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BMC Endocrine Disorders

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Open Access 01-12-2021 | Obesity | Research article

Investigation of candidate genes and mechanisms underlying obesity associated type 2 diabetes mellitus using bioinformatics analysis and screening of small drug molecules

Authors: G. Prashanth, Basavaraj Vastrad, Anandkumar Tengli, Chanabasayya Vastrad, Iranna Kotturshetti

Published in: BMC Endocrine Disorders | Issue 1/2021

Abstract

Background

Obesity associated type 2 diabetes mellitus is a metabolic disorder ; however, the etiology of obesity associated type 2 diabetes mellitus remains largely unknown. There is an urgent need to further broaden the understanding of the molecular mechanism associated in obesity associated type 2 diabetes mellitus.

Methods

To screen the differentially expressed genes (DEGs) that might play essential roles in obesity associated type 2 diabetes mellitus, the publicly available expression profiling by high throughput sequencing data (GSE143319) was downloaded and screened for DEGs. Then, Gene Ontology (GO) and REACTOME pathway enrichment analysis were performed. The protein - protein interaction network, miRNA - target genes regulatory network and TF-target gene regulatory network were constructed and analyzed for identification of hub and target genes. The hub genes were validated by receiver operating characteristic (ROC) curve analysis and RT- PCR analysis. Finally, a molecular docking study was performed on over expressed proteins to predict the target small drug molecules.

Results

A total of 820 DEGs were identified between healthy obese and metabolically unhealthy obese, among 409 up regulated and 411 down regulated genes. The GO enrichment analysis results showed that these DEGs were significantly enriched in ion transmembrane transport, intrinsic component of plasma membrane, transferase activity, transferring phosphorus-containing groups, cell adhesion, integral component of plasma membrane and signaling receptor binding, whereas, the REACTOME pathway enrichment analysis results showed that these DEGs were significantly enriched in integration of energy metabolism and extracellular matrix organization. The hub genes CEBPD, TP73, ESR2, TAB1, MAP 3K5, FN1, UBD, RUNX1, PIK3R2 and TNF, which might play an essential role in obesity associated type 2 diabetes mellitus was further screened.

Conclusions

The present study could deepen the understanding of the molecular mechanism of obesity associated type 2 diabetes mellitus, which could be useful in developing therapeutic targets for obesity associated type 2 diabetes mellitus.

Pulgaron ER, Delamater AM. Obesity and type 2 diabetes in children: epidemiology and treatment. Curr Diab Rep. 2014;14(8):508. https://doi.org/10.1007/s11892-014-0508-y.CrossRefPubMedPubMedCentral

Taylor R. Type 2 diabetes: etiology and reversibility. Diab Care. 2013;36(4):1047–55. https://doi.org/10.2337/dc12-1805.CrossRef

Catalán V, Gómez-Ambrosi J, Rodríguez A, Ramírez B, Rotellar F, Valentí V, Silva C, Gil MJ, Salvador J, Frühbeck G. Increased circulating and visceral adipose tissue expression levels of YKL-40 in obesity-associated type 2 diabetes are related to inflammation: impact of conventional weight loss and gastric bypass. J Clin Endocrinol Metab. 2011;96(1):200–9. https://doi.org/10.1210/jc.2010-0994.CrossRefPubMed

Fukushima A, Lopaschuk GD. Acetylation control of cardiac fatty acid β-oxidation and energy metabolism in obesity, diabetes, and heart failure. Biochim Biophys Acta. 2016;1862(12):2211–20. https://doi.org/10.1016/j.bbadis.2016.07.020.CrossRefPubMed

Pugazhenthi S, Qin L, Reddy PH. Common neurodegenerative pathways in obesity, diabetes, and Alzheimer's disease. Biochim Biophys Acta Mol Basis Dis. 2017;1863(5):1037–45. https://doi.org/10.1016/j.bbadis.2016.04.017.CrossRefPubMed

Chagnac A, Zingerman B, Rozen-Zvi B, Herman-Edelstein M. Consequences of Glomerular Hyperfiltration: The Role of Physical Forces in the Pathogenesis of Chronic Kidney Disease in Diabetes and Obesity. Nephron. 2019;143(1):38–42. https://doi.org/10.1159/000499486.CrossRefPubMed

Cheung N, Wong TY. Obesity and eye diseases. Surv Ophthalmol. 2007;52(2):180–95. https://doi.org/10.1016/j.survophthal.2006.12.003.CrossRefPubMedPubMedCentral

Temelkova-Kurktschiev T, Stefanov T. Lifestyle and genetics in obesity and type 2 diabetes. Exp Clin Endocrinol Diabetes. 2012;120(1):1–6. https://doi.org/10.1055/s-0031-1285832.CrossRefPubMed

Wen X, Qian C, Zhang Y, Wu R, Lu L, Zhu C, Cheng X, Cui R, You H, Mei F, et al. Key pathway and gene alterations in the gastric mucosa associated with obesity and obesity-related diabetes. J Cell Biochem. 2019;120(4):6763–71. https://doi.org/10.1002/jcb.27976.CrossRefPubMed

10.

Kruse R, Vienberg SG, Vind BF, Andersen B, Højlund K. Effects of insulin and exercise training on FGF21, its receptors and target genes in obesity and type 2 diabetes. Diabetologia. 2017;60(10):2042–51. https://doi.org/10.1007/s00125-017-4373-5.CrossRefPubMed

11.

Davison LJ, Holder A, Catchpole B, O'Callaghan CA. The Canine POMC Gene, Obesity in Labrador Retrievers and Susceptibility to Diabetes Mellitus. J Vet Intern Med. 2017;31(2):343–8. https://doi.org/10.1111/jvim.14636.CrossRefPubMedPubMedCentral

12.

Huang X, Liu G, Guo J, Su Z. The PI3K/AKT pathway in obesity and type 2 diabetes. Int J Biol Sci. 2018;14(11):1483–96. https://doi.org/10.7150/ijbs.27173.CrossRefPubMedPubMedCentral

13.

Gurzov EN, Stanley WJ, Pappas EG, Thomas HE, Gough DJ. The JAK/STAT pathway in obesity and diabetes. FEBS J. 2016;283(16):3002–15. https://doi.org/10.1111/febs.13709.CrossRefPubMed

14.

Xin Y, Kim J, Okamoto H, Ni M, Wei Y, Adler C, Murphy AJ, Yancopoulos GD, Lin C, Gromada J. RNA Sequencing of Single Human Islet Cells Reveals Type 2 Diabetes Genes. Cell Metab. 2016;24(4):608–15. https://doi.org/10.1016/j.cmet.2016.08.018.CrossRefPubMed

15.

Clough E, Barrett T. The Gene Expression Omnibus Database. Methods Mol Biol. 2016;1418:93–110. https://doi.org/10.1007/978-1-4939-3578-9_5.CrossRefPubMedPubMedCentral

16.

Ding X, Iyer R, Novotny C, Metzger D, Zhou HH, Smith GI, Yoshino M, Yoshino J, Klein S, Swaminath G, et al. Inhibition of Grb14, a negative modulator of insulin signaling, improves glucose homeostasis without causing cardiac dysfunction. Sci Rep. 2020;10(1):3417. https://doi.org/10.1038/s41598-020-60290-1.CrossRefPubMedPubMedCentral

17.

Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, Smyth GK. Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43(7):e47. https://doi.org/10.1093/nar/gkv007.CrossRefPubMedPubMedCentral

18.

Chen J, Bardes EE, Aronow BJ, Jegga AG. ToppGene Suite for gene list enrichment analysis and candidate gene prioritization. Nucleic Acids Res. 2009; 37(Web Server issue):W305-W311. doi:https://doi.org/10.1093/nar/gkp427

19.

Thomas PD. The Gene Ontology and the Meaning of Biological Function. Methods Mol Biol. 2017;1446:15–24. https://doi.org/10.1007/978-1-4939-3743-1_2.CrossRefPubMedPubMedCentral

20.

Fabregat A, Jupe S, Matthews L, Sidiropoulos K, Gillespie M, Garapati P, Haw R, Jassal B, Korninger F, May B, et al. The Reactome Pathway Knowledgebase. Nucleic Acids Res. 2018;46(D1):D649–55. https://doi.org/10.1093/nar/gkx1132.CrossRefPubMed

21.

Orchard S, Kerrien S, Abbani S, Aranda B, Bhate J, Bidwell S, Bridge A, Briganti L, Brinkman FS, Cesareni G, et al. Protein interaction data curation: the International Molecular Exchange (IMEx) consortium. Nat Methods. 2012;9(4):345–50. https://doi.org/10.1038/nmeth.1931.CrossRefPubMedPubMedCentral

22.

Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13(11):2498–504. https://doi.org/10.1101/gr.1239303.CrossRefPubMedPubMedCentral

23.

Przulj N, Wigle DA, Jurisica I. Functional topology in a network of protein interactions. Bioinformatics. 2004;20(3):340–8. https://doi.org/10.1093/bioinformatics/btg415.CrossRefPubMed

24.

Nguyen TP, Liu WC, Jordán F. Inferring pleiotropy by network analysis: linked diseases in the human PPI network. BMC Syst Biol. 2011; 5:179. Published 2011 Oct 31. doi: https://doi.org/10.1186/1752-0509-5-179

25.

Shi Z, Zhang B. Fast network centrality analysis using GPUs. BMC Bioinformatics. 2011;12:149. https://doi.org/10.1186/1471-2105-12-149.CrossRefPubMedPubMedCentral

26.

Fadhal E, Gamieldien J, Mwambene EC. Protein interaction networks as metric spaces: a novel perspective on distribution of hubs. BMC Syst Biol. 2014;8:6. https://doi.org/10.1186/1752-0509-8-6.CrossRefPubMedPubMedCentral

27.

Zaki N, Efimov D, Berengueres J. Protein complex detection using interaction reliability assessment and weighted clustering coefficient. BMC Bioinform. 2013;14:163. https://doi.org/10.1186/1471-2105-14.CrossRef

28.

Fan Y, Xia J. miRNet-Functional Analysis and Visual Exploration of miRNA-Target Interactions in a Network Context. Methods Mol Biol. 2018;1819:215–33. https://doi.org/10.1007/978-1-4939-8618-7_10.CrossRefPubMed

29.

Zhou G, Soufan O, Ewald J, Hancock REW, Basu N, Xia J. NetworkAnalyst 3.0: a visual analytics platform for comprehensive gene expression profiling and meta-analysis. Nucleic Acids Res. 2019;47:W234–41. https://doi.org/10.1093/nar/gkz240.CrossRefPubMedPubMedCentral

30.

Robin X, Turck N, Hainard A, Tiberti N, Lisacek F, Sanchez JC, Müller M. pROC: an open-source package for R and S+ to analyze and compare ROC curves. BMC Bioinform. 2011;12:77. https://doi.org/10.1186/1471-2105-12-77.CrossRef

31.

Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25(4):402–8. https://doi.org/10.1006/meth.2001.CrossRefPubMed

32.

Naim MJ, Alam O, Alam MJ, Hassan MQ, Siddiqui N, Naidu VGM, Alam MI. Design, synthesis and molecular docking of thiazolidinedione based benzene sulphonamide derivatives containing pyrazole core as potential anti-diabetic agents. Bioorg Chem. 2018;76:98–112. https://doi.org/10.1016/j.bioorg.2017.11.010.CrossRefPubMed

33.

Mohammadi-Khanaposhtani M, Rezaei S, Khalifeh R, Imanparast S, Faramarzi MA, Bahadorikhalili S, Safavi M, Bandarian F, Nasli Esfahani E, Mahdavi M, et al. Design, synthesis, docking study, α-glucosidase inhibition, and cytotoxic activities of acridine linked to thioacetamides as novel agents in treatment of type 2 diabetes. Bioorg Chem. 2018;80:288–95. https://doi.org/10.1016/j.bioorg.2018.06.035.CrossRefPubMed

34.

Rojas LB, Gomes MB. Metformin: an old but still the best treatment for type 2 diabetes. Diabetol Metab Syndr. 2013;5(1):6. https://doi.org/10.1186/1758-5996-5-6.CrossRefPubMedPubMedCentral

35.

Thakral S, Narang R, Kumar M, Singh V. Synthesis, molecular docking and molecular dynamic simulation studies of 2-chloro-5-[(4-chlorophenyl) sulfamoyl]-N-(alkyl/aryl)-4-nitrobenzamide derivatives as antidiabetic agents. BMC Chem. 2020;14(1):1–6. https://doi.org/10.1186/s13065-020-00703-4.CrossRef

36.

Srikanth Kumar K, Lakshmana Rao A, Basaveswara Rao MV. Design, synthesis, biological evaluation and molecular docking studies of novel 3-substituted-5-[(indol-3-yl)methylene]-thiazolidine-2,4-dione derivatives. Heliyon. 2018;4(9):e00807. https://doi.org/10.1016/j.heliyon.2018.e00807.CrossRefPubMedPubMedCentral

37.

Mohammad S, Ahmad J. Management of obesity in patients with type 2 diabetes mellitus in primary care. Diab Metab Syndr. 2016;10(3):171–81. https://doi.org/10.1016/j.dsx.2016.01.017.CrossRef

38.

Rao M, Gao C, Xu L, Jiang L, Zhu J, Chen G, Law BYK, Xu Y. Effect of Inulin-Type Carbohydrates on Insulin Resistance in Patients with Type 2 Diabetes and Obesity: A Systematic Review and Meta-Analysis. J Diab Res. 2019:5101423. https://doi.org/10.1155/2019/5101423.

39.

Al-Sulaiti H, Diboun I, Agha MV, et al. Metabolic signature of obesity-associated insulin resistance and type 2 diabetes. J Transl Med. 2019;17(1):348. https://doi.org/10.1186/s12967-019-2096-8.CrossRefPubMedPubMedCentral

40.

Sugimura K, Tanaka T, Tanaka Y, Takano H, Kanagawa K, Sakamoto N, Ikemoto S, Kawashima H, Nakatani T. Decreased sulfotransferase SULT1C2 gene expression in DPT-induced polycystic kidney. Kidney Int. 2002;62(3):757–62. https://doi.org/10.1046/j.1523-1755.2002.00512.x.CrossRefPubMed

41.

Zhang JY, Wang M, Tian L, Genovese G, Yan P, Wilson JG, Thadhani R, Mottl AK, Appel GB, Bick AG, et al. UBD modifies APOL1-induced kidney disease risk. Proc Natl Acad Sci U S A. 2018;115(13):3446–51. https://doi.org/10.1073/pnas.1716113115.CrossRefPubMedPubMedCentral

42.

Ma ZJ, Sun P, Guo G, Zhang R, Chen LM. Association of the HLA-DQA1 and HLA-DQB1 Alleles in Type 2 Diabetes Mellitus and Diabetic Nephropathy in the Han Ethnicity of China. J Diab Res. 2013;2013:452537. https://doi.org/10.1155/2013/452537.CrossRef

43.

Kołodziejski PA, Pruszyńska-Oszmałek E, Korek E, Sassek M, Szczepankiewicz D, Kaczmarek P, Nogowski L, Maćkowiak P, Nowak KW, Krauss H, et al. Serum levels of spexin and kisspeptin negatively correlate with obesity and insulin resistance in women. Physiol Res. 2018;67(1):45–56. https://doi.org/10.33549/physiolres.933467.CrossRefPubMed

44.

Onat A, Can G, Hergenç G, Yazici M, Karabulut A, Albayrak S. Serum apolipoprotein B predicts dyslipidemia, metabolic syndrome and, in women, hypertension and diabetes, independent of markers of central obesity and inflammation. Int J Obes (Lond). 2007;31(7):1119–25. https://doi.org/10.1038/sj.ijo.0803552.CrossRef

45.

Ravn LS, Hofman-Bang J, Dixen U, Larsen SO, Jensen G, Haunsø S, Svendsen JH, Christiansen M. Relation of 97T polymorphism in KCNE5 to risk of atrial fibrillation. Am J Cardiol. 2005;96(3):405–7. https://doi.org/10.1016/j.amjcard.2005.03.086.CrossRefPubMed

46.

Man W, Gu J, Wang B, Zhang M, Hu J, Lin J, Sun D, Xiong Z, Gu X, Hao K, et al. SHANK3 Co-ordinately Regulates Autophagy and Apoptosis in Myocardial Infarction. Front Physiol. 2020;11:1082. https://doi.org/10.3389/fphys.2020.01082.CrossRefPubMedPubMedCentral

47.

Refaat MM, Aouizerat BE, Pullinger CR, Malloy M, Kane J, Tseng ZH. Association of CASQ2 polymorphisms with sudden cardiac arrest and heart failure in patients with coronary artery disease. Heart Rhythm. 2014;11(4):646–52. https://doi.org/10.1016/j.hrthm.2014.01.015.CrossRefPubMedPubMedCentral

48.

Pritchard AB, Kanai SM, Krock B, Schindewolf E, Oliver-Krasinski J, Khalek N, Okashah N, Lambert NA, Tavares ALP, Zackai E, et al. Loss-of-function of Endothelin receptor type A results in Oro-Oto-Cardiac syndrome. Am J Med Genet A. 2020;182(5):1104–16. https://doi.org/10.1002/ajmg.a.61531.CrossRefPubMedPubMedCentral

49.

Yang D, Jin C, Ma H, Huang M, Shi GP, Wang J, Xiang M. EphrinB2/EphB4 pathway in postnatal angiogenesis: a potential therapeutic target for ischemic cardiovascular disease. Angiogenesis. 2016;19(3):297–309. https://doi.org/10.1007/s10456-016-9514-9.CrossRefPubMed

50.

Jorholt J, Formicheva Y, Vershinina T, Kiselev A, Muravyev A, Demchenko E, Fedotov P, Zlotina A, Rygkov A, Vasichkina E, et al. Cardiomyopathy and Skeletal Muscle Features Associated with ALPK3 Homozygous and Compound Heterozygous Variants. Genes (Basel). 2020;11(10):1201. https://doi.org/10.3390/genes11101201.CrossRefPubMedCentral

51.

Touma M, Kang X, Gao F, Zhao Y, Cass AA, Biniwale R, Xiao X, Eghbali M, Coppola G, Reemtsen B, et al. Wnt11 regulates cardiac chamber development and disease during perinatal maturation. JCI Insight. 2017;2(17):e94904. https://doi.org/10.1172/jci.insight.94904.CrossRefPubMedCentral

52.

Liu Z, Zhao N, Zhu H, Zhu S, Pan S, Xu J, Zhang X, Zhang Y, Wang J. Circulating interleukin-1β promotes endoplasmic reticulum stress-induced myocytes apoptosis in diabetic cardiomyopathy via interleukin-1 receptor-associated kinase-2. Cardiovasc Diabetol. 2015;14:125. https://doi.org/10.1186/s12933-015-0288-y.CrossRefPubMedPubMedCentral

53.

Barrett PM, Topol EJ. The fibrillin-1 gene: unlocking new therapeutic pathways in cardiovascular disease. Heart. 2013;99(2):83–90. https://doi.org/10.1136/heartjnl-2012-301840.CrossRefPubMed

54.

Wu Y, Liu X, Zheng H, Zhu H, Mai W, Huang X, Huang Y. Multiple Roles of sFRP2 in Cardiac Development and Cardiovascular Disease. Int J Biol Sci. 2020;16(5):730–8. https://doi.org/10.7150/ijbs.40923.CrossRefPubMedPubMedCentral

55.

Mao Z, Wang Y, Peng H, He F, Zhu L, Huang H, Huang X, Lu X, Tan X. A newly identified missense mutation in CLCA2 is associated with autosomal dominant cardiac conduction block. Gene. 2019;714:143990. https://doi.org/10.1016/j.gene.2019.143990.CrossRefPubMed

56.

Wu C, Yan H, Sun J, Yang F, Song C, Jiang F, Li Y, Dong J, Zheng GY, Tian XL, et al. NEXN is a novel susceptibility gene for coronary artery disease in Han Chinese. PLoS One. 2013;8(12):e82135. https://doi.org/10.1371/journal.pone.0082135.CrossRefPubMedPubMedCentral

57.

Hoke M, Schillinger M, Dick P, Exner M, Koppensteiner R, Minar E, Mlekusch W, Schlager O, Wagner O, Mannhalter C. Polymorphism of the palladin gene and cardiovascular outcome in patients with atherosclerosis. Eur J Clin Invest. 2011;41(4):365–71. https://doi.org/10.1111/j.1365-2362.2010.02416.x.CrossRefPubMed

58.

Wang Y, Wang Y, Adi D, He X, Liu F, Abudesimu A, Fu Z, Ma Y. Dab2 gene variant is associated with increased coronary artery disease risk in Chinese Han population. Medicine (Baltimore). 2020;99(27):e20924. https://doi.org/10.1097/MD.0000000000020924.CrossRefPubMedPubMedCentral

59.

Harman JL, Sayers J, Chapman C, Pellet-Many C. Emerging Roles for Neuropilin-2 in Cardiovascular Disease. Int J Mol Sci. 2020;21(14):5154. https://doi.org/10.3390/ijms21145154.CrossRefPubMedCentral

60.

Wang Y, Fu W, Xie F, Wang Y, Chu X, Wang H, Shen M, Wang Y, Wang Y, Sun WL, et al. Common polymorphisms in ITGA2, PON1 and THBS2 are associated with coronary atherosclerosis in a candidate gene association study of the Chinese Han population. J Hum Genet. 2010;55(8):490–4. https://doi.org/10.1038/jhg.2010.53.CrossRefPubMed

61.

Wei Y, Zhu M, Corbalán-Campos J, Heyll K, Weber C, Schober A. Regulation of Csf1r and Bcl6 in macrophages mediates the stage-specific effects of microRNA-155 on atherosclerosis. Arterioscler Thromb Vasc Biol. 2015;35(4):796–803. https://doi.org/10.1161/ATVBAHA.114.304723.CrossRefPubMed

62.

Long QQ, Wang H, Gao W, Fan Y, Li YF, Ma Y, Yang Y, Shi HJ, Chen BR, Meng HY, et al. Long Noncoding RNA Kcna2 Antisense RNA Contributes to Ventricular Arrhythmias via Silencing Kcna2 in Rats With Congestive Heart Failure. J Am Heart Assoc. 2017;6(12):e005965. https://doi.org/10.1161/JAHA.117.005965.CrossRefPubMedPubMedCentral

63.

Beitelshees AL, Navare H, Wang D, Gong Y, Wessel J, Moss JI, Langaee TY, Cooper-DeHoff RM, Sadee W, Pepine CJ, et al. CACNA1C gene polymorphisms, cardiovascular disease outcomes, and treatment response. Circ Cardiovasc Genet. 2009;2(4):362–70. https://doi.org/10.1161/CIRCGENETICS.109.857839.CrossRefPubMedPubMedCentral

64.

Gigante B, Vikström M, Meuzelaar LS, Chernogubova E, Silveira A, Hooft FV, Hamsten A, de Faire U. Variants in the coagulation factor 2 receptor (F2R) gene influence the risk of myocardial infarction in men through an interaction with interleukin 6 serum levels. Thromb Haemost. 2009;101(5):943–53.CrossRefPubMed

65.

Lei Q, Yi T, Li H, Yan Z, Lv Z, Li G, Wang Y. Ubiquitin C-terminal hydrolase L1 (UCHL1) regulates post-myocardial infarction cardiac fibrosis through glucose-regulated protein of 78 kDa (GRP78). Sci Rep. 2020;10(1):10604. https://doi.org/10.1038/s41598-020-67746-4.CrossRefPubMedPubMedCentral

66.

de Jager SC, Bongaerts BW, Weber M, Kraaijeveld AO, Rousch M, Dimmeler S, van Dieijen-Visser MP, Cleutjens KB, Nelemans PJ, van Berkel TJ, et al. Chemokines CCL3/MIP1α, CCL5/RANTES and CCL18/PARC are independent risk predictors of short-term mortality in patients with acute coronary syndromes. PLoS One. 2012;7(9):e45804. https://doi.org/10.1371/journal.pone.0045804.CrossRefPubMedPubMedCentral

67.

Ruppert V, Meyer T, Richter A, Maisch B, Pankuweit S. German Competence Network of Heart Failure. Identification of a missense mutation in the melusin-encoding ITGB1BP2 gene in a patient with dilated cardiomyopathy. Gene. 2013;512(2):206–10. https://doi.org/10.1016/j.gene.2012.10.055.CrossRefPubMed

68.

Andenæs K, Lunde IG, Mohammadzadeh N, Dahl CP, Aronsen JM, Strand ME, Palmero S, Sjaastad I, Christensen G, Engebretsen KVT, et al. The extracellular matrix proteoglycan fibromodulin is upregulated in clinical and experimental heart failure and affects cardiac remodeling. PLoS One. 2018;13(7):e0201422. https://doi.org/10.1371/journal.pone.0201422.CrossRefPubMedPubMedCentral

69.

Hu Z, Xiao X, Zhang Z, Li M. Genetic insights and neurobiological implications from NRXN1 in neuropsychiatric disorders. Mol Psychiatr. 2019;24(10):1400–14. https://doi.org/10.1038/s41380-019-0438-9.CrossRef

70.

Liu Z, Liu W, Yao L, Yang C, Xiao L, Wan Q, Gao K, Wang H, Zhu F, Wang G, et al. Negative life events and corticotropin-releasing-hormone receptor1 gene in recurrent major depressive disorder. Sci Rep. 2013;3:1548. https://doi.org/10.1038/srep01548.CrossRefPubMedPubMedCentral

71.

Eltokhi A, Rappold G, Sprengel R. Distinct Phenotypes of Shank2 Mouse Models Reflect Neuropsychiatric Spectrum Disorders of Human Patients With SHANK2 Variants. Front Mol Neurosci. 2018;11:240. https://doi.org/10.3389/fnmol.2018.00240.CrossRefPubMedPubMedCentral

72.

Cai Y, An SS, Kim S. Mutations in presenilin 2 and its implications in Alzheimer's disease and other dementia-associated disorders. Clin Interv Aging. 2015;10:1163–72. https://doi.org/10.2147/CIA.S85808.CrossRefPubMedPubMedCentral

73.

Pfeiffer FE, Homburger HA, Houser OW, Baker HL Jr, Yanagihara T. Elevation of serum creatine kinase B-subunit levels by radiographic contrast agents in patients with neurologic disorders. Mayo Clin Proc. 1987;62(5):351–7. https://doi.org/10.1016/s0025-6196(12)65438-x.CrossRefPubMed

74.

Lin S, He L, Shen R, Fang F, Pan H, Zhu X, Wang M, Zhou Z, Liu Z, Wang X, et al. Identification of the CD200R1 promoter and the association of its polymorphisms with the risk of Parkinson's disease. Eur J Neurol. 2020;27(7):1224–30. https://doi.org/10.1111/ene.14224.CrossRefPubMed

75.

Royer-Zemmour B, Ponsole-Lenfant M, Gara H, Roll P, Lévêque C, Massacrier A, Ferracci G, Cillario J, Robaglia-Schlupp A, Vincentelli R, et al. Epileptic and developmental disorders of the speech cortex: ligand/receptor interaction of wild-type and mutant SRPX2 with the plasminogen activator receptor uPAR. Hum Mol Genet. 2008;17(23):3617–30. https://doi.org/10.1093/hmg/ddn256.CrossRefPubMed

76.

Pastor M, Fernández-Calle R, Di Geronimo B, Vicente-Rodríguez M, Zapico JM, Gramage E, Coderch C, Pérez-García C, Lasek AW, Puchades-Carrasco L, et al. Development of inhibitors of receptor protein tyrosine phosphatase β/ζ (PTPRZ1) as candidates for CNS disorders. Eur J Med Chem. 2018;144:318–29. https://doi.org/10.1016/j.ejmech.2017.11.080.CrossRefPubMed

77.

Goodspeed K, Pérez-Palma E, Iqbal S, Cooper D, Scimemi A, Johannesen KM, Stefanski A, Demarest S, Helbig KL, Kang J, et al. Current knowledge of SLC6A1-related neurodevelopmental disorders. Brain Commun. 2020;2:fcaa170. https://doi.org/10.1093/braincomms/fcaa170.CrossRefPubMedPubMedCentral

78.

Zhang T, Li J, Yu H, Shi Y, Li Z, Wang L, Wang Z, Lu T, Wang L, Yue W, et al. Meta-analysis of GABRB2 polymorphisms and the risk of schizophrenia combined with GWAS data of the Han Chinese population and psychiatric genomics consortium. PLoS One. 2018;13(6):e0198690. https://doi.org/10.1371/journal.pone.0198690.CrossRefPubMedPubMedCentral

79.

Rogers A, Golumbek P, Cellini E, Doccini V, Guerrini R, Wallgren-Pettersson C, Thuresson AC, Gurnett CA. De novo KCNA1 variants in the PVP motif cause infantile epileptic encephalopathy and cognitive impairment similar to recurrent KCNA2 variants. Am J Med Genet A. 2018;176(8):1748–52. https://doi.org/10.1002/ajmg.a.38840.CrossRefPubMed

80.

Su Y, Yang L, Li Z, Wang W, Xing M, Fang Y, Cheng Y, Lin GN, Cui D. The interaction of ASAH1 and NGF gene involving in neurotrophin signaling pathway contributes to schizophrenia susceptibility and psychopathology. Prog Neuropsychopharmacol Biol Psychiatry. 2021;104:110015. https://doi.org/10.1016/j.pnpbp.2020.110015.CrossRefPubMed

81.

Foale S, Berry M, Logan A, Fulton D, Ahmed Z. LINGO-1 and AMIGO3, potential therapeutic targets for neurological and dysmyelinating disorders? Neural Regen Res. 2017;12(8):1247–51. https://doi.org/10.4103/1673-5374.213538.CrossRefPubMedPubMedCentral

82.

Ravichandran S, Finlin BS, Kern PA, Özcan S. Sphk2-/- mice are protected from obesity and insulin resistance. Biochim Biophys Acta Mol Basis Dis. 2019;1865(3):570–6. https://doi.org/10.1016/j.bbadis.2018.12.012.CrossRefPubMed

83.

Labonté ED, Camarota LM, Rojas JC, Jandacek RJ, Gilham DE, Davies JP, Ioannou YA, Tso P, Hui DY, Howles PN. Reduced absorption of saturated fatty acids and resistance to diet-induced obesity and diabetes by ezetimibe-treated and Npc1l1-/- mice. Am J Physiol Gastrointest Liver Physiol. 2008;295(4):G776–83. https://doi.org/10.1152/ajpgi.90275.2008.CrossRefPubMedPubMedCentral

84.

Watt MJ, Dzamko N, Thomas WG, Rose-John S, Ernst M, Carling D, Kemp BE, Febbraio MA, Steinberg GR. CNTF reverses obesity-induced insulin resistance by activating skeletal muscle AMPK. Nat Med. 2006;12(5):541–8. https://doi.org/10.1038/nm1383.CrossRefPubMed

85.

Yang Q, Graham TE, Mody N, Preitner F, Peroni OD, Zabolotny JM, Kotani K, Quadro L, Kahn BB. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature. 2005;436(7049):356–62. https://doi.org/10.1038/nature03711.CrossRefPubMed

86.

Awazawa M, Gabel P, Tsaousidou E, Nolte H, Krüger M, Schmitz J, Ackermann PJ, Brandt C, Altmüller J, Motameny S, et al. A microRNA screen reveals that elevated hepatic ectodysplasin A expression contributes to obesity-induced insulin resistance in skeletal muscle. Nat Med. 2017;23(12):1466–73. https://doi.org/10.1038/nm.4420.CrossRefPubMed

87.

Ludvigsen TP, Olsen LH, Pedersen HD, Christoffersen BØ, Jensen LJ. Hyperglycemia-induced transcriptional regulation of ROCK1 and TGM2 expression is involved in small artery remodeling in obese diabetic Göttingen Minipigs. Clin Sci (Lond). 2019;133(24):2499–516. https://doi.org/10.1042/CS20191066.CrossRefPubMed

88.

Cockburn BN, Ostrega DM, Sturis J, Kubstrup C, Polonsky KS, Bell GI. Changes in pancreatic islet glucokinase and hexokinase activities with increasing age, obesity, and the onset of diabetes. Diabetes. 1997;46(9):1434–9. https://doi.org/10.2337/diab.46.9.1434.CrossRefPubMed

89.

Berndt J, Kovacs P, Ruschke K, Klöting N, Fasshauer M, Schön MR, Körner A, Stumvoll M, Blüher M. Fatty acid synthase gene expression in human adipose tissue: association with obesity and type 2 diabetes. Diabetologia. 2007;50(7):1472–80. https://doi.org/10.1007/s00125-007-0689-x.CrossRefPubMed

90.

Williams KH, Viera de Ribeiro AJ, Prakoso E, Veillard AS, Shackel NA, Bu Y, Brooks B, Cavanagh E, Raleigh J, et al. Lower serum fibroblast activation protein shows promise in the exclusion of clinically significant liver fibrosis due to non-alcoholic fatty liver disease in diabetes and obesity. Diab Res Clin Pract. 2015;108(3):466–72. https://doi.org/10.1016/j.diabres.2015.02.024.CrossRef

91.

de Brito G, Lupinacci FC, Beraldo FH, Santos TG, Roffé M, Lopes MH, de Lima VC, Martins VR, Hajj GN. Loss of prion protein is associated with the development of insulin resistance and obesity. Biochem J. 2017;474(17):2981–91. https://doi.org/10.1042/BCJ20170137.CrossRefPubMed

92.

Michurina SV, Ishchenko IY, Arkhipov SA, Klimontov VV, Rachkovskaya LN, Konenkov VI, Zavyalov EL. Effects of Melatonin, Aluminum Oxide, and Polymethylsiloxane Complex on the Expression of LYVE-1 in the Liver of Mice with Obesity and Type 2 Diabetes Mellitus. Bull Exp Biol Med. 2016;162(2):269–72. https://doi.org/10.1007/s10517-016-3592-y.CrossRefPubMed

93.

Kaur P, Reis MD, Couchman GR, Forjuoh SN, Greene JF, Asea A. SERPINE 1 Links Obesity and Diabetes: A Pilot Study. J Proteomics Bioinform. 2010;3(6):191–9. https://doi.org/10.4172/jpb.1000139.CrossRefPubMedPubMedCentral

94.

Serino M, Menghini R, Fiorentino L, Amoruso R, Mauriello A, Lauro D, Sbraccia P, Hribal ML, Lauro R, Federici M. Mice heterozygous for tumor necrosis factor-alpha converting enzyme are protected from obesity-induced insulin resistance and diabetes. Diabetes. 2007;56(10):2541–6. https://doi.org/10.2337/db07-0360.CrossRefPubMed

95.

Blüher M, Klöting N, Wueest S, Schoenle EJ, Schön MR, Dietrich A, Fasshauer M, Stumvoll M, Konrad D. Fas and FasL expression in human adipose tissue is related to obesity, insulin resistance, and type 2 diabetes. J Clin Endocrinol Metab. 2014;99(1):E36–44. https://doi.org/10.1210/jc.2013-2488.CrossRefPubMed

96.

Muratsu J, Iwabayashi M, Sanada F, Taniyama Y, Otsu R, Rakugi H, Morishita R. Hepatocyte Growth Factor Prevented High-Fat Diet-Induced Obesity and Improved Insulin Resistance in Mice. Sci Rep. 2017;7(1):130. https://doi.org/10.1038/s41598-017-00199-4.CrossRefPubMedPubMedCentral

97.

Xiong XQ, Geng Z, Zhou B, Zhang F, Han Y, Zhou YB, Wang JJ, Gao XY, Chen Q, Li YH, et al. FNDC5 attenuates adipose tissue inflammation and insulin resistance via AMPK-mediated macrophage polarization in obesity. Metabolism. 2018;83:31–41. https://doi.org/10.1016/j.metabol.2018.01.013.CrossRefPubMed

98.

Kim KE, Cho YS, Baek KS, Li L, Baek KH, Kim JH, Kim HS, Sheen YH. Lipopolysaccharide-binding protein plasma levels as a biomarker of obesity-related insulin resistance in adolescents. Korean J Pediatr. 2016;59(5):231–8. https://doi.org/10.3345/kjp.2016.59.5.231.CrossRefPubMedPubMedCentral

99.

Daley EJ, Pajevic PD, Roy S, Trackman PC. Impaired Gastric Hormone Regulation of Osteoblasts and Lysyl Oxidase Drives Bone Disease in Diabetes Mellitus. JBMR Plus. 2019;3(10):e10212. https://doi.org/10.1002/jbm4.10212.CrossRefPubMedPubMedCentral

100.

Hirai H, Miura J, Hu Y, Larsson H, Larsson K, Lernmark A, Ivarsson SA, Wu T, Kingman A, Tzioufas AG, et al. Selective screening of secretory vesicle-associated proteins for autoantigens in type 1 diabetes: VAMP2 and NPY are new minor autoantigens. Clin Immunol. 2008;127(3):366–74. https://doi.org/10.1016/j.clim.2008.01.018.CrossRefPubMedPubMedCentral

101.

Vuori N, Sandholm N, Kumar A, Hietala K, Syreeni A, Forsblom C, Juuti-Uusitalo K, Skottman H, Imamura M, Maeda S, et al. CACNB2 Is a Novel Susceptibility Gene for Diabetic Retinopathy in Type 1 Diabetes. Diabetes. 2019;68(11):2165–74. https://doi.org/10.2337/db19-0130.CrossRefPubMedPubMedCentral

102.

Porta M, Toppila I, Sandholm N, Hosseini SM, Forsblom C, Hietala K, Borio L, Harjutsalo V, Klein BE, Klein R, et al. Variation in SLC19A3 and Protection From Microvascular Damage in Type 1 Diabetes. Diabetes. 2016;65(4):1022–30. https://doi.org/10.2337/db15-1247.CrossRefPubMed

103.

Nomoto H, Pei L, Montemurro C, Rosenberger M, Furterer A, Coppola G, Nadel B, Pellegrini M, Gurlo T, Butler PC, et al. Activation of the HIF1α/PFKFB3 stress response pathway in beta cells in type 1 diabetes. Diabetologia. 2020;63(1):149–61. https://doi.org/10.1007/s00125-019-05030-5.CrossRefPubMed

104.

Blindbæk SL, Schlosser A, Green A, Holmskov U, Sorensen GL, Grauslund J. Association between microfibrillar-associated protein 4 (MFAP4) and micro- and macrovascular complications in long-term type 1 diabetes mellitus. Acta Diabetol. 2017;54(4):367–72. https://doi.org/10.1007/s00592-016-0953-y.CrossRefPubMed

105.

Hu Z, Liu F, Li M, He J, Huang J, Rao DC, Hixson JE, Gu C, Kelly TN, Chen S, et al. Associations of Variants in the CACNA1A and CACNA1C Genes With Longitudinal Blood Pressure Changes and Hypertension Incidence: The GenSalt Study. Am J Hypertens. 2016;29(11):1301–6. https://doi.org/10.1093/ajh/hpw070.CrossRefPubMedPubMedCentral

106.

Tabbò F, D'Aveni A, Tota D, Pignataro D, Bironzo P, Carnio S, Cappia S, Cortese G, Righi L, Novello S. Pulmonary Arterial Hypertension in ALK Receptor Tyrosine Kinase-Positive Lung Cancer Patient: Adverse Event or Disease Spread? J Thorac Oncol. 2019;14(2):e38–40. https://doi.org/10.1016/j.jtho.2018.10.154.CrossRefPubMed

107.

Yang HC, Liang YJ, Chen JW, Chiang KM, Chung CM, Ho HY, Ting CT, Lin TH, Sheu SH, Tsai WC, et al. Identification of IGF1, SLC4A4, WWOX, and SFMBT1 as hypertension susceptibility genes in Han Chinese with a genome-wide gene-based association study. PLoS One. 2012;7(3):e32907. https://doi.org/10.1371/journal.pone.0032907.CrossRefPubMedPubMedCentral

108.

Erlandsson L, Ducat A, Castille J, Zia I, Kalapotharakos G, Hedström E, Vilotte JL, Vaiman D, Hansson SR. lpha-1 microglobulin as a potential therapeutic candidate for treatment of hypertension and oxidative stress in the STOX1 preeclampsia mouse model. Sci Rep. 2019;9(1):8561. https://doi.org/10.1038/s41598-019-44639-9.CrossRefPubMedPubMedCentral

109.

Samokhin AO, Stephens T, Wertheim BM, Wang RS, Vargas SO, Yung LM, Cao M, Brown M, Arons E, Dieffenbach PB, et al. NEDD9 targets COL3A1 to promote endothelial fibrosis and pulmonary arterial hypertension. Sci Transl Med. 2018;10(445):eaap7294. https://doi.org/10.1126/scitranslmed.aap7294.CrossRefPubMedPubMedCentral

110.

Fava C, Montagnana M, Danese E, Sjögren M, Almgren P, Engström G, Hedblad B, Guidi GC, Minuz P, Melander O. Vanin-1 T26I polymorphism, hypertension and cardiovascular events in two large urban-based prospective studies in Swedes. Nutr Metab Cardiovasc Dis. 2013;23(1):53–60. https://doi.org/10.1016/j.numecd.2011.01.012.CrossRefPubMed

111.

Wang L, Li H, Yang B, Guo L, Han X, Li L, Li M, Huang J, Gu D. The Hypertension Risk Variant Rs820430 Functions as an Enhancer of SLC4A7. Am J Hypertens. 2017;30(2):202–8. https://doi.org/10.1093/ajh/hpw127.CrossRefPubMed

112.

Bhupatiraju C, Patkar S, Pandharpurkar D, Joshi S, Tirunilai P. Association and interaction of -58C>T and ±9 bp polymorphisms of BDKRB2 gene causing susceptibility to essential hypertension. Clin Exp Hypertens. 2012;34(3):230–5. https://doi.org/10.3109/10641963.2011.631653.CrossRefPubMed

113.

Zhang H, Sun ZQ, Liu SS, Yang LN. Association between GRK4 and DRD1 gene polymorphisms and hypertension: a meta-analysis. Clin Interv Aging. 2015;11:17–27. https://doi.org/10.2147/CIA.S94510.CrossRefPubMedPubMedCentral

114.

Xu K, Ma L, Li Y, Wang F, Zheng GY, Sun Z, Jiang F, Chen Y, Liu H, Dang A, et al. Genetic and Functional Evidence Supports LPAR1 as a Susceptibility Gene for Hypertension. Hypertension. 2015;66(3):641–6. https://doi.org/10.1161/HYPERTENSIONAHA.115.05515.CrossRefPubMed

115.

Lee SM, Baik J, Nguyen D, Nguyen V, Liu S, Hu Z, Abbott GW. Kcne2 deletion impairs insulin secretion and causes type 2 diabetes mellitus. FASEB J. 2017;31(6):2674–85. https://doi.org/10.1096/fj.201601347.CrossRefPubMed

116.

Deng Z, Shen J, Ye J, Shu Q, Zhao J, Fang M, Zhang T. Association between single nucleotide polymorphisms of delta/notch-like epidermal growth factor (EGF)-related receptor (DNER) and Delta-like 1 Ligand (DLL 1) with the risk of type 2 diabetes mellitus in a Chinese Han population. Cell Biochem Biophys. 2015;71(1):331–5. https://doi.org/10.1007/s12013-014-0202-3.CrossRefPubMed

117.

Emdin CA, Khera AV, Aragam K, Haas M, Chaffin M, Klarin D, Natarajan P, Bick A, Zekavat SM, Nomura A, et al. DNA Sequence Variation in ACVR1C Encoding the Activin Receptor-Like Kinase 7 Influences Body Fat Distribution and Protects Against Type 2 Diabetes. Diabetes. 2019;68(1):226–34. https://doi.org/10.2337/db18-0857.CrossRefPubMed

118.

Kim KS, Jung Yang H, Lee IS, Kim KH, Park J, Jeong HS, Kim Y, Seok Ahn K, et al. The aglycone of ginsenoside Rg3 enables glucagon-like peptide-1 secretion in enteroendocrine cells and alleviates hyperglycemia in type 2 diabetic mice. Sci Rep. 2015;5:18325. https://doi.org/10.1038/srep18325.CrossRefPubMedPubMedCentral

119.

Mtiraoui N, Turki A, Nemr R, Echtay A, Izzidi I, Al-Zaben GS, Irani-Hakime N, Keleshian SH, Mahjoub T, Almawi WY. Contribution of common variants of ENPP1, IGF2BP2, KCNJ11, MLXIPL, PPARγ, SLC30A8 and TCF7L2 to the risk of type 2 diabetes in Lebanese and Tunisian Arabs. Diabetes Metab. 2012;38(5):444–9. https://doi.org/10.1016/j.diabet.2012.05.002.CrossRefPubMed

120.

Ishii H, Niiya T, Ono Y, Inaba N, Jinnouchi H, Watada H. Improvement of quality of life through glycemic control by liraglutide, a GLP-1 analog, in insulin-naive patients with type 2 diabetes mellitus: the PAGE1 study. Diabetol Metab Syndr. 2017;9:3. https://doi.org/10.1186/s13098-016-0202-0.CrossRefPubMedPubMedCentral

121.

Jiang YD, Chang YC, Chiu YF, Chang TJ, Li HY, Lin WH, Yuan HY, Chen YT, Chuang LM. SLC2A10 genetic polymorphism predicts development of peripheral arterial disease in patients with type 2 diabetes. SLC2A10 and PAD in type 2 diabetes. BMC Med Genet. 2010;11:126. https://doi.org/10.1186/1471-2350-11-126.CrossRefPubMedPubMedCentral

122.

Harder MN, Ribel-Madsen R, Justesen JM, Sparsø T, Andersson EA, Grarup N, Jørgensen T, Linneberg A, Hansen T, Pedersen O. Type 2 diabetes risk alleles near BCAR1 and in ANK1 associate with decreased β-cell function whereas risk alleles near ANKRD55 and GRB14 associate with decreased insulin sensitivity in the Danish Inter99 cohort. J Clin Endocrinol Metab. 2013;98(4):E801–6. https://doi.org/10.1210/jc.2012-4169.CrossRefPubMed

123.

Aruga M, Tokita Y, Nakajima K, Kamachi K, Tanaka A. The effect of combined diet and exercise intervention on body weight and the serum GPIHBP1 concentration in overweight/obese middle-aged women. Clin Chim Acta. 2017;475:109–15. https://doi.org/10.1016/j.cca.2017.10.017.CrossRefPubMed

124.

Baruch A, Wong C, Chinn LW, Vaze A, Sonoda J, Gelzleichter T, Chen S, Lewin-Koh N, Morrow L, Dheerendra S, et al. Antibody-mediated activation of the FGFR1/Klothoβ complex corrects metabolic dysfunction and alters food preference in obese humans. Proc Natl Acad Sci U S A. 2020;117(46):28992–9000. https://doi.org/10.1073/pnas.2012073117.CrossRefPubMedPubMedCentral

125.

Soussi H, Reggio S, Alili R, Prado C, Mutel S, Pini M, Rouault C, Clément K, Dugail I. DAPK2 Downregulation Associates With Attenuated Adipocyte Autophagic Clearance in Human Obesity. Diabetes. 2015;64(10):3452–63. https://doi.org/10.2337/db14-1933.CrossRefPubMed

126.

Haim Y, Blüher M, Konrad D, Goldstein N, Klöting N, Harman-Boehm I, Kirshtein B, Ginsberg D, Tarnovscki T, Gepner Y, et al. ASK1 (MAP 3K5) is transcriptionally upregulated by E2F1 in adipose tissue in obesity, molecularly defining a human dys-metabolic obese phenotype. Mol Metab. 2017;6(7):725–36. https://doi.org/10.1016/j.molmet.2017.05.003.CrossRefPubMedPubMedCentral

127.

Aliasghari F, Nazm SA, Yasari S, Mahdavi R, Bonyadi M. Associations of the ANKK1 and DRD2 gene polymorphisms with overweight, obesity and hedonic hunger among women from the Northwest of Iran [published online ahead of print, 2020 Feb 4]. Eat Weight Disord. 2020;10.1007/s40519-020-00851-5. doi:https://doi.org/10.1007/s40519-020-00851-5

128.

Koschinsky T, Gries FA, Herberg L. Regulation of glycerol kinase by insulin in isolated fat cells and liver of Bar Harbor obese mice. Diabetologia. 1971;7(5):316–22. https://doi.org/10.1007/BF01219464.CrossRefPubMed

129.

Xie J, Shao Y, Liu J, Cui M, Xiao X, Gong J, Xue B, Zhang Q, Hu X, Duan H. K27Q/K29Q mutations in sphingosine kinase 1 attenuate high-fat diet induced obesity and altered glucose homeostasis in mice. Sci Rep. 2020;10(1):20038. https://doi.org/10.1038/s41598-020-77096-w.CrossRefPubMedPubMedCentral

130.

Schwindinger WF, Borrell BM, Waldman LC, Robishaw JD. Mice lacking the G protein gamma3-subunit show resistance to opioids and diet induced obesity. Am J Physiol Regul Integr Comp Physiol. 2009;297(5):R1494–502. https://doi.org/10.1152/ajpregu.00308.2009.CrossRefPubMedPubMedCentral

131.

Founds SA, Ren D, Roberts JM, Jeyabalan A, Powers RW. Follistatin-like 3 across gestation in preeclampsia and uncomplicated pregnancies among lean and obese women. Reprod Sci. 2015;22(4):402–9. https://doi.org/10.1177/1933719114529372.CrossRefPubMed

132.

Liu KY, Sengillo JD, Velez G, Jauregui R, Sakai LY, Maumenee IH, Bassuk AG, Mahajan VB, Tsang SH. Missense mutation in SLIT2 associated with congenital myopia, anisometropia, connective tissue abnormalities, and obesity. Orphanet J Rare Dis. 2018;13(1):138. https://doi.org/10.1186/s13023-018-0885-4.CrossRefPubMedPubMedCentral

133.

Osorio-Conles O, Guitart M, Moreno-Navarrete JM, Escoté X, Duran X, Fernandez-Real JM, Gomez-Foix AM, Fernández-Veledo S, Vendrell J. Adipose tissue and serum CCDC80 in obesity and its association with related metabolic disease. Mol Med. 2017;23:225–34. https://doi.org/10.2119/molmed.2017.00067.CrossRefPubMedPubMedCentral

134.

Dankel SN, Røst TH, Kulyté A, Fandalyuk Z, Skurk T, Hauner H, Sagen JV, Rydén M, Arner P, Mellgren G. The Rho GTPase RND3 regulates adipocyte lipolysis. Metabolism. 2019;101:153999. https://doi.org/10.1016/j.metabol.2019.153999.CrossRefPubMed

135.

Yasui M, Tamura Y, Minami M, Higuchi S, Fujikawa R, Ikedo T, Nagata M, Arai H, Murayama T, Yokode M. The Prostaglandin E2 Receptor EP4 Regulates Obesity-Related Inflammation and Insulin Sensitivity. PLoS One. 2015;10(8):e0136304. https://doi.org/10.1371/journal.pone.0136304.CrossRefPubMedPubMedCentral

136.

Lu F, Liu Q. Validation of RUNX1 as a potential target for treating circadian clock-induced obesity through preventing migration of group 3 innate lymphoid cells into intestine. Med Hypotheses. 2018;113:98–101. https://doi.org/10.1016/j.mehy.2018.02.015.CrossRefPubMed

137.

Masaki M, Kurisaki T, Shirakawa K, Sehara-Fujisawa A. Role of meltrin {alpha} (ADAM12) in obesity induced by high- fat diet. Endocrinology. 2005;146(4):1752–63. https://doi.org/10.1210/en.2004-1082.CrossRefPubMed

138.

Khaidakov M, Mitra S, Kang BY, Wang X, Kadlubar S, Novelli G, Raj V, Winters M, Carter WC, Mehta JL. Oxidized LDL receptor 1 (OLR1) as a possible link between obesity, dyslipidemia and cancer. PLoS One. 2011;6(5):e20277. https://doi.org/10.1371/journal.pone.0020277.CrossRefPubMedPubMedCentral

139.

Matsuo Y, Tanaka M, Yamakage H, Sasaki Y, Muranaka K, Hata H, Ikai I, Shimatsu A, Inoue M, Chun TH, et al. Thrombospondin 1 as a novel biological marker of obesity and metabolic syndrome. Metabolism. 2015;64(11):1490–9. https://doi.org/10.1016/j.metabol.2015.07.016.CrossRefPubMedPubMedCentral

140.

Poggi M, Morin SO, Bastelica D, Govers R, Canault M, Bernot D, Georgelin O, Verdier M, Burcelin R, Olive D, et al. CD28 deletion improves obesity-induced liver steatosis but increases adiposity in mice. Int J Obes (Lond). 2015;39(6):977–85. https://doi.org/10.1038/ijo.2015.26.CrossRef

141.

Zhu Y, Wen L, Wang S, Zhang K, Cui Y, Zhang C, Feng L, Yu F, Chen Y, Wang R, et al. Omega-3 fatty acids improve flow-induced vasodilation by enhancing TRPV4 in arteries from diet-induced obese mice. Cardiovasc Res. 2020:cvaa296. https://doi.org/10.1093/cvr/cvaa296.

142.

He L, Gunn TM, Bouley DM, Lu XY, Watson SJ, Schlossman SF, Duke-Cohan JS, Barsh GS. A biochemical function for attractin in agouti-induced pigmentation and obesity. Nat Genet. 2001;27(1):40–7. https://doi.org/10.1038/83741.CrossRefPubMed

143.

Moreno-Navarrete JM, Ortega F, Gómez-Serrano M, García-Santos E, Ricart W, Tinahones F, Mingrone G, Peral B, Fernández-Real JM. The MRC1/CD68 ratio is positively associated with adipose tissue lipogenesis and with muscle mitochondrial gene expression in humans. PLoS One. 2013;8(8):e70810. https://doi.org/10.1371/journal.pone.0070810.CrossRefPubMedPubMedCentral

144.

Nam JS, Ahn CW, Park HJ, Kim YS. Semaphorin 3 C is a Novel Adipokine Representing Exercise-Induced Improvements of Metabolism in Metabolically Healthy Obese Young Males. Sci Rep. 2020;10(1):10005. https://doi.org/10.1038/s41598-020-67004-7.CrossRefPubMedPubMedCentral

145.

Kwak SH, Park BL, Kim H, German MS, Go MJ, Jung HS, Koo BK, Cho YM, Choi SH, Cho YS, et al. Association of variations in TPH1 and HTR2B with gestational weight gain and measures of obesity. Obesity (Silver Spring). 2012;20(1):233–8. https://doi.org/10.1038/oby.2011.253.CrossRef

146.

Muñoz M, López-Oliva ME, Rodríguez C, Martínez MP, Sáenz-Medina J, Sánchez A, Climent B, Benedito S, García-Sacristán A, Rivera L, et al. Differential contribution of Nox1, Nox2 and Nox4 to kidney vascular oxidative stress and endothelial dysfunction in obesity. Redox Biol. 2020;28:101330. https://doi.org/10.1016/j.redox.2019.101330.CrossRefPubMed

147.

Klöting N, Wilke B, Klöting I. Alleles on rat chromosome 4 (D4Got41-Fabp1/Tacr1) regulate subphenotypes of obesity. Obes Res. 2005;13(3):589–95. https://doi.org/10.1038/oby.2005.63.CrossRefPubMed

148.

Van Camp JK, De Freitas F, Zegers D, Beckers S, Verhulst SL, Van Hoorenbeeck K, Massa G, Verrijken A, Desager KN, Van Gaal LF, et al. Investigation of common and rare genetic variation in the BAMBI genomic region in light of human obesity. Endocrine. 2016;52(2):277–86. https://doi.org/10.1007/s12020-015-0778-4.CrossRefPubMed

149.

Zhang ZB, Ruan CC, Lin JR, Xu L, Chen XH, Du YN, Fu MX, Kong LR, Zhu DL, Gao PJ. Perivascular Adipose Tissue-Derived PDGF-D Contributes to Aortic Aneurysm Formation During Obesity. Diabetes. 2018;67(8):1549–60. https://doi.org/10.2337/db18-0098.CrossRefPubMed

150.

Suriyaprom K, Pheungruang B, Tungtrongchitr R, Sroijit OY. Relationships of apelin concentration and APLN T-1860C polymorphism with obesity in Thai children. BMC Pediatr. 2020;20(1):455. https://doi.org/10.1186/s12887-020-02350-z.CrossRefPubMedPubMedCentral

151.

Vaittinen M, Kolehmainen M, Rydén M, Eskelinen M, Wabitsch M, Pihlajamäki J, Uusitupa M, Pulkkinen L. MFAP5 is related to obesity-associated adipose tissue and extracellular matrix remodeling and inflammation. Obesity (Silver Spring). 2015;23(7):1371-1378. doi:https://doi.org/10.1002/oby.21103

152.

Wolff G, Taranko AE, Meln I, Weinmann J, Sijmonsma T, Lerch S, Heide D, Billeter AT, Tews D, Krunic D, et al. Diet-dependent function of the extracellular matrix proteoglycan Lumican in obesity and glucose homeostasis. Mol Metab. 2019;19:97–106. https://doi.org/10.1016/j.molmet.2018.10.007.CrossRefPubMed

153.

Soomro I, Hong A, Li Z, Duncan JS, Skolnik EY. Discoidin Domain Receptor 1 (DDR1) tyrosine kinase is upregulated in PKD kidneys but does not play a role in the pathogenesis of polycystic kidney disease. PLoS One. 2019;14(7):e0211670. https://doi.org/10.1371/journal.pone.0211670.CrossRefPubMedPubMedCentral

154.

Zeng H, Qi X, Xu X, Wu Y. TAB1 regulates glycolysis and activation of macrophages in diabetic nephropathy. Inflamm Res. 2020;69(12):1215–34. https://doi.org/10.1007/s00011-020-01411-4.CrossRefPubMedPubMedCentral

155.

Zalli D, Bayliss R, Fry AM. The Nek8 protein kinase, mutated in the human cystic kidney disease nephronophthisis, is both activated and degraded during ciliogenesis. Hum Mol Genet. 2012;21(5):1155–71. https://doi.org/10.1093/hmg/ddr544.CrossRefPubMed

156.

Li YB, Wu Q, Liu J, Fan YZ, Yu KF, Cai Y. miR-199a-3p is involved in the pathogenesis and progression of diabetic neuropathy through downregulation of SerpinE2. Mol Med Rep. 2017;16(3):2417–24. https://doi.org/10.3892/mmr.2017.6874.CrossRefPubMedPubMedCentral

157.

Zhou XJ, Cheng FJ, Qi YY, Zhao YF, Hou P, Zhu L, Lv JC, Zhang H. FCGR2B and FCRLB gene polymorphisms associated with IgA nephropathy. PLoS One. 2013;8(4):e61208. https://doi.org/10.1371/journal.pone.0061208.CrossRefPubMedPubMedCentral

158.

Tsai YC, Kuo PL, Hung WW, Wu LY, Wu PH, Chang WA, Kuo MC, Hsu YL. Angpt2 Induces Mesangial Cell Apoptosis through the MicroRNA-33-5p-SOCS5 Loop in Diabetic Nephropathy. Mol Ther Nucleic Acids. 2018;13:543–55. https://doi.org/10.1016/j.omtn.2018.10.003.CrossRefPubMedPubMedCentral

159.

Ohtsubo H, Okada T, Nozu K, Takaoka Y, Shono A, Asanuma K, Zhang L, Nakanishi K, Taniguchi-Ikeda M, Kaito H, et al. Identification of mutations in FN1 leading to glomerulopathy with fibronectin deposits. Pediatr Nephrol. 2016;31(9):1459–67. https://doi.org/10.1007/s00467-016-3368-7.CrossRefPubMed

160.

Gerarduzzi C, Kumar RK, Trivedi P, Ajay AK, Iyer A, Boswell S, Hutchinson JN, Waikar SS, Vaidya VS. Silencing SMOC2 ameliorates kidney fibrosis by inhibiting fibroblast to myofibroblast transformation. JCI Insight. 2017;2(8):e90299. https://doi.org/10.1172/jci.insight.90299.CrossRefPubMedCentral

161.

Kim JM, Wu H, Green G, Winkler CA, Kopp JB, Miner JH, Unanue ER, Shaw AS. CD2-associated protein haploinsufficiency is linked to glomerular disease susceptibility. Science. 2003;300(5623):1298–300. https://doi.org/10.1126/science.1081068.CrossRefPubMed

162.

Li QS, Cheng P, Favis R, Wickenden A, Romano G, Wang H. SCN9A Variants May be Implicated in Neuropathic Pain Associated With Diabetic Peripheral Neuropathy and Pain Severity. Clin J Pain. 2015;31(11):976–82. https://doi.org/10.1097/AJP.0000000000000205.CrossRefPubMedPubMedCentral

163.

Bennett CE, Nsengimana J, Bostock JA, Cymbalista C, Futers TS, Knight BL, McCormack LJ, Prasad UK, Riches K, Rolton D, et al. CCAAT/enhancer binding protein alpha, beta and delta gene variants: associations with obesity related phenotypes in the Leeds Family Study. Diab Vasc Dis Res. 2010;7(3):195–203. https://doi.org/10.1177/1479164110366274.CrossRefPubMed

164.

Domingues-Montanari S, Subirana I, Tomás M, Marrugat J, Sentí M. Association between ESR2 genetic variants and risk of myocardial infarction. Clin Chem. 2008;54(7):1183–9. https://doi.org/10.1373/clinchem.2007.102400.CrossRefPubMed

165.

Eberlé D, Clément K, Meyre D, Sahbatou M, Vaxillaire M, Le Gall A, Ferré P, Basdevant A, Froguel P, Foufelle F. SREBF-1 gene polymorphisms are associated with obesity and type 2 diabetes in French obese and diabetic cohorts. Diabetes. 2004;53(8):2153–7. https://doi.org/10.2337/diabetes.53.8.2153.CrossRefPubMed

166.

Cheng J, Song J, He X, Zhang M, Hu S, Zhang S, Yu Q, Yang P, Xiong F, Wang DW, et al. Loss of Mbd2 Protects Mice Against High-Fat Diet-Induced Obesity and Insulin Resistance by Regulating the Homeostasis of Energy Storage and Expenditure. Diabetes. 2016;65(11):3384–95. https://doi.org/10.2337/db16-0151.CrossRefPubMed

167.

Cavallari JF, Fullerton MD, Duggan BM, Foley KP, Denou E, Smith BK, Desjardins EM, Henriksbo BD, Kim KJ, Tuinema BR, et al. Muramyl Dipeptide-Based Postbiotics Mitigate Obesity-Induced Insulin Resistance via IRF4. Cell Metab. 2017; 25(5):1063-1074.e3. doi:https://doi.org/10.1016/j.cmet.2017.03.021

168.

Qi L, Saberi M, Zmuda E, Wang Y, Altarejos J, Zhang X, Dentin R, Hedrick S, Bandyopadhyay G, Hai T, et al. Adipocyte CREB promotes insulin resistance in obesity. Cell Metab. 2009;9(3):277–86. https://doi.org/10.1016/j.cmet.2009.01.006.CrossRefPubMedPubMedCentral

169.

Yan X, Zhu MJ, Xu W, Tong JF, Ford SP, Nathanielsz PW, Du M. Up-regulation of Toll-like receptor 4/nuclear factor-kappaB signaling is associated with enhanced adipogenesis and insulin resistance in fetal skeletal muscle of obese sheep at late gestation. Endocrinology. 2010;151(1):380–7. https://doi.org/10.1210/en.2009-0849.CrossRefPubMed

170.

Matsha TE, Kengne AP, Hector S, Mbu DL, Yako YY, Erasmus RT. MicroRNA profiling and their pathways in South African individuals with prediabetes and newly diagnosed type 2 diabetes mellitus. Oncotarget. 2018;9(55):30485–98. https://doi.org/10.18632/oncotarget.25271.CrossRefPubMedPubMedCentral

171.

Ding L, Ai D, Wu R, Zhang T, Jing L, Lu J, Zhong L. Identification of the differential expression of serum microRNA in type 2 diabetes. Biosci Biotechnol Biochem. 2016;80(3):461–5. https://doi.org/10.1080/09168451.2015.1107460.CrossRefPubMed

172.

Hall CL, Akhtar MM, Sabater-Molina M, Futema M, Asimaki A, Protonotarios A, Dalageorgou C, Pittman AM, Suarez MP, Aguilera B, et al. Filamin C variants are associated with a distinctive clinical and immunohistochemical arrhythmogenic cardiomyopathy phenotype. Int J Cardiol. 2020;307:101–8. https://doi.org/10.1016/j.Eijcard.2019.09.048.CrossRefPubMed

173.

Salazar-Mendiguchía J, Ochoa JP, Palomino-Doza J, Domínguez F, Díez-López C, Akhtar M, Ramiro-León S, Clemente MM, Pérez-Cejas A, Robledo M, et al. Mutations in TRIM63 cause an autosomal-recessive form of hypertrophic cardiomyopathy. Heart. 2020;106(17):1342–8. https://doi.org/10.1136/heartjnl-2020-316913.CrossRefPubMed

174.

Xiao Y, Deng Y, Yuan F, Xia T, Liu H, Li Z, Chen S, Liu Z, Ying H, Liu Y, et al. An ATF4-ATG5 signaling in hypothalamic POMC neurons regulates obesity. Autophagy. 2017;13(6):1088–9. https://doi.org/10.1080/15548627.2017.1307488.CrossRefPubMedPubMedCentral

175.

Stratigopoulos G, LeDuc CA, Cremona ML, Chung WK, Leibel RL. Cut-like homeobox 1 (CUX1) regulates expression of the fat mass and obesity-associated and retinitis pigmentosa GTPase regulator-interacting protein-1-like (RPGRIP1L) genes and coordinates leptin receptor signaling. J Biol Chem. 2011;286(3):2155–70. https://doi.org/10.1074/jbc.M110.188482.

176.

Zhou JP, Ren YD, Xu QY, Song Y, Zhou F, Chen MY, Liu JJ, Chen LG, Pan JS. Obesity-Induced Upregulation of ZBTB7A Promotes Lipid Accumulation through SREBP1. Biomed Res Int. 2020:4087928. https://doi.org/10.1155/2020/4087928.

Title: Investigation of candidate genes and mechanisms underlying obesity associated type 2 diabetes mellitus using bioinformatics analysis and screening of small drug molecules
Authors: G. Prashanth
Basavaraj Vastrad
Anandkumar Tengli
Chanabasayya Vastrad
Iranna Kotturshetti
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Obesity
Obesity
Diabetes
Type 2 Diabetes
Published in: BMC Endocrine Disorders / Issue 1/2021
Electronic ISSN: 1472-6823
DOI: https://doi.org/10.1186/s12902-021-00718-5

Obesity Clinical Trial Summary

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STEP AAG HeroTeaserCollection image/© Tarek / Generated with AI / Stock.adobe.com, ACC 2024 Pediatric and Congenital Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Pulmonary Vascular Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Valvular Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 HF and Cardiomyopathies: Year in Review/© 2024 American College of Cardiology, Woman out walking/© Seventyfour / stock.adobe.com (symbolic image with model), Woman checking smartwatch /© saltdium / stock.adobe.com (symbolic image with model), Cardiac catheterization/© Damian / stock.adobe.com

At a glance: The STEP trials

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