predispose to adult-onset autoimmune diabetes. Diabetologia 2014; 57:1859-68. [PMID: 24906951 DOI: 10.1007/s00125-014-3287-8] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2014] [Accepted: 05/13/2014] [Indexed: 01/14/2023]
Abstract
AIMS/HYPOTHESIS Latent autoimmune diabetes in adults (LADA) is phenotypically a hybrid of type 1 and type 2 diabetes. Genetically LADA is poorly characterised but does share genetic predisposition with type 1 diabetes. We aimed to improve the genetic characterisation of LADA and hypothesised that type 2 diabetes-associated gene variants also predispose to LADA, and that the associations would be strongest in LADA patients with low levels of GAD autoantibodies (GADA). METHODS We assessed 41 type 2 diabetes-associated gene variants in Finnish (phase I) and Swedish (phase II) patients with LADA (n = 911) or type 1 diabetes (n = 406), all diagnosed after the age of 35 years, as well as in non-diabetic control individuals 40 years or older (n = 4,002). RESULTS Variants in the ZMIZ1 (rs12571751, p = 4.1 × 10(-5)) and TCF7L2 (rs7903146, p = 5.8 × 10(-4)) loci were strongly associated with LADA. Variants in the KCNQ1 (rs2237895, p = 0.0012), HHEX (rs1111875, p = 0.0024 in Finns) and MTNR1B (rs10830963, p = 0.0039) loci showed the strongest association in patients with low GADA, supporting the hypothesis that the disease in these patients is more like type 2 diabetes. In contrast, variants in the KLHDC5 (rs10842994, p = 9.5 × 10(-4) in Finns), TP53INP1 (rs896854, p = 0.005), CDKAL1 (rs7756992, p = 7.0 × 10(-4); rs7754840, p = 8.8 × 10(-4)) and PROX1 (rs340874, p = 0.003) loci showed the strongest association in patients with high GADA. For type 1 diabetes, a strong association was seen for MTNR1B (rs10830963, p = 3.2 × 10(-6)) and HNF1A (rs2650000, p = 0.0012). CONCLUSIONS/INTERPRETATION LADA and adult-onset type 1 diabetes share genetic risk variants with type 2 diabetes, supporting the idea of a hybrid form of diabetes and distinguishing them from patients with classical young-onset type 1 diabetes.
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Affiliation(s)
- Mette K Andersen
- Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland,
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30
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Grarup N, Sandholt CH, Hansen T, Pedersen O. Genetic susceptibility to type 2 diabetes and obesity: from genome-wide association studies to rare variants and beyond. Diabetologia 2014; 57:1528-41. [PMID: 24859358 DOI: 10.1007/s00125-014-3270-4] [Citation(s) in RCA: 127] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2013] [Accepted: 04/22/2014] [Indexed: 12/29/2022]
Abstract
During the past 7 years, genome-wide association studies have shed light on the contribution of common genomic variants to the genetic architecture of type 2 diabetes, obesity and related intermediate phenotypes. The discoveries have firmly established more than 175 genomic loci associated with these phenotypes. Despite the tight correlation between type 2 diabetes and obesity, these conditions do not appear to share a common genetic background, since they have few genetic risk loci in common. The recent genetic discoveries do however highlight specific details of the interplay between the pathogenesis of type 2 diabetes, insulin resistance and obesity. The focus is currently shifting towards investigations of data from targeted array-based genotyping and exome and genome sequencing to study the individual and combined effect of low-frequency and rare variants in metabolic disease. Here we review recent progress as regards the concepts, methodologies and derived outcomes of studies of the genetics of type 2 diabetes and obesity, and discuss avenues to be investigated in the future within this research field.
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Affiliation(s)
- Niels Grarup
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, DIKU Building, Universitetsparken 1, 2100, Copenhagen Ø, Denmark,
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31
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Zhou Y, Park SY, Su J, Bailey K, Ottosson-Laakso E, Shcherbina L, Oskolkov N, Zhang E, Thevenin T, Fadista J, Bennet H, Vikman P, Wierup N, Fex M, Rung J, Wollheim C, Nobrega M, Renström E, Groop L, Hansson O. TCF7L2 is a master regulator of insulin production and processing. Hum Mol Genet 2014; 23:6419-31. [PMID: 25015099 PMCID: PMC4240194 DOI: 10.1093/hmg/ddu359] [Citation(s) in RCA: 135] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Genome-wide association studies have revealed >60 loci associated with type 2 diabetes (T2D), but the underlying causal variants and functional mechanisms remain largely elusive. Although variants in TCF7L2 confer the strongest risk of T2D among common variants by presumed effects on islet function, the molecular mechanisms are not yet well understood. Using RNA-sequencing, we have identified a TCF7L2-regulated transcriptional network responsible for its effect on insulin secretion in rodent and human pancreatic islets. ISL1 is a primary target of TCF7L2 and regulates proinsulin production and processing via MAFA, PDX1, NKX6.1, PCSK1, PCSK2 and SLC30A8, thereby providing evidence for a coordinated regulation of insulin production and processing. The risk T-allele of rs7903146 was associated with increased TCF7L2 expression, and decreased insulin content and secretion. Using gene expression profiles of 66 human pancreatic islets donors’, we also show that the identified TCF7L2-ISL1 transcriptional network is regulated in a genotype-dependent manner. Taken together, these results demonstrate that not only synthesis of proinsulin is regulated by TCF7L2 but also processing and possibly clearance of proinsulin and insulin. These multiple targets in key pathways may explain why TCF7L2 has emerged as the gene showing one of the strongest associations with T2D.
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Affiliation(s)
- Yuedan Zhou
- Department of Clinical Sciences, CRC, Lund University, Malmö 20502, Sweden
| | | | - Jing Su
- European Bioinformatics Institute, Functional Genomics, Hinxton, Cambridge CB10 1SD, UK
| | - Kathleen Bailey
- Department of Human Genetics, University of Chicago, IL 60637, USA
| | | | - Liliya Shcherbina
- Department of Clinical Sciences, CRC, Lund University, Malmö 20502, Sweden
| | - Nikolay Oskolkov
- Department of Clinical Sciences, CRC, Lund University, Malmö 20502, Sweden
| | - Enming Zhang
- Department of Clinical Sciences, CRC, Lund University, Malmö 20502, Sweden
| | - Thomas Thevenin
- Department of Clinical Sciences, CRC, Lund University, Malmö 20502, Sweden
| | - João Fadista
- Department of Clinical Sciences, CRC, Lund University, Malmö 20502, Sweden
| | - Hedvig Bennet
- Department of Clinical Sciences, CRC, Lund University, Malmö 20502, Sweden
| | - Petter Vikman
- Department of Clinical Sciences, CRC, Lund University, Malmö 20502, Sweden
| | - Nils Wierup
- Department of Clinical Sciences, CRC, Lund University, Malmö 20502, Sweden
| | - Malin Fex
- Department of Clinical Sciences, CRC, Lund University, Malmö 20502, Sweden
| | - Johan Rung
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala 75185, Sweden and
| | - Claes Wollheim
- Department of Clinical Sciences, CRC, Lund University, Malmö 20502, Sweden, Department of Cell Physiology and Metabolism, Université de Genève, University Medical Centre, 1 rue Michel-Servet, Geneva 4 1211, Switzerland
| | - Marcelo Nobrega
- Department of Human Genetics, University of Chicago, IL 60637, USA
| | - Erik Renström
- Department of Clinical Sciences, CRC, Lund University, Malmö 20502, Sweden
| | - Leif Groop
- Department of Clinical Sciences, CRC, Lund University, Malmö 20502, Sweden
| | - Ola Hansson
- Department of Clinical Sciences, CRC, Lund University, Malmö 20502, Sweden,
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Fang N, Zhang W, Xu S, Lin H, Wang Z, Liu H, Fang Q, Li C, Peng L, Lou J. TRIB3 alters endoplasmic reticulum stress-induced β-cell apoptosis via the NF-κB pathway. Metabolism 2014; 63:822-30. [PMID: 24746137 DOI: 10.1016/j.metabol.2014.03.003] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2013] [Revised: 02/06/2014] [Accepted: 03/04/2014] [Indexed: 12/13/2022]
Abstract
OBJECTIVE To examine the effect of TRIB3 on endoplasmic reticulum stress induced β-cell apoptosis and to investigate the mechanism with a specific emphasis on the role of NF-κB pathway. MATERIALS/METHODS We investigated the effect of TRIB3 on ER stress-induced β-cell apoptosis in INS-1 cells and primary rodent islets. The potential role of TRIB3 in ER stress inducer thapsigargin (Tg)-induced β-cell apoptosis was assessed using overexpression and siRNA knockdown approaches. Inducible TRIB3 β-cells, regulated by the tet-on system, were used for sub-renal capsule transplantation in streptozotocin (STZ)-diabetic mice, to study the effect of TRIB3 on ER stress-induced β-cell apoptosis in vivo. Apoptosis was determined by TUNEL staining both in vivo and in vitro, while the molecular mechanisms of NF-κB activation were investigated. RESULTS TRIB3 was induced in ER-stressed INS-1 cells and rodent islets, and its overexpression was accompanied by increased β-cell apoptosis. Specifically, TRIB3 overexpression enhanced Tg-induced INS-1 derived β-cell apoptosis both in vitro and in sub-renal capsular transplantation animal model. Additionally, knockdown of Trib3 blocked Tg-induced apoptosis. Mechanistically, the induction of TRIB3 during ER stress resulted in the activation of NF-κB and aggravated INS-1 derived β-cell apoptosis, while inhibiting the NF-κB pathway significantly abrogated this response and prevented β-cell apoptosis, both in vitro and in sub-renal capsular transplantation animal model. CONCLUSION TRIB3 mediated ER stress-induced β-cell apoptosis via the NF-κB pathway.
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Affiliation(s)
- Ni Fang
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, P. R. China; Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, P. R. China
| | - Wenjian Zhang
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, P. R. China
| | - Shiqing Xu
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, P. R. China
| | - Hua Lin
- Department of Gynaecology and Obstetrics, China-Japan Friendship Hospital, Beijing 100029, P. R. China
| | - Zai Wang
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, P. R. China
| | - Honglin Liu
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, P. R. China
| | - Qing Fang
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, P. R. China
| | - Chenghui Li
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, P. R. China
| | - Liang Peng
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, P. R. China.
| | - Jinning Lou
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, P. R. China; Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, P. R. China.
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Qin J, Fang N, Lou J, Zhang W, Xu S, Liu H, Fang Q, Wang Z, Liu J, Men X, Peng L, Chen L. TRB3 is involved in free fatty acid-induced INS-1-derived cell apoptosis via the protein kinase C δ pathway. PLoS One 2014; 9:e96089. [PMID: 24824999 PMCID: PMC4019472 DOI: 10.1371/journal.pone.0096089] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Accepted: 04/02/2014] [Indexed: 12/16/2022] Open
Abstract
Chronic exposure to free fatty acids (FFAs) may induce β cell apoptosis in type 2 diabetes. However, the precise mechanism by which FFAs trigger β cell apoptosis is still unclear. Tribbles homolog 3 (TRB3) is a pseudokinase inhibiting Akt, a key mediator of insulin signaling, and contributes to insulin resistance in insulin target tissues. This paper outlined the role of TRB3 in FFAs-induced INS-1 β cell apoptosis. TRB3 was promptly induced in INS-1 cells after stimulation by FFAs, and this was accompanied by enhanced INS-1 cell apoptosis. The overexpression of TRB3 led to exacerbated apoptosis triggered by FFAs in INS-1-derived cell line and the subrenal capsular transplantation animal model. In contrast, cell apoptosis induced by FFAs was attenuated when TRB3 was knocked down. Moreover, we observed that activation and nuclear accumulation of protein kinase C (PKC) δ was enhanced by upregulation of TRB3. Preventing PKCδ nuclear translocation and PKCδ selective antagonist both significantly lessened the pro-apoptotic effect. These findings suggest that TRB3 was involved in lipoapoptosis of INS-1 β cell, and thus could be an attractive pharmacological target in the prevention and treatment of T2DM.
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Affiliation(s)
- Jun Qin
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Ni Fang
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Jinning Lou
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Wenjian Zhang
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Shiqing Xu
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Honglin Liu
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Qing Fang
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Zai Wang
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Jiang Liu
- Department of Neurosurgery, China-Japan Friendship Hospital, Beijing, China
| | - Xiuli Men
- Department of Pathophysiology, North China Coal Medical University, Tangshan, China
| | - Liang Peng
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Li Chen
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, Shandong, China
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Kameswaran V, Bramswig NC, McKenna LB, Penn M, Schug J, Hand NJ, Chen Y, Choi I, Vourekas A, Won KJ, Liu C, Vivek K, Naji A, Friedman JR, Kaestner KH. Epigenetic regulation of the DLK1-MEG3 microRNA cluster in human type 2 diabetic islets. Cell Metab 2014; 19:135-45. [PMID: 24374217 PMCID: PMC3932527 DOI: 10.1016/j.cmet.2013.11.016] [Citation(s) in RCA: 269] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2013] [Revised: 09/25/2013] [Accepted: 11/15/2013] [Indexed: 01/09/2023]
Abstract
Type 2 diabetes mellitus (T2DM) is a complex disease characterized by the inability of the insulin-producing β cells in the endocrine pancreas to overcome insulin resistance in peripheral tissues. To determine if microRNAs are involved in the pathogenesis of human T2DM, we sequenced the small RNAs of human islets from diabetic and nondiabetic organ donors. We identified a cluster of microRNAs in an imprinted locus on human chromosome 14q32 that is highly and specifically expressed in human β cells and dramatically downregulated in islets from T2DM organ donors. The downregulation of this locus strongly correlates with hypermethylation of its promoter. Using HITS-CLIP for the essential RISC-component Argonaute, we identified disease-relevant targets of the chromosome 14q32 microRNAs, such as IAPP and TP53INP1, that cause increased β cell apoptosis upon overexpression in human islets. Our results support a role for microRNAs and their epigenetic control by DNA methylation in the pathogenesis of T2DM.
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Affiliation(s)
- Vasumathi Kameswaran
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Nuria C Bramswig
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Lindsay B McKenna
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Melinda Penn
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Jonathan Schug
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Nicholas J Hand
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Ying Chen
- Genomics and Computational Biology Graduate Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Inchan Choi
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Anastassios Vourekas
- Department of Pathology and Laboratory Medicine, Division of Neuropathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Kyoung-Jae Won
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Chengyang Liu
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Kumar Vivek
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Ali Naji
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Joshua R Friedman
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Klaus H Kaestner
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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Trombetta M, Bonetti S, Boselli ML, Miccoli R, Trabetti E, Malerba G, Pignatti PF, Bonora E, Del Prato S, Bonadonna RC. PPARG2 Pro12Ala and ADAMTS9 rs4607103 as "insulin resistance loci" and "insulin secretion loci" in Italian individuals. The GENFIEV study and the Verona Newly Diagnosed Type 2 Diabetes Study (VNDS) 4. Acta Diabetol 2013; 50:401-8. [PMID: 23161442 DOI: 10.1007/s00592-012-0443-9] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2012] [Accepted: 11/05/2012] [Indexed: 12/16/2022]
Abstract
We investigated cross-sectionally whether the type 2 diabetes (T2DM) risk alleles of rs1801282 (PPARG2) and rs4607103 (ADAMTS9) were associated with T2DM and/or insulin sensitivity (IS) and beta cell function (βF) in Italians without and with newly diagnosed T2DM. In 676 nondiabetic subjects (336 NGR and 340 IGR) from the GENFIEV study and in 597 patients from the Verona Newly Diagnosed Type 2 Diabetes Study (VNDS), we (1) genotyped rs1801282 and rs4607103, (2) assessed βF by C-peptide/glucose modeling after OGTT, and (3) assessed IS by HOMA-IR in both studies and by euglycemic insulin clamp in VNDS only. Logistic, linear, and two-stage least squares regression analyses were used to test (a) genetic associations with T2DM and with pathophysiological phenotypes, (b) causal relationships of the latter ones with T2DM by a Mendelian randomization design. Both SNPs were associated with T2DM. The rs4607103 risk allele was associated to impaired βF (p < 0.01) in the GENFIEV study and in both cohorts combined. The rs1801282 genotype was associated with IS both in the GENFIEV study (p < 0.03) and in the VNDS (p < 0.03), whereas rs4607103 did so in the VNDS only (p = 0.01). In a Mendelian randomization design, both HOMA-IR (instrumental variables: rs1801282, rs4607103) and βF (instrumental variable: rs4607103) were related to T2DM (p < 0.03-0.01 and p < 0.03, respectively). PPARG2 and ADAMTS9 variants are both associated with T2DM and with insulin resistance, whereas only ADAMTS9 may be related to βF. Thus, at least in Italians, they may be considered bona fide "insulin resistance genes".
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Affiliation(s)
- M Trombetta
- Division of Endocrinology and Metabolism, Department of Medicine, Ospedale Civile Maggiore, University of Verona, Piazzale Stefani 1, 37126, Verona, Italy.
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c-Abl mediates angiotensin II-induced apoptosis in podocytes. J Mol Histol 2013; 44:597-608. [PMID: 23515840 DOI: 10.1007/s10735-013-9505-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2012] [Accepted: 03/14/2013] [Indexed: 10/27/2022]
Abstract
Angiotensin II (Ang II) has been reported to cause podocyte apoptosis in rats both in vivo and in vitro studies. However, the underlying mechanisms are poorly understood. In the present study, we investigated the role of the nonreceptor tyrosine kinase c-Abl in Ang II-induced podocyte apoptosis. Male Sprague-Dawley rats in groups of 12 were administered either Ang II (400 kg/kg/min) or Ang II + STI-571 (50 mg/kg/day) by osmotic minipumps. In addition, 12 rats-receiving normal saline served as the control. Glomeruli c-Abl expression was carried out by real time PCR, Western blotting and immunolabeled, and occurrence of apoptosis was carried out by TUNEL staining and transmission electron microscopic analysis. In vitro studies, conditionally immortalized mouse podocytes were treated with Ang II (10(-9)-10(-6) M) in the presence or absence of either c-Abl inhibitor, Src-I1, specific c-Abl siRNA, or c-Abl plasmid alone. Quantification of podocyte c-Abl expression and c-Abl phosphorylation at Y245 and Y412 was carried out by real time PCR, Western blotting and immunofluorescence imaging. The nuclear c-Abl and p53 were quantified by co-immunoprecipitation and Western blotting studies. Podocyte apoptosis was analysed by flow cytometry and Hoechst-33342 staining. c-Abl expression was demonstrated in rat kidney podocytes in vivo and cultured mouse podocytes in vitro. Ang II-receiving rats displayed enhanced podocyte c-Abl expression. And Ang II significantly stimulated c-Abl expression in cultured podocytes. Furthermore Ang II upregulated podocyte c-Abl phosphorylation at Y245 and Y412. Ang II also induced an increase of nuclear p53 protein and nuclear c-Abl-p53 complexes in podocytes and podocyte apoptosis. Down-regulation of c-Abl expression by c-Abl inhibitor (Src-I1) as well as specific siRNA inhibited Ang II-induced podocyte apoptosis; conversely, podoctyes transfected with c-Abl plasmid displayed enhanced apoptosis. These findings indicate that c-Abl may mediates Ang II-induced podocyte apoptosis, and inhibition of c-Abl expression can protect podocytes from Ang II-induced injury.
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Liu Y, Li Z, Zhang M, Deng Y, Yi Z, Shi T. Exploring the pathogenetic association between schizophrenia and type 2 diabetes mellitus diseases based on pathway analysis. BMC Med Genomics 2013; 6 Suppl 1:S17. [PMID: 23369358 PMCID: PMC3552677 DOI: 10.1186/1755-8794-6-s1-s17] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
BACKGROUND Schizophrenia (SCZ) and type 2 diabetes mellitus (T2D) are both complex diseases. Accumulated studies indicate that schizophrenia patients are prone to present the type 2 diabetes symptoms, but the potential mechanisms behind their association remain unknown. Here we explored the pathogenetic association between SCZ and T2D based on pathway analysis and protein-protein interaction. RESULTS With sets of prioritized susceptibility genes for SCZ and T2D, we identified significant pathways (with adjusted p-value < 0.05) specific for SCZ or T2D and for both diseases based on pathway enrichment analysis. We also constructed a network to explore the crosstalk among those significant pathways. Our results revealed that some pathways are shared by both SCZ and T2D diseases through a number of susceptibility genes. With 382 unique susceptibility proteins for SCZ and T2D, we further built a protein-protein interaction network by extracting their nearest interacting neighbours. Among 2,104 retrieved proteins, 364 of them were found simultaneously interacted with susceptibility proteins of both SCZ and T2D, and proposed as new candidate risk factors for both diseases. Literature mining supported the potential association of partial new candidate proteins with both SCZ and T2D. Moreover, some proteins were hub proteins with high connectivity and interacted with multiple proteins involved in both diseases, implying their pleiotropic effects for the pathogenic association. Some of these hub proteins are the components of our identified enriched pathways, including calcium signaling, g-secretase mediated ErbB4 signaling, adipocytokine signaling, insulin signaling, AKT signaling and type II diabetes mellitus pathways. Through the integration of multiple lines of information, we proposed that those signaling pathways, which contain susceptibility genes for both diseases, could be the key pathways to bridge SCZ and T2D. AKT could be one of the important shared components and may play a pivotal role to link both of the pathogenetic processes. CONCLUSIONS Our study is the first network and pathway-based systematic analysis for SCZ and T2D, and provides the general pathway-based view of pathogenetic association between two diseases. Moreover, we identified a set of candidate genes potentially contributing to the linkage between these two diseases. This research offers new insights into the potential mechanisms underlying the co-occurrence of SCZ and T2D, and thus, could facilitate the inference of novel hypotheses for the co-morbidity of the two diseases. Some etiological factors that exert pleiotropic effects shared by the significant pathways of two diseases may have important implications for the diseases and could be therapeutic intervention targets.
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Affiliation(s)
- Yanli Liu
- Center for Bioinformatics and Computational Biology, and The Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China
| | - Zezhi Li
- Department of Neurology, Shanghai Changhai Hospital, Secondary Military Medical University, 168 Changhai Road, Shanghai, China
| | - Meixia Zhang
- Department of Ophthalmology, West China Hospital, Sichuan University 37 Guoxuexiang, Chengdu, Sichuan, 610041, China
| | - Youping Deng
- Rush University Cancer Center, Department of Internal Medicine, Rush University Medical Center, Chicago, IL 60612, USA
| | - Zhenghui Yi
- Schizophrenia Program, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, 600 Wan Ping Nan Road, Shanghai 200030, China
| | - Tieliu Shi
- Center for Bioinformatics and Computational Biology, and The Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China
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Renström E. Impact of transcription factor 7-like 2 (TCF7L2) on pancreatic islet function and morphology in mice and men. Diabetologia 2012; 55:2559-2561. [PMID: 22864463 PMCID: PMC3433659 DOI: 10.1007/s00125-012-2659-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2012] [Accepted: 06/22/2012] [Indexed: 12/22/2022]
Abstract
Common genetic variations in the gene encoding transcription factor 7-like 2 (TCF7L2) reveal the strongest association with type 2-diabetes known to date. These lead to impaired insulin production and output, but the mechanisms of disease remain incompletely known. In this issue of Diabetologia, two publications provide new insights into TCF7L2-dependent diabetes.
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Affiliation(s)
- E Renström
- Lund University Diabetes Center, Inga-Marie Nilssons gata 53 floor 3, 205 02, Malmö, Sweden.
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Frietze S, Wang R, Yao L, Tak YG, Ye Z, Gaddis M, Witt H, Farnham PJ, Jin VX. Cell type-specific binding patterns reveal that TCF7L2 can be tethered to the genome by association with GATA3. Genome Biol 2012; 13:R52. [PMID: 22951069 PMCID: PMC3491396 DOI: 10.1186/gb-2012-13-9-r52] [Citation(s) in RCA: 85] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2012] [Revised: 03/09/2012] [Accepted: 05/25/2012] [Indexed: 12/23/2022] Open
Abstract
Background The TCF7L2 transcription factor is linked to a variety of human diseases, including type 2 diabetes and cancer. One mechanism by which TCF7L2 could influence expression of genes involved in diverse diseases is by binding to distinct regulatory regions in different tissues. To test this hypothesis, we performed ChIP-seq for TCF7L2 in six human cell lines. Results We identified 116,000 non-redundant TCF7L2 binding sites, with only 1,864 sites common to the six cell lines. Using ChIP-seq, we showed that many genomic regions that are marked by both H3K4me1 and H3K27Ac are also bound by TCF7L2, suggesting that TCF7L2 plays a critical role in enhancer activity. Bioinformatic analysis of the cell type-specific TCF7L2 binding sites revealed enrichment for multiple transcription factors, including HNF4alpha and FOXA2 motifs in HepG2 cells and the GATA3 motif in MCF7 cells. ChIP-seq analysis revealed that TCF7L2 co-localizes with HNF4alpha and FOXA2 in HepG2 cells and with GATA3 in MCF7 cells. Interestingly, in MCF7 cells the TCF7L2 motif is enriched in most TCF7L2 sites but is not enriched in the sites bound by both GATA3 and TCF7L2. This analysis suggested that GATA3 might tether TCF7L2 to the genome at these sites. To test this hypothesis, we depleted GATA3 in MCF7 cells and showed that TCF7L2 binding was lost at a subset of sites. RNA-seq analysis suggested that TCF7L2 represses transcription when tethered to the genome via GATA3. Conclusions Our studies demonstrate a novel relationship between GATA3 and TCF7L2, and reveal important insights into TCF7L2-mediated gene regulation.
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Affiliation(s)
- Seth Frietze
- Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA
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Savic D, Bell GI, Nobrega MA. An in vivo cis-regulatory screen at the type 2 diabetes associated TCF7L2 locus identifies multiple tissue-specific enhancers. PLoS One 2012; 7:e36501. [PMID: 22590553 PMCID: PMC3349716 DOI: 10.1371/journal.pone.0036501] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2012] [Accepted: 04/02/2012] [Indexed: 12/21/2022] Open
Abstract
Genome-wide association studies (GWAS) have repeatedly shown an association between non-coding variants in the TCF7L2 locus and risk for type 2 diabetes (T2D), implicating a role for cis-regulatory variation within this locus in disease etiology. Supporting this hypothesis, we previously localized complex regulatory activity to the TCF7L2 T2D-associated interval using an in vivo bacterial artificial chromosome (BAC) enhancer-trapping reporter strategy. To follow-up on this broad initial survey of the TCF7L2 regulatory landscape, we performed a fine-mapping enhancer scan using in vivo mouse transgenic reporter assays. We functionally interrogated approximately 50% of the sequences within the T2D-associated interval, utilizing sequence conservation within this 92-kb interval to determine the regulatory potential of all evolutionary conserved sequences that exhibited conservation to the non-eutherian mammal opossum. Included in this study was a detailed functional interrogation of sequences spanning both protective and risk alleles of single nucleotide polymorphism (SNP) rs7903146, which has exhibited allele-specific enhancer function in pancreatic beta cells. Using these assays, we identified nine segments regulating various aspects of the TCF7L2 expression profile and that constitute nearly 70% of the sequences tested. These results highlight the regulatory complexity of this interval and support the notion that a TCF7L2 cis-regulatory disruption leads to T2D predisposition.
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Affiliation(s)
- Daniel Savic
- Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America.
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Ansari D, Chen BC, Dong L, Zhou MT, Andersson R. Pancreatic cancer: translational research aspects and clinical implications. World J Gastroenterol 2012; 18:1417-1424. [PMID: 22509073 PMCID: PMC3319937 DOI: 10.3748/wjg.v18.i13.1417] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2011] [Revised: 12/29/2011] [Accepted: 01/18/2012] [Indexed: 02/06/2023] Open
Abstract
Despite improvements in surgical techniques and adjuvant chemotherapy, the overall mortality rates in pancreatic cancer have generally remained relatively unchanged and the 5-year survival rate is actually below 2%. This paper will address the importance of achieving an early diagnosis and identifying markers for prognosis and response to therapy such as genes, proteins, microRNAs or epigenetic modifications. However, there are still major hurdles when translating investigational biomarkers into routine clinical practice. Furthermore, novel ways of secondary screening in high-risk individuals, such as artificial neural networks and modern imaging, will be discussed. Drug resistance is ubiquitous in pancreatic cancer. Several mechanisms of drug resistance have already been revealed, including human equilibrative nucleoside transporter-1 status, multidrug resistance proteins, aberrant signaling pathways, microRNAs, stromal influence, epithelial-mesenchymal transition-type cells and recently the presence of cancer stem cells/cancer-initiating cells. These factors must be considered when developing more customized types of intervention ("personalized medicine"). In the future, multifunctional nanoparticles that combine a specific targeting agent, an imaging probe, a cell-penetrating agent, a biocompatible polymer and an anti-cancer drug may become valuable for the management of patients with pancreatic cancer.
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Affiliation(s)
- D Meyre
- McMaster University, Hamilton, ON L8S 4L8, Canada.
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