Skip to content
2000
image of Cytokeratin 8 as a Novel Therapeutic Target in Type 2 Diabetes Mellitus: Suppression of Hepatic Glycogen Synthesis via IRS1/PI3K/Akt/GSK3β Signaling
file format pdf download PDF

Abstract

Introduction

Recent studies have established that cytokeratin 8 (CK8) is closely linked to glycogen synthesis; however, its mechanistic role in hepatic glycogen synthesis in type 2 diabetes mellitus (T2DM) remains unclear. This study aimed to elucidate the effects and underlying molecular mechanisms of CK8.

Methods

We analyzed CK8 expression and the IRS1 (Insulin Receptor Substrate 1)/PI3K (Phosphoinositide 3-Kinase)/Akt (Protein Kinase B)/GSK3β (Glycogen Synthase Kinase 3 beta) pathway in liver samples from T2DM patients, diabetic C57BL/6J mouse models, and high glucose-treated NCTC 1469 cells using Western blotting, immunohistochemistry, and PAS staining.

Results

CK8 was significantly upregulated in all T2DM models, correlating with suppressed IRS1/PI3K/Akt/GSK3β signaling and reduced glycogen synthesis. Our functional studies demonstrated that CK8 overexpression exacerbated these effects, while CK8 knockdown restored glycogen levels to near-normal.

Discussion

In our study, CK8 was identified as a negative regulator of hepatic glycogen synthesis by modulating the IRS1/PI3K/Akt/GSK3β pathway.

Conclusion

These findings position CK8 as a promising therapeutic target for T2DM, with CK8 inhibition offering a novel strategy to improve hepatic insulin resistance and glycogen storage without requiring β-cell stimulation.

© 2025 The Author(s). Published by Bentham Science Publishers.
This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode
Loading

Article metrics loading...

/content/journals/cdt/10.2174/0113894501394500250903095958
2025-10-01
2025-11-07

  • From This Site

    /content/journals/cdt/10.2174/0113894501394500250903095958
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

/deliver/fulltext/cdt/10.2174/0113894501394500250903095958/BMS-CDT-2025-140.html?itemId=/content/journals/cdt/10.2174/0113894501394500250903095958&mimeType=html&fmt=ahah

References

  1. Liu Y. Deng J. Fan D. Ginsenoside Rk3 ameliorates high-fat-diet/streptozocin induced type 2 diabetes mellitus in mice via the AMPK/Akt signaling pathway. Food Funct. 2019 10 5 2538 2551 10.1039/C9FO00095J 30993294
    [Google Scholar]
  2. Kaur P. Mittal A. Nayak S.K. Vyas M. Mishra V. Khatik G.L. Current strategies and drug targets in the management of type 2 diabetes mellitus. Curr. Drug Targets 2018 19 15 1738 1766 10.2174/1389450119666180727142902 30051787
    [Google Scholar]
  3. Holman N. Young B. Gadsby R. Current prevalence of type 1 and type 2 diabetes in adults and children in the UK. Diabet. Med. 2015 32 9 1119 1120 10.1111/dme.12791 25962518
    [Google Scholar]
  4. Li X. Wan T. Li Y. Role of FoxO1 in regulating autophagy in type 2 diabetes mellitus (Review). Exp. Ther. Med. 2021 22 1 707 10.3892/etm.2021.10139 34007316
    [Google Scholar]
  5. Galicia-Garcia U. Benito-Vicente A. Jebari S. Larrea-Sebal A. Siddiqi H. Uribe K.B. Ostolaza H. Martín C. Pathophysiology of type 2 diabetes mellitus. Int. J. Mol. Sci. 2020 21 17 6275 10.3390/ijms21176275 32872570
    [Google Scholar]
  6. DeFronzo R.A. Banting Lecture. From the triumvirate to the ominous octet: A new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 2009 58 4 773 795 10.2337/db09‑9028 19336687
    [Google Scholar]
  7. Pappachan J.M. Fernandez C.J. Chacko E.C. Diabesity and antidiabetic drugs. Mol. Aspects Med. 2019 66 3 12 10.1016/j.mam.2018.10.004 30391234
    [Google Scholar]
  8. Ji J. Zhang C. Luo X. Wang L. Zhang R. Wang Z. Fan D. Yang H. Deng J. Effect of stay-green wheat, a novel variety of wheat in china, on glucose and lipid metabolism in high- fat diet induced type 2 diabetic rats. Nutrients 2015 7 7 5143 5155 10.3390/nu7075143 26132991
    [Google Scholar]
  9. Sharma S Taliyan R. Histone deacetylase inhibitors: Future therapeutics for insulin resistance and type 2 diabetes. Pharmacol Res 2016 113 Pt A 320 326 10.1016/j.phrs.2016.09.009 27620069
    [Google Scholar]
  10. Wu J. Chen Y. Li X. Ran L. Liu X. Wang X. Zhen M. Shao S. Zeng L. Wang C. Liang B. Zhao J. Wu Y. Functionalized gadofullerene ameliorates impaired glycolipid metabolism in type 2 diabetic mice. J. Genet. Genomics 2022 49 4 364 376 10.1016/j.jgg.2021.09.004 34687945
    [Google Scholar]
  11. Zhang B. Shen Q. Chen Y. Pan R. Kuang S. Liu G. Sun G. Sun X. Myricitrin alleviates oxidative stress-induced inflammation and apoptosis and protects mice against diabetic cardiomyopathy. Sci. Rep. 2017 7 1 44239 10.1038/srep44239 28287141
    [Google Scholar]
  12. Dey P. Togra J. Mitra S. Intermediate filament: Structure, function, and applications in cytology. Diagn. Cytopathol. 2014 42 7 628 635 10.1002/dc.23132 24591257
    [Google Scholar]
  13. Wang D. Zhang P. Xu X. Wang J. Wang D. Peng P. Zheng C. Meng Q.J. Yang L. Luo Z. Knockdown of cytokeratin 8 overcomes chemoresistance of chordoma cells by aggravating endoplasmic reticulum stress through PERK/eIF2α arm of unfolded protein response and blocking autophagy. Cell Death Dis. 2019 10 12 887 10.1038/s41419‑019‑2125‑9 31767864
    [Google Scholar]
  14. Guo D. Xu Q. Pabla S. Koomen J. Biddinger P. Sharma A. Pabla S. Pacholczyk R. Chang C.C. Friedrich K. Mohammed K. Smallridge R. Copland J. She J.X. Weinberger P. Cytokeratin-8 in anaplastic thyroid carcinoma: More than a simple structural cytoskeletal protein. Int. J. Mol. Sci. 2018 19 2 577 10.3390/ijms19020577 29443941
    [Google Scholar]
  15. Ashmaig M. Cytokeratin 8 in association with sdLDL and ELISA development. N. Am. J. Med. Sci. 2015 7 10 459 466 10.4103/1947‑2714.168673 26713292
    [Google Scholar]
  16. Lähdeniemi I.A.K. Misiorek J.O. Antila C.J.M. Landor S.K.J. Stenvall C.G.A. Fortelius L.E. Bergström L.K. Sahlgren C. Toivola D.M. Keratins regulate colonic epithelial cell differentiation through the Notch1 signalling pathway. Cell Death Differ. 2017 24 6 984 996 10.1038/cdd.2017.28 28475172
    [Google Scholar]
  17. Lau A.T.Y. Chiu J.F. The possible role of cytokeratin 8 in cadmium-induced adaptation and carcinogenesis. Cancer Res. 2007 67 5 2107 2113 10.1158/0008‑5472.CAN‑06‑3771 17332340
    [Google Scholar]
  18. Bozza W.P. Zhang Y. Zhang B. Cytokeratin 8/18 protects breast cancer cell lines from TRAIL-induced apoptosis. Oncotarget 2018 9 33 23264 23273 10.18632/oncotarget.25297 29796187
    [Google Scholar]
  19. Liu F. Chen Z. Wang J. Shao X. Cui Z. Yang C. Zhu Z. Xiong D. Overexpression of cell surface cytokeratin 8 in multidrug-resistant MCF-7/MX cells enhances cell adhesion to the extracellular matrix. Neoplasia 2008 10 11 1275 1284 10.1593/neo.08810 18953437
    [Google Scholar]
  20. Mathew J. Loranger A. Gilbert S. Faure R. Marceau N. Keratin 8/18 regulation of glucose metabolism in normal versus cancerous hepatic cells through differential modulation of hexokinase status and insulin signaling. Exp. Cell Res. 2013 319 4 474 486 10.1016/j.yexcr.2012.11.011 23164509
    [Google Scholar]
  21. Fan X. Jiao G. Pang T. Wen T. He Z. Han J. Zhang F. Chen W. Ameliorative effects of mangiferin derivative TPX on insulin resistance via PI3K/AKT and AMPK signaling pathways in human HepG2 and HL-7702 hepatocytes. Phytomedicine 2023 114 154740 10.1016/j.phymed.2023.154740 36965373
    [Google Scholar]
  22. Xu T. Xu L. Meng P. Ma X. Yang X. Zhou Y. Feng M. Angptl7 promotes insulin resistance and type 2 diabetes mellitus by multiple mechanisms including SOCS3-mediated IRS1 degradation. FASEB J. 2020 34 10 13548 13560 10.1096/fj.202000246RR 32786125
    [Google Scholar]
  23. Sajan M.P. Ivey R.A. Lee M.C. Farese R.V. Hepatic insulin resistance in ob/ob mice involves increases in ceramide, aPKC activity, and selective impairment of Akt-dependent FoxO1 phosphorylation. J. Lipid Res. 2015 56 1 70 80 10.1194/jlr.M052977 25395359
    [Google Scholar]
  24. Tian C. Chang H. La X. Li J. Wushenziye formula improves skeletal muscle insulin resistance in type 2 diabetes mellitus via PTP1B-IRS1-Akt-GLUT4 signaling pathway. Evid. Based Complement. Alternat. Med. 2017 2017 1 4393529 10.1155/2017/4393529 29479370
    [Google Scholar]
  25. Chen S.H. Liu X.N. Peng Y. MicroRNA-351 eases insulin resistance and liver gluconeogenesis via the PI3K/AKT pathway by inhibiting FLOT2 in mice of gestational diabetes mellitus. J. Cell. Mol. Med. 2019 23 9 5895 5906 10.1111/jcmm.14079 31287224
    [Google Scholar]
  26. Liu T.Y. Shi C.X. Gao R. Sun H.J. Xiong X.Q. Ding L. Chen Q. Li Y.H. Wang J.J. Kang Y.M. Zhu G.Q. Irisin inhibits hepatic gluconeogenesis and increases glycogen synthesis via the PI3K/Akt pathway in type 2 diabetic mice and hepatocytes. Clin. Sci. (Lond.) 2015 129 10 839 850 10.1042/CS20150009 26201094
    [Google Scholar]
  27. Guo H. Wu H. Hou Y. Hu P. Du J. Cao L. Yang R. Dong X. Li Z. Oat β-D-glucan ameliorates type II diabetes through TLR4/PI3K/AKT mediated metabolic axis. Int. J. Biol. Macromol. 2023 249 126039 10.1016/j.ijbiomac.2023.126039 37516222
    [Google Scholar]
  28. Das G.C. Hollinger F.B. GSK-3β as a potential coordinator of anabolic and catabolic pathways in hepatitis C virus insulin resistance. Intervirology 2024 67 1 6 18 10.1159/000535787 38104537
    [Google Scholar]
  29. Cheng Z. Luo C. Guo Z. LncRNA-XIST/microRNA-126 sponge mediates cell proliferation and glucose metabolism through the IRS1/PI3K/Akt pathway in glioma. J. Cell. Biochem. 2020 121 3 2170 2183 10.1002/jcb.29440 31680298
    [Google Scholar]
  30. Roux A. Loranger A. Lavoie J.N. Marceau N. Keratin 8/18 regulation of insulin receptor signaling and trafficking in hepatocytes through a concerted phosphoinositide-dependent Akt and Rab5 modulation. FASEB J. 2017 31 8 3555 3573 10.1096/fj.201700036R 28442548
    [Google Scholar]
  31. Shukla P. Dange P. Mohanty B.S. Gadewal N. Chaudhari P. Sarin R. ARID2 suppression promotes tumor progression and upregulates cytokeratin 8, 18 and β-4 integrin expression in TP53-mutated tobacco-related oral cancer and has prognostic implications. Cancer Gene Ther. 2022 29 12 1908 1917 10.1038/s41417‑022‑00505‑x 35869277
    [Google Scholar]
  32. Xi Y.L. Li H.X. Chen C. Liu Y.Q. Lv H.M. Dong S.Q. Luo E.F. Gu M.B. Liu H. Baicalin attenuates high fat diet-induced insulin resistance and ectopic fat storage in skeletal muscle, through modulating the protein kinase B/Glycogen synthase kinase 3 beta pathway. Chin. J. Nat. Med. 2016 14 1 48 55 10.3724/SP.J.1009.2016.00048 26850346
    [Google Scholar]
  33. Heydemann A. An overview of murine high fat diet as a model for type 2 diabetes mellitus. J. Diabetes Res. 2016 2016 1 14 10.1155/2016/2902351 27547764
    [Google Scholar]
  34. Liu Y. Kang X. Niu G. He S. Zhang T. Bai Y. Li Y. Hao H. Chen C. Shou Z. Li B. Shikonin induces apoptosis and prosurvival autophagy in human melanoma A375 cells via ROS-mediated ER stress and p38 pathways. Artif. Cells Nanomed. Biotechnol. 2019 47 1 626 635 10.1080/21691401.2019.1575229 30873870
    [Google Scholar]
  35. Kang X. Wang H. Li Y. Xiao Y. Zhao L. Zhang T. Zhou S. Zhou X. Li Y. Shou Z. Chen C. Li B. Alantolactone induces apoptosis through ROS-mediated AKT pathway and inhibition of PINK1- mediated mitophagy in human HepG2 cells. Artif. Cells Nanomed. Biotechnol. 2019 47 1 1961 1970 10.1080/21691401.2019.1593854 31116036
    [Google Scholar]
  36. Alenazy L.A. Javed M. Elsiesy H. Raddaoui E. Al-Hamoudi W.K. Glycogenic hepatopathy: A Rare hepatic complication of poorly controlled type 1 DM. Case Rep. Med. 2020 2020 1 5 10.1155/2020/1294074 32328105
    [Google Scholar]
  37. Sun M.Z. Dang S.S. Wang W.J. Jia X.L. Zhai S. Zhang X. Li M. Li Y.P. Xun M. Cytokeratin 8 is increased in hepatitis C virus cells and its ectopic expression induces apoptosis of SMMC7721 cells. World J. Gastroenterol. 2013 19 37 6178 6187 10.3748/wjg.v19.i37.6178 24115814
    [Google Scholar]
  38. Lan X. Han J. Wang B. Sun M. Integrated analysis of transcriptome profiling of lncRNAs and mRNAs in livers of type 2 diabetes mellitus. Physiol. Genomics 2022 54 2 86 97 10.1152/physiolgenomics.00105.2021 35073196
    [Google Scholar]
  39. Alam C.M. Silvander J.S.G. Helenius T.O. Toivola D.M. Decreased levels of keratin 8 sensitize mice to streptozotocin-induced diabetes. Acta Physiol. 2018 224 2 e13085 10.1111/apha.13085 29719117
    [Google Scholar]
  40. Ijaz A. Babar S. Sarwar S. Shahid S.U. Shabana The combined role of allelic variants of IRS-1 and IRS-2 genes in susceptibility to type2 diabetes in the Punjabi Pakistani subjects. Diabetol. Metab. Syndr. 2019 11 1 64 10.1186/s13098‑019‑0459‑1 31404179
    [Google Scholar]
  41. Jiang Y. Zhang Q. Soderland C. Steinle J.J. TNFα and SOCS3 regulate IRS-1 to increase retinal endothelial cell apoptosis. Cell. Signal. 2012 24 5 1086 1092 10.1016/j.cellsig.2012.01.003 22266116
    [Google Scholar]
  42. Huang S. Yu C. Hu M. Wen Q. Wen X. Li S. Li K. Ma H. Electroacupuncture ameliorates hepatic defects in a rat model of polycystic ovary syndrome induced by letrozole and a high-fat diet. Acupunct. Med. 2024 42 2 87 99 10.1177/09645284231207863 38044823
    [Google Scholar]
  43. Deng Q. Ma D. Sun G. Yuan X. Wang Z. Liu G. PTEN influences insulin and lipid metabolism in bovine hepatocytes in vitro. J. Dairy Res. 2019 86 1 73 76 10.1017/S0022029919000128 30819264
    [Google Scholar]
  44. Yang Q. Graham T.E. Mody N. Preitner F. Peroni O.D. Zabolotny J.M. Kotani K. Quadro L. Kahn B.B. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature 2005 436 7049 356 362 10.1038/nature03711 16034410
    [Google Scholar]
  45. Kaleem A. Javed S. Rehman N. Abdullah R. Iqtedar M. Aftab M.N. Hoessli D.C. Haq I.U. Phosphorylated and O-GlcNAc modified IRS-1 (Ser1101) and -2 (Ser1149) contribute to human diabetes type II. Protein Pept. Lett. 2021 28 3 333 339 10.2174/0929866527666200813210407 32798372
    [Google Scholar]
  46. Wang F. Chang C. Li R. Zhang Z. Jiang H. Zeng N. Li D. Chen L. Xiao Y. Chen W. Wang Q. Retinol binding protein 4 mediates MEHP-induced glucometabolic abnormalities in HepG2 cells. Toxicology 2019 424 152236 10.1016/j.tox.2019.06.007 31228551
    [Google Scholar]
  47. Liu P. Shi L. Cang X. Huang J. Wu X. Yan J. Chen L. Cui S. Ye X. CtBP2 ameliorates palmitate-induced insulin resistance in HepG2 cells through ROS mediated JNK pathway. Gen. Comp. Endocrinol. 2017 247 66 73 10.1016/j.ygcen.2017.01.018 28111233
    [Google Scholar]
  48. Sreelekshmi M. Raghu K.G. Vanillic acid mitigates the impairments in glucose metabolism in HepG2 cells through BAD–GK interaction during hyperinsulinemia. J. Biochem. Mol. Toxicol. 2021 35 6 1 8 10.1002/jbt.22750 33651899
    [Google Scholar]
  49. Yousef A. Behiry E. Abd Allah W. Hussien A. Abdelmoneam A. Imam M. Hikal D. IRS-1 genetic polymorphism (r.2963G>A) in type 2 diabetes mellitus patients associated with insulin resistance. Appl. Clin. Genet. 2018 11 99 106 10.2147/TACG.S171096 30319284
    [Google Scholar]
  50. Albegali A.A. Shahzad M. Mahmood S. Ullah M.I. Genetic association of insulin receptor substrate-1 (IRS-1, rs1801278) gene with insulin resistant of type 2 diabetes mellitus in a Pakistani population. Mol. Biol. Rep. 2019 46 6 6065 6070 10.1007/s11033‑019‑05041‑w 31446532
    [Google Scholar]
  51. Cang X. Wang X. Liu P. Wu X. Yan J. Chen J. Wu G. Jin Y. Xu F. Su J. Wan C. Wang X. PINK1 alleviates palmitate induced insulin resistance in HepG2 cells by suppressing ROS mediated MAPK pathways. Biochem. Biophys. Res. Commun. 2016 478 1 431 438 10.1016/j.bbrc.2016.07.004 27423393
    [Google Scholar]
  52. Jang E.H. Ko J.H. Ahn C.W. Lee H.H. Shin J.K. Chang S.J. Park C.S. Kang J.H. in vivo and in vitro application of black soybean peptides in the amelioration of endoplasmic reticulum stress and improvement of insulin resistance. Life Sci. 2010 86 7-8 267 274 10.1016/j.lfs.2009.12.012 20045417
    [Google Scholar]
  53. Lee M. Li H. Zhao H. Suo M. Liu D. Effects of hydroxysafflor yellow A on the PI3K/AKT pathway and apoptosis of pancreatic β- cells in type 2 diabetes mellitus rats. Diabetes Metab. Syndr. Obes. 2020 13 1097 1107 10.2147/DMSO.S246381 32308459
    [Google Scholar]
  54. Bathina S. Das U.N. Dysregulation of PI3K-Akt-mTOR pathway in brain of streptozotocin-induced type 2 diabetes mellitus in Wistar rats. Lipids Health Dis. 2018 17 1 168 10.1186/s12944‑018‑0809‑2 30041644
    [Google Scholar]
  55. Li Y. Tang Y. Shi S. Gao S. Wang Y. Xiao D. Chen T. He Q. Zhang J. Lin Y. Tetrahedral framework nucleic acids ameliorate insulin resistance in type 2 diabetes mellitus via the PI3K/Akt pathway. ACS Appl. Mater. Interfaces 2021 13 34 40354 40364 10.1021/acsami.1c11468 34410099
    [Google Scholar]
  56. Yang Y. Li W. Li Y. Wang Q. Gao L. Zhao J. Dietary Lycium barbarum polysaccharide induces Nrf2/ARE pathway and ameliorates insulin resistance induced by high-fat via activation of PI3K/AKT signaling. Oxid. Med. Cell. Longev. 2014 2014 1 10 10.1155/2014/145641 25045414
    [Google Scholar]
  57. Fang Z. Gao W. Jiang Q. Loor J.J. Zhao C. Du X. Zhang M. Song Y. Wang Z. Liu G. Li X. Lei L. Targeting IRE1α and PERK in the endoplasmic reticulum stress pathway attenuates fatty acid-induced insulin resistance in bovine hepatocytes. J. Dairy Sci. 2022 105 8 6895 6908 10.3168/jds.2021‑21754 35840398
    [Google Scholar]
  58. Mi L. Chen Y. Zheng X. Li Y. Zhang Q. Mo D. Yang G. MicroRNA-139-5p suppresses 3T3-L1 preadipocyte differentiation through notch and IRS1/PI3K/Akt insulin signaling pathways. J. Cell. Biochem. 2015 116 7 1195 1204 10.1002/jcb.25065 25536154
    [Google Scholar]
  59. Cao Y.L. Liu D.J. Zhang H.G. MiR-7 regulates the PI3K/AKT/VEGF pathway of retinal capillary endothelial cell and retinal pericytes in diabetic rat model through IRS-1 and inhibits cell proliferation. Eur. Rev. Med. Pharmacol. Sci. 2018 22 14 4427 4430 10.26355/eurrev_201807_15493 30058674
    [Google Scholar]
  60. Collino M. Aragno M. Castiglia S. Miglio G. Tomasinelli C. Boccuzzi G. Thiemermann C. Fantozzi R. RETRACTED: Pioglitazone improves lipid and insulin levels in overweight rats on a high cholesterol and fructose diet by decreasing hepatic inflammation. Br. J. Pharmacol. 2010 160 8 1892 1902 10.1111/j.1476‑5381.2010.00671.x 20233219
    [Google Scholar]
  61. Lindborg K.A. Teachey M.K. Jacob S. Henriksen E.J. Effects of in vitro antagonism of endocannabinoid-1 receptors on the glucose transport system in normal and insulin-resistant rat skeletal muscle. Diabetes Obes. Metab. 2010 12 8 722 730 10.1111/j.1463‑1326.2010.01227.x 20590750
    [Google Scholar]
  62. Guo X. Sun W. Luo G. Wu L. Xu G. Hou D. Hou Y. Guo X. Mu X. Qin L. Liu T. Panax notoginseng saponins alleviate skeletal muscle insulin resistance by regulating the IRS 1– PI 3K– AKT signaling pathway and GLUT 4 expression. FEBS Open Bio 2019 9 5 1008 1019 10.1002/2211‑5463.12635 30945455
    [Google Scholar]
  63. Varma S. Shrivastav A. Changela S. Khandelwal R.L. Long-term effects of rapamycin treatment on insulin mediated phosphorylation of Akt/PKB and glycogen synthase activity. Exp. Cell Res. 2008 314 6 1281 1291 10.1016/j.yexcr.2007.12.019 18261725
    [Google Scholar]
  64. Zhu T. Zhao R. Zhang L. Bernier M. Liu J. Pyrrolidine dithiocarbamate enhances hepatic glycogen synthesis and reduces FoxO1- mediated gene transcription in type 2 diabetic rats. Am. J. Physiol. Endocrinol. Metab. 2012 302 4 E409 E416 10.1152/ajpendo.00453.2011 22127228
    [Google Scholar]
  65. Tonry C.L. Evans R.M. Ruddock M.W. Duggan B. McCloskey O. Maxwell A.P. O’Rourke D. Boyd R.E. Watt J. Reid C.N. Curry D.J. Stevenson M. Young M.K. Jamison C.S. Gallagher J. Fitzgerald S.P. Lamont J. Watson C.J. Clinical features and predictive biomarkers for bladder cancer in patients with type 2 diabetes presenting with haematuria. Diabetes Metab. Res. Rev. 2022 38 6 e3546 10.1002/dmrr.3546 35578575
    [Google Scholar]
  66. Halaby M.J. Kastein B.K. Yang D.Q. Chloroquine stimulates glucose uptake and glycogen synthase in muscle cells through activation of Akt. Biochem. Biophys. Res. Commun. 2013 435 4 708 713 10.1016/j.bbrc.2013.05.047 23702482
    [Google Scholar]
  67. Hara M Oohara K Dai DF Liapis H Mitotic catastrophe causes podocyte loss in the urine of human diabetics. Am J Pathol 2019 189 2 248 257 10.1016/j.ajpath.2018.10.016 30472210
    [Google Scholar]
  68. Taniai-Riya E. Miyajima K. Kakimoto K. Ohta T. Yasui Y. Kemmochi Y. Anagawa-Nakamura A. Toyoda K. Takahashi A. Shoda T. Hepatocellular adenoma with severe fatty change in a male Spontaneously Diabetic Torii rat. J. Toxicol. Pathol. 2017 30 1 69 73 10.1293/tox.2016‑0051 28190927
    [Google Scholar]
  69. Kakehashi A. Kato A. Inoue M. Ishii N. Okazaki E. Wei M. Tachibana T. Wanibuchi H. Cytokeratin 8/18 as a new marker of mouse liver preneoplastic lesions. Toxicol. Appl. Pharmacol. 2010 242 1 47 55 10.1016/j.taap.2009.09.013 19796649
    [Google Scholar]
  70. Nasir G.A. Mohsin S. Khan M. Shams S. Ali G. Khan S.N. Riazuddin S. Mesenchymal stem cells and Interleukin-6 attenuate liver fibrosis in mice. J. Transl. Med. 2013 11 1 78 10.1186/1479‑5876‑11‑78 23531302
    [Google Scholar]
  71. Yang X. Wang W. Li X. in vitro hepatic differentiation of human endometrial stromal stem cells. in vitro Cell. Dev. Biol. Anim. 2014 50 2 162 170 10.1007/s11626‑013‑9688‑z 24052474
    [Google Scholar]
  72. Mei Z. Hong Y. Yang H. Cai S. Hu Y. Chen Q. Yuan Z. Liu X. Ferulic acid alleviates high fat diet-induced cognitive impairment by inhibiting oxidative stress and apoptosis. Eur. J. Pharmacol. 2023 946 175642 10.1016/j.ejphar.2023.175642 36871664
    [Google Scholar]
  73. Herzog N. Hansen M. Miethbauer S. Schmidtke K.U. Anderer U. Lupp A. Sperling S. Seehofer D. Damm G. Scheibner K. Küpper J.H. Primary-like human hepatocytes genetically engineered to obtain proliferation competence display hepatic differentiation characteristics in monolayer and organotypical spheroid cultures. Cell Biol. Int. 2016 40 3 341 353 10.1002/cbin.10574 26715207
    [Google Scholar]
  74. Huang S. Xie W. Ye Y. Liu J. Qu H. Shen Y. Xu T. Zhao Z. Shi Y. Shen J. Leng Y. Coronarin A modulated hepatic glycogen synthesis and gluconeogenesis via inhibiting mTORC1/S6K1 signaling and ameliorated glucose homeostasis of diabetic mice. Acta Pharmacol. Sin. 2023 44 3 596 609 10.1038/s41401‑022‑00985‑5 36085523
    [Google Scholar]
  75. Wong S.K. Mohamad N.V. Jayusman P.A. Ibrahim N.I. A review on the crosstalk between insulin and Wnt/β-catenin signalling for bone health. Int. J. Mol. Sci. 2023 24 15 12441 10.3390/ijms241512441 37569816
    [Google Scholar]
/content/journals/cdt/10.2174/0113894501394500250903095958
Loading
Cytokeratin 8 as a Novel Therapeutic Target in Type 2 Diabetes Mellitus: Suppression of Hepatic Glycogen Synthesis via IRS1/PI3K/Akt/GSK3β Signaling
Bentham Science Publishers ; https://doi.org/10.2174/0113894501394500250903095958
/content/journals/cdt/10.2174/0113894501394500250903095958
/content/journals/cdt/10.2174/0113894501394500250903095958
Loading

Data & Media loading...


  • Article Type:     Research Article
Keywords: hepatic glycogen synthesis ; cytokeratin 8 ; IRS1/PI3K/Akt/GSK3β pathway ; Type 2 diabetes mellitus ; therapeutic target, insulin resistance, hepatic glucose metabolism

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test