Review Article

Overview on Thioredoxin-Interacting Protein (TXNIP): A Potential Target for Diabetes Intervention

Author(s): Rajesh Basnet*, Til Bahadur Basnet, Buddha Bahadur Basnet and Sandhya Khadka

Volume 23, Issue 7, 2022

Published on: 14 April, 2022

Page: [761 - 767] Pages: 7

DOI: 10.2174/1389450123666220303092324

Price: $65

Abstract

Background: Diabetes mellitus (DM) is a common metabolic disorder characterized by a persistent increment of blood glucose. Type 2 DM is characterized by insulin resistance and β-cell dysfunction. Thioredoxin-interacting protein (TXNIP) is among the factors that control the production and loss of pancreatic β-cells.

Objective: Recent studies have shown that high glucose can significantly up-regulate the expression of the TXNIP. Overexpression of TXNIP in β-cells not only induced apoptosis but also decreased the production of insulin. At the same time, TXNIP deficiency protected the apoptosis of β-cells, leading to increased insulin production. Therefore, finding small molecules that can modulate TXNIP expression and downstream signalling pathways is essential. Thus, the inhibition of TXNIP has beneficial effects on the cardiovascular system and other tissues such as the heart and the kidney in DM. Therefore, DM treatment must target small TXNIP activity, inhibit expression, and promote endogenous cell mass and insulin production.

Conclusion: This review briefly describes the effect mechanism, regulatory mechanism, and crystal structure of TXNIP. In addition, we highlight how TXNIP signalling networks contribute to diabetes and interact with drugs that inhibit the development often and its complexes. Finally, the current status and prospects of TXNIP targeted therapy are also discussed.

Keywords: TXNIP, β-cells, DM, FOXO1, ChREBP, insulin.

« Previous
Graphical Abstract

[1]
Kharroubi AT, Darwish HM. Diabetes mellitus: The epidemic of the century. World J Diabetes 2015; 6(6): 850-67.
[http://dx.doi.org/10.4239/wjd.v6.i6.850] [PMID: 26131326]
[2]
Roberto S, Crisafulli A. Consequences of type 1 and 2 diabetes mellitus on the cardiovascular regulation during exercise: A brief review. Curr Diabetes Rev 2017; 13(6): 560-5.
[http://dx.doi.org/10.2174/1573399812666160614123226] [PMID: 27306960]
[3]
Lotfy M, Adeghate J, Kalasz H, Singh J, Adeghate E. Chronic complications of diabetes mellitus: A mini review. Curr Diabetes Rev 2017; 13(1): 3-10.
[http://dx.doi.org/10.2174/1573399812666151016101622] [PMID: 26472574]
[4]
Atkinson MA, Eisenbarth GS, Michels AW. Type 1 diabetes. Lancet 2014; 383(9911): 69-82.
[http://dx.doi.org/10.1016/S0140-6736(13)60591-7] [PMID: 23890997]
[5]
Sørgjerd EP. Type 1 diabetes-related autoantibodies in different forms of diabetes. Curr Diabetes Rev 2019; 15(3): 199-204.
[http://dx.doi.org/10.2174/1573399814666180730105351] [PMID: 30058495]
[6]
Olokoba AB, Obateru OA, Olokoba LB. Type 2 diabetes mellitus: A review of current trends. Oman Med J 2012; 27(4): 269-73.
[http://dx.doi.org/10.5001/omj.2012.68] [PMID: 23071876]
[7]
Berbudi A, Rahmadika N, Tjahjadi AI, Ruslami R. Type 2 diabetes and its impact on the immune system. Curr Diabetes Rev 2020; 16(5): 442-9.
[http://dx.doi.org/10.2174/1573399815666191024085838] [PMID: 31657690]
[8]
Elizabeth MM, Alarcon-Aguilar JF, Clara OC, Del Carmen M. Pancreatic -cells and type 2 diabetes development. Curr Diabetes Rev 2017; 13(2): 108-21.
[http://dx.doi.org/10.2174/1573399812666151020101222] [PMID: 28917077]
[9]
Kampmann U, Madsen LR, Skajaa GO, Iversen DS, Moeller N, Ovesen P. Gestational diabetes: A clinical update. World J Diabetes 2015; 6(8): 1065-72.
[http://dx.doi.org/10.4239/wjd.v6.i8.1065] [PMID: 26240703]
[10]
Davey RX. Gestational diabetes mellitus: A review from 2004. Curr Diabetes Rev 2005; 1(2): 203-13.
[http://dx.doi.org/10.2174/1573399054022776] [PMID: 18220596]
[11]
Shalev A. Minireview: Thioredoxin-interacting protein: Regulation and function in the pancreatic -cell. Mol Endocrinol 2014; 28(8): 1211-20.
[http://dx.doi.org/10.1210/me.2014-1095] [PMID: 24911120]
[12]
Chen KS, DeLuca HF. Isolation and characterization of a novel cDNA from HL-60 cells treated with 1,25-dihydroxyvitamin D-3. Biochim Biophys Acta 1994; 1219(1): 26-32.
[http://dx.doi.org/10.1016/0167-4781(94)90242-9] [PMID: 8086474]
[13]
Nishiyama A, Matsui M, Iwata S, et al. Identification of thioredoxin-binding protein-2/vitamin D(3) up-regulated protein 1 as a negative regulator of thioredoxin function and expression. J Biol Chem 1999; 274(31): 21645-50.
[http://dx.doi.org/10.1074/jbc.274.31.21645] [PMID: 10419473]
[14]
Yamanaka H, Maehira F, Oshiro M, et al. A possible interaction of thioredoxin with VDUP1 in HeLa cells detected in a yeast two-hybrid system. Biochem Biophys Res Commun 2000; 271(3): 796-800.
[http://dx.doi.org/10.1006/bbrc.2000.2699] [PMID: 10814541]
[15]
Junn E, Han SH, Im JY, et al. Vitamin D3 up-regulated protein 1 mediates oxidative stress via suppressing the thioredoxin function. J Immunol 2000; 164(12): 6287-95.
[http://dx.doi.org/10.4049/jimmunol.164.12.6287] [PMID: 10843682]
[16]
Nishiyama A, Masutani H, Nakamura H, Nishinaka Y, Yodoi J. Redox regulation by thioredoxin and thioredoxin-binding proteins. IUBMB Life 2001; 52(1-2): 29-33.
[http://dx.doi.org/10.1080/15216540252774739] [PMID: 11795589]
[17]
Patwari P, Higgins LJ, Chutkow WA, Yoshioka J, Lee RT. The interaction of thioredoxin with Txnip. Evidence for formation of a mixed disulfide by disulfide exchange. J Biol Chem 2006; 281(31): 21884-91.
[http://dx.doi.org/10.1074/jbc.M600427200] [PMID: 16766796]
[18]
Fould B, Lamamy V, Guenin SP, et al. Mutagenic analysis in a pure molecular system shows that thioredoxin-interacting protein residue Cys247 is necessary and sufficient for a mixed disulfide formation with thioredoxin. Protein Sci 2012; 21(9): 1323-33.
[19]
Zhou R, Tardivel A, Thorens B, Choi I, Tschopp J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat Immunol 2010; 11(2): 136-40.
[http://dx.doi.org/10.1038/ni.1831] [PMID: 20023662]
[20]
Nishinaka Y, Nishiyama A, Masutani H, et al. Loss of thioredoxin-binding protein-2/vitamin D3 up-regulated protein 1 in human T-cell leukemia virus type I-dependent T-cell transformation: Implications for adult T-cell leukemia leukemogenesis. Cancer Res 2004; 64(4): 1287-92.
[http://dx.doi.org/10.1158/0008-5472.CAN-03-0908] [PMID: 14983878]
[21]
Oka S, Yoshihara E, Bizen-Abe A, et al. Thioredoxin binding protein-2/thioredoxin-interacting protein is a critical regulator of insulin secretion and peroxisome proliferator-activated receptor function. Endocrinology 2009; 150(3): 1225-34.
[http://dx.doi.org/10.1210/en.2008-0646] [PMID: 18974273]
[22]
Alhawiti NM, Al Mahri S, Aziz MA, Malik SS, Mohammad S. TXNIP in metabolic regulation: Physiological role and therapeutic outlook. Curr Drug Targets 2017; 18(9): 1095-103.
[http://dx.doi.org/10.2174/1389450118666170130145514] [PMID: 28137209]
[23]
Shakya A, Chaudary SK, Garabadu D, Bhat HR, Kakoti BB, Ghosh SK. A comprehensive review on preclinical diabetic models. Curr Diabetes Rev 2020; 16(2): 104-16.
[http://dx.doi.org/10.2174/1573399815666190510112035] [PMID: 31074371]
[24]
Gillespie KM. Type 1 diabetes: Pathogenesis and prevention. CMAJ 2006; 175(2): 165-70.
[http://dx.doi.org/10.1503/cmaj.060244] [PMID: 16847277]
[25]
Ozougwu J, Obimba K, Belonwu C, Unakalamba C. The pathogenesis and pathophysiology of type 1 and type 2 diabetes mellitus. J Physiol Pathophysiol 2013; 4(4): 46-57.
[http://dx.doi.org/10.5897/JPAP2013.0001]
[26]
Basnet R, Khadka S, Basnet BB, Gupta R. Perspective on acetylcholinesterase: A potential target for Alzheimer’s disease intervention. Curr Enzym Inhib 2020; 16(3): 181-8.
[http://dx.doi.org/10.2174/1573408016999200801021329]
[27]
Li L, Ismael S, Nasoohi S, et al. Thioredoxin-Interacting Protein (TXNIP) associated NLRP3 inflammasome activation in human Alzheimer’s disease brain. J Alzheimers Dis 2019; 68(1): 255-65.
[http://dx.doi.org/10.3233/JAD-180814] [PMID: 30741672]
[28]
Nasoohi S, Parveen K, Ishrat T. Metabolic syndrome, brain insulin resistance, and Alzheimer’s disease: Thioredoxin Interacting Protein (TXNIP) and inflammasome as core amplifiers. J Alzheimers Dis 2018; 66(3): 857-85.
[http://dx.doi.org/10.3233/JAD-180735] [PMID: 30372683]
[29]
Zhang M, Hu G, Shao N, et al. Thioredoxin-interacting protein (TXNIP) as a target for Alzheimer’s disease: Flavonoids and phenols. Inflammopharmacology 2021; 29(5): 1317-29.
[http://dx.doi.org/10.1007/s10787-021-00861-4] [PMID: 34350508]
[30]
Xiao YD, Huang YY, Wang HX, et al. Thioredoxin-interacting protein mediates NLRP3 inflammasome activation involved in the susceptibility to ischemic acute kidney injury in diabetes. Oxidative Med Cell Longev 2016. 2016.
[http://dx.doi.org/10.1155/2016/2386068]
[31]
Yu J, Nagasu H, Murakami T, et al. Inflammasome activation leads to Caspase-1-dependent mitochondrial damage and block of mitophagy. Proc Natl Acad Sci 2014; 111(43): 15514-9.
[http://dx.doi.org/10.1073/pnas.1414859111] [PMID: 25313054]
[32]
Banerjee M, Saxena M. Interleukin-1 (IL-1) family of cytokines: Role in type 2 diabetes. Clin Chim Acta 2012; 413(15-16): 1163-70.
[http://dx.doi.org/10.1016/j.cca.2012.03.021] [PMID: 22521751]
[33]
Bolívar BE, Vogel TP, Bouchier-Hayes L. Inflammatory caspase regulation: Maintaining balance between inflammation and cell death in health and disease. FEBS J 2019; 286(14): 2628-44.
[http://dx.doi.org/10.1111/febs.14926] [PMID: 31090171]
[34]
Parikh H, Carlsson E, Chutkow WA, et al. TXNIP regulates peripheral glucose metabolism in humans. PLoS Med 2007; 4(5)e158
[http://dx.doi.org/10.1371/journal.pmed.0040158] [PMID: 17472435]
[35]
Chutkow WA, Patwari P, Yoshioka J, Lee RT. Thioredoxin-Interacting Protein (Txnip) is a critical regulator of hepatic glucose production. J Biol Chem 2008; 283(4): 2397-406.
[http://dx.doi.org/10.1074/jbc.M708169200] [PMID: 17998203]
[36]
Hong K, Xu G, Grayson TB, Shalev A. Cytokines regulate -cell thioredoxin-interacting protein (TXNIP) via distinct mechanisms and pathways. J Biol Chem 2016; 291(16): 8428-39.
[http://dx.doi.org/10.1074/jbc.M115.698365] [PMID: 26858253]
[37]
Minn AH, Hafele C, Shalev A. Thioredoxin-interacting protein is stimulated by glucose through a carbohydrate response element and induces -cell apoptosis. Endocrinology 2005; 146(5): 2397-405.
[http://dx.doi.org/10.1210/en.2004-1378] [PMID: 15705778]
[38]
Xu G, Chen J, Jing G, Shalev A. Thioredoxin-interacting protein regulates insulin transcription through microRNA-204. Nat Med 2013; 19(9): 1141-6.
[http://dx.doi.org/10.1038/nm.3287] [PMID: 23975026]
[39]
Saxena G, Chen J, Shalev A. Intracellular shuttling and mitochondrial function of thioredoxin-interacting protein. J Biol Chem 2010; 285(6): 3997-4005.
[http://dx.doi.org/10.1074/jbc.M109.034421] [PMID: 19959470]
[40]
Filios SR, Xu G, Chen J, Hong K, Jing G, Shalev A. MicroRNA-200 is induced by thioredoxin-interacting protein and regulates Zeb1 protein signaling and beta cell apoptosis. J Biol Chem 2014; 289(52): 36275-83.
[http://dx.doi.org/10.1074/jbc.M114.592360] [PMID: 25391656]
[41]
Jing G, Westwell-Roper C, Chen J, Xu G, Verchere CB, Shalev A. Thioredoxin-interacting protein promotes islet amyloid polypeptide expression through miR-124a and FoxA2. J Biol Chem 2014; 289(17): 11807-15.
[http://dx.doi.org/10.1074/jbc.M113.525022] [PMID: 24627476]
[42]
Westermark P, Andersson A, Westermark GT. Islet amyloid polypeptide, islet amyloid, and diabetes mellitus. Physiol Rev 2011; 91(3): 795-826.
[http://dx.doi.org/10.1152/physrev.00042.2009] [PMID: 21742788]
[43]
Abedini A, Schmidt AM. Mechanisms of islet amyloidosis toxicity in type 2 diabetes. FEBS Lett 2013; 587(8): 1119-27.
[http://dx.doi.org/10.1016/j.febslet.2013.01.017] [PMID: 23337872]
[44]
Metukuri MR, Zhang P, Basantani MK, et al. ChREBP mediates glucose-stimulated pancreatic -cell proliferation. Diabetes 2012; 61(8): 2004-15.
[http://dx.doi.org/10.2337/db11-0802] [PMID: 22586588]
[45]
Poungvarin N, Lee JK, Yechoor VK, et al. Carbohydrate Response Element-Binding Protein (ChREBP) plays a pivotal role in beta cell glucotoxicity. Diabetologia 2012; 55(6): 1783-96.
[http://dx.doi.org/10.1007/s00125-012-2506-4] [PMID: 22382520]
[46]
Yu FX, Luo Y. Tandem ChoRE and CCAAT motifs and associated factors regulate Txnip expression in response to glucose or adenosine-containing molecules. PLoS One 2009; 4(12)e8397
[http://dx.doi.org/10.1371/journal.pone.0008397] [PMID: 20027290]
[47]
Jeong Y-S, Kim D, Lee YS, et al. Integrated expression profiling and genome-wide analysis of ChREBP targets reveals the dual role for ChREBP in glucose-regulated gene expression. PLoS One 2011; 6(7)e22544
[http://dx.doi.org/10.1371/journal.pone.0022544] [PMID: 21811631]
[48]
Filhoulaud G, Guilmeau S, Dentin R, Girard J, Postic C. Novel insights into ChREBP regulation and function. Trends Endocrinol Metab 2013; 24(5): 257-68.
[http://dx.doi.org/10.1016/j.tem.2013.01.003] [PMID: 23597489]
[49]
Davies MN, O’Callaghan BL, Towle HC. Glucose activates ChREBP by increasing its rate of nuclear entry and relieving repression of its transcriptional activity. J Biol Chem 2008; 283(35): 24029-38.
[http://dx.doi.org/10.1074/jbc.M801539200] [PMID: 18591247]
[50]
Kibbe C, Chen J, Xu G, Jing G, Shalev A. FOXO1 competes with Carbohydrate Response Element-Binding Protein (ChREBP) and inhibits thioredoxin-interacting protein (TXNIP) transcription in pancreatic beta cells. J Biol Chem 2013; 288(32): 23194-202.
[http://dx.doi.org/10.1074/jbc.M113.473082] [PMID: 23803610]
[51]
Kibbe C, Chen J, Xu G, Jing G, Shalev A. FOXO1 competes with chREBP and inhibits TXNIP transcription in pancreatic beta cells. J Biol Chem 2013; 288(32): 23194-02.
[52]
Hang Y, Stein R. MafA and MafB activity in pancreatic cells. Trends Endocrinol Metab 2011; 22(9): 364-73.
[http://dx.doi.org/10.1016/j.tem.2011.05.003] [PMID: 21719305]
[53]
Kim DH, Zhang T, Ringquist S, Dong HH. Targeting FoxO1 for hypertriglyceridemia. Curr Drug Targets 2011; 12(9): 1245-55.
[http://dx.doi.org/10.2174/138945011796150262] [PMID: 21443465]
[54]
Pandey A, Kumar GS, Kadakol A, Malek V, Gaikwad AB. FoxO1 inhibitors: The future medicine for metabolic disorders? Curr Diabetes Rev 2016; 12(3): 223-30.
[http://dx.doi.org/10.2174/1573399811666150804104858] [PMID: 26239835]
[55]
Kaneto H, Matsuoka TA, Katakami N, Matsuhisa M. Combination of MafA, PDX-1 and NeuroD is a useful tool to efficiently induce insulin-producing surrogate beta-cells. Curr Med Chem 2009; 16(24): 3144-51.
[http://dx.doi.org/10.2174/092986709788802980] [PMID: 19689288]
[56]
Kaneto H. Pancreatic -cell glucose toxicity in type 2 diabetes mellitus. Curr Diabetes Rev 2015; 11(1): 2-6.
[http://dx.doi.org/10.2174/1573399811666141216160217] [PMID: 25515340]
[57]
Hwang J, Suh HW, Jeon YH, et al. The structural basis for the negative regulation of thioredoxin by thioredoxin-interacting protein. Nat Commun 2014; 5(1): 2958.
[http://dx.doi.org/10.1038/ncomms3958] [PMID: 24389582]
[58]
Liu Y, Lau J, Li W, et al. Structural basis for the regulatory role of the PPxY motifs in the thioredoxin-interacting protein TXNIP. Biochem J 2016; 473(2): 179-87.
[http://dx.doi.org/10.1042/BJ20150830] [PMID: 26527736]
[59]
Protein Data Bank. Crystal Structure of the VAV2 SH2 domain in complex with TXNIP phosphorylated peptide. 2014. Available www.rcsb.org/structure/4ROJ
[60]
Protein Data Bank. Crystal Structure of ITCH WW3 domain in complex with TXNIP peptide. 2014. Available from: www.rcsb.org/structure/5DWS
[61]
Protein Data Bank. Crystal Structure of WW4 domain of ITCH in complex with TXNIP peptide. 2014. Available from: www.rcsb.org/structure/5DZD
[62]
Spindel ON, Burke RM, Yan C, Berk BC. Thioredoxin-interacting protein is a biomechanical regulator of Src activity: Key role in endothelial cell stress fiber formation. Circ Res 2014; 114(7): 1125-32.
[http://dx.doi.org/10.1161/CIRCRESAHA.114.301315] [PMID: 24515523]
[63]
Ahn B, Soundarapandian MM, Sessions H, et al. MondoA coordinately regulates skeletal myocyte lipid homeostasis and insulin signaling. J Clin Invest 2016; 126(9): 3567-79.
[http://dx.doi.org/10.1172/JCI87382] [PMID: 27500491]
[64]
Krammer P, Gülow K, Sass S. Inhibitors of Thioredoxin- Interacting Protein (TXNIP) for therapy. Google Patent EP2657340A1, 2015.
[65]
Krammer P, Gülow K, Sass S. Inhibitors of Thioredoxin- Interacting Protein (TXNIP) for therapy. Google Patents WO2013159879A1 2013.
[66]
Thielen L, Chen J, Xu G, et al. Novel small molecule TXNIP inhibitor protects against diabetes. Am Diabetes Assoc 2018; 67: 87.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy