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image of Analysis of the Mechanism of PGLP-1 Inhibiting Gluconeogenesis Based on Whole Transcriptome Sequencing

Abstract

Objective

Through comprehensive transcriptome sequencing of liver RNA in mice induced with streptozotocin (STZ) to develop hyperglycemia, we uncovered crucial genes associated with hyperglycemic processes, shedding light on their respective functions. Furthermore, we delved deeply into a discussion surrounding the mechanism behind plasma glucagon-like peptide 1 (PGLP-1) and its role in inhibiting gluconeogenesis.

Methods

Liver tissues from mice induced with STZ to develop hyperglycemia (M group), as well as those treated with PGLP-1 (P11 group) and Exendin-4 (E group), were collected. RNA extraction was performed for comprehensive transcriptome sequencing. Differentially expressed mRNA, microRNA (miRNA), and long-chain non-coding RNA (lncRNA) were identified and subjected to analysis of their respective GO and KEGG pathways. An association network involving mRNA-miRNA-lncRNA was constructed to pinpoint target molecules associated with gluconeogenesis. Furthermore, personalized analysis focused on eight gluconeogenesis-related signal pathways obtained from KEGG.

Results

A total of 289 differentially expressed mRNA (dif-mRNA), 21 differentially expressed miRNA (dif-miRNA), and 463 differentially expressed lncRNA (dif-lncRNA) were screened from the M group and P11 group. 182 dif-mRNA, 239 dif-miRNA, and 384 dif-lncRNA were screened from the M group and E group. A total of 427 dif-mRNA, 261 dif-miRNA, and 525 dif-lncRNA were screened from the E group and the P11 group. Among them, mRNA was enriched to the PI3K-Akt signaling pathway, Type ll diabetes mellitus, the Insulin signaling pathway, and the PPAR signaling pathway, while lncRNA was mainly enriched in PI3K-Akt signaling pathway. Similar to the whole transcriptome sequencing, the results of gluconeogenesis personalized analysis showed that the PI3K-Akt signaling pathway was the key pathway, and Gck and Cyp7a1 were highly expressed after PGLP-1 was administered.

Conclusion

According to our findings, we believe that PGLP-1 is a potential regulator of non-coding RNAs, including miRNAs and lncRNAs. Additionally, it modulates the PI3K-Akt signaling pathway, resulting in the upregulation of GcK and Cyp7a1. In this way, it effectively inhibits gluconeogenesis.

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2025-05-16
2025-09-08

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References

  1. Classification of diabetes mellitus. 2019 1 11
    [Google Scholar]
  2. 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]
  3. Shah A.M. Wondisford F.E. Tracking the carbons supplying gluconeogenesis. J. Biol. Chem. 2020 295 42 14419 14429 10.1074/jbc.REV120.012758 32817317
    [Google Scholar]
  4. Sanches J.M. Zhao L.N. Salehi A. Wollheim C.B. Kaldis P. Pathophysiology of type 2 diabetes and the impact of altered metabolic interorgan crosstalk. FEBS J. 2023 290 3 620 648 10.1111/febs.16306 34847289
    [Google Scholar]
  5. Bonnefond A. Froguel P. Vaxillaire M. The emerging genetics of type 2 diabetes. Trends Mol. Med. 2010 16 9 407 416 10.1016/j.molmed.2010.06.004 20728409
    [Google Scholar]
  6. Cui S.C. Yu J. Zhang X.H. Cheng M.Z. Yang L.W. Xu J.Y. Antihyperglycemic and antioxidant activity of water extract from Anoectochilus roxburghii in experimental diabetes. Exp. Toxicol. Pathol. 2013 65 5 485 488 10.1016/j.etp.2012.02.003 22440113
    [Google Scholar]
  7. Reed J. Bain S. Kanamarlapudi V. A Review of Current Trends with Type 2 Diabetes Epidemiology, Aetiology, Pathogenesis, Treatments and Future Perspectives. Diabetes Metab. Syndr. Obes. 2021 14 3567 3602 10.2147/DMSO.S319895 34413662
    [Google Scholar]
  8. Dhillon J. Viscarra J.A. Newman J.W. Fiehn O. Crocker D.E. Ortiz R.M. Exogenous GLP-1 stimulates TCA cycle and suppresses gluconeogenesis and ketogenesis in late-fasted northern elephant seals pups. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2021 320 4 R393 R403 10.1152/ajpregu.00211.2020 33407018
    [Google Scholar]
  9. Saini K. Sharma S. Khan Y. DPP-4 inhibitors for treating T2DM - hype or hope? an analysis based on the current literature. Front. Mol. Biosci. 2023 10 1130625 10.3389/fmolb.2023.1130625 37287751
    [Google Scholar]
  10. Trujillo J.M. Nuffer W. Smith B.A. GLP-1 receptor agonists: an updated review of head-to-head clinical studies. Ther. Adv. Endocrinol. Metab. 2021 12 2042018821997320 10.1177/2042018821997320 33767808
    [Google Scholar]
  11. Nasr N.E. Sadek K.M. Role and mechanism(s) of incretin-dependent therapies for treating diabetes mellitus. Environ. Sci. Pollut. Res. Int. 2022 29 13 18408 18422 10.1007/s11356‑022‑18534‑2 35031999
    [Google Scholar]
  12. Gao H. Zhao Q. Song Z. Yang Z. Wu Y. Tang S. Alahdal M. Zhang Y. Jin L. PGLP‐1, a novel long‐acting dual‐function GLP‐1 analog, ameliorates streptozotocin‐induced hyperglycemia and inhibits body weight loss. FASEB J. 2017 31 8 3527 3539 10.1096/fj.201700002R 28461341
    [Google Scholar]
  13. Lv Y. Wang Y. Zhang Z. Potentials of lncRNA–miRNA–mRNA networks as biomarkers for laryngeal squamous cell carcinoma. Hum. Cell 2022 36 1 76 97 10.1007/s13577‑022‑00799‑x 36181662
    [Google Scholar]
  14. Fahmideh L. Khodadadi E. Khodadadi E. Zeinalzadeh E. Dao S. Köse Ş. Kafil H. Transcriptome Analysis Methods: From the Serial Analysis of Gene Expression and Microarray to Sequencing new Generation Methods. Biointerface Res. Appl. Chem. 2023 13 6 543 10.33263/BRIAC136.543
    [Google Scholar]
  15. Yang L. Wang Y.W. Lu Y.Y. Li B. Chen K.P. Li C.J. Genome‐wide identification and characterization of long non‐coding RNAs in Tribolium castaneum. Insect Sci. 2021 28 5 1262 1276 10.1111/1744‑7917.12867 32978885
    [Google Scholar]
  16. Lao Q. Zhang Q. Qiao Z. Li S. Liu L. Martin F.L. Pang W. Whole transcriptome sequencing and competitive endogenous RNA regulation network construction analysis in benzo[a]pyrene-treated breast cancer cells. Sci. Total Environ. 2023 861 160564 10.1016/j.scitotenv.2022.160564 36455743
    [Google Scholar]
  17. Wang Q. Long Z. Zhu F. Li H. Xiang Z. Liang H. Wu Y. Dai X. Zhu Z. Integrated analysis of lncRNA/circRNA–miRNA–mRNA in the proliferative phase of liver regeneration in mice with liver fibrosis. BMC Genomics 2023 24 1 417 10.1186/s12864‑023‑09478‑z 37488484
    [Google Scholar]
  18. Poy M.N. Eliasson L. Krutzfeldt J. Kuwajima S. Ma X. MacDonald P.E. Pfeffer S. Tuschl T. Rajewsky N. Rorsman P. Stoffel M. A pancreatic islet-specific microRNA regulates insulin secretion. Nature 2004 432 7014 226 230 10.1038/nature03076 15538371
    [Google Scholar]
  19. Liu Q. Qiao A.M. Yi L.T. Liu Z.L. Sheng S.M. Protection of kinsenoside against AGEs-induced endothelial dysfunction in human umbilical vein endothelial cells. Life Sci. 2016 162 102 107 10.1016/j.lfs.2016.08.022 27567684
    [Google Scholar]
  20. Kuan Y.C. Lee W.T. Hung C.L. Yang C. Sheu F. Investigating the function of a novel protein from Anoectochilus formosanus which induced macrophage differentiation through TLR4-mediated NF-κB activation. Int. Immunopharmacol. 2012 14 1 114 120 10.1016/j.intimp.2012.06.014 22749731
    [Google Scholar]
  21. Chung S.T. Hsia D.S. Chacko S.K. Rodriguez L.M. Haymond M.W. Increased gluconeogenesis in youth with newly diagnosed type 2 diabetes. Diabetologia 2015 58 3 596 603 10.1007/s00125‑014‑3455‑x 25447079
    [Google Scholar]
  22. Lin X. Shi H. Cui Y. Wang X. Zhang J. Yu W. Wei M. Dendrobium mixture regulates hepatic gluconeogenesis in diabetic rats via the phosphoinositide‑3‑kinase/protein kinase B signaling pathway. Exp. Ther. Med. 2018 16 1 204 212 10.3892/etm.2018.6194 29896241
    [Google Scholar]
  23. Salmena L. Poliseno L. Tay Y. Kats L. Pandolfi P.P. A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language? Cell 2011 146 3 353 358 10.1016/j.cell.2011.07.014 21802130
    [Google Scholar]
  24. Huang L. Cao Y. Xu H. Chen G. Separation and purification of ergosterol and stigmasterol in Anoectochilus roxburghii (wall) Lindl by high‐speed counter‐current chromatography. J. Sep. Sci. 2011 34 4 385 392 10.1002/jssc.201000577 21259433
    [Google Scholar]
  25. Zeng B. Su M. Chen Q. Chang Q. Wang W. Li H. Protective effect of a polysaccharide from Anoectochilus roxburghii against carbon tetrachloride-induced acute liver injury in mice. J. Ethnopharmacol. 2017 200 124 135 10.1016/j.jep.2017.02.018 28229921
    [Google Scholar]
  26. Ropelle E.R. Pauli J.R. Prada P. Cintra D.E. Rocha G.Z. Moraes J.C. Frederico M.J.S. da Luz G. Pinho R.A. Carvalheira J.B.C. Velloso L.A. Saad M.A. De Souza C.T. Inhibition of hypothalamic Foxo1 expression reduced food intake in diet‐induced obesity rats. J. Physiol. 2009 587 10 2341 2351 10.1113/jphysiol.2009.170050 19332486
    [Google Scholar]
  27. Buteau J. Accili D. Regulation of pancreatic β‐cell function by the forkhead protein FoxO1. Diabetes Obes. Metab. 2007 9 s2 140 146.(Suppl. 2) 10.1111/j.1463‑1326.2007.00782.x 17919188
    [Google Scholar]
  28. Meyer C. Dostou J.M. Welle S.L. Gerich J.E. Role of human liver, kidney, and skeletal muscle in postprandial glucose homeostasis. Am. J. Physiol. Endocrinol. Metab. 2002 282 2 E419 E427 10.1152/ajpendo.00032.2001 11788375
    [Google Scholar]
  29. Rui L. Energy metabolism in the liver. Compr. Physiol. 2014 4 1 177 197 10.1002/j.2040‑4603.2014.tb00548.x 24692138
    [Google Scholar]
  30. Ozcan L. Wong C.C.L. Li G. Xu T. Pajvani U. Park S.K.R. Wronska A. Chen B.X. Marks A.R. Fukamizu A. Backs J. Singer H.A. Yates J.R. III Accili D. Tabas I. Calcium signaling through CaMKII regulates hepatic glucose production in fasting and obesity. Cell Metab. 2012 15 5 739 751 10.1016/j.cmet.2012.03.002 22503562
    [Google Scholar]
  31. 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]
  32. Liu Q. Zhang F.G. Zhang W.S. Pan A. Yang Y.L. Liu J.F. Li P. Liu B.L. Qi L.W. Ginsenoside Rg1 Inhibits Glucagon-Induced Hepatic Gluconeogenesis through Akt-FoxO1 Interaction. Theranostics 2017 7 16 4001 4012 10.7150/thno.18788 29109794
    [Google Scholar]
  33. Cook J.R. Langlet F. Kido Y. Accili D. Pathogenesis of selective insulin resistance in isolated hepatocytes. J. Biol. Chem. 2015 290 22 13972 13980 10.1074/jbc.M115.638197 25873396
    [Google Scholar]
  34. Reilly S.M. Ahmadian M. Zamarron B.F. Chang L. Uhm M. Poirier B. Peng X. Krause D.M. Korytnaya E. Neidert A. Liddle C. Yu R.T. Lumeng C.N. Oral E.A. Downes M. Evans R.M. Saltiel A.R. A subcutaneous adipose tissue–liver signalling axis controls hepatic gluconeogenesis. Nat. Commun. 2015 6 1 6047 10.1038/ncomms7047 25581158
    [Google Scholar]
  35. Hiukka A. Maranghi M. Matikainen N. Taskinen M.R. PPARα: an emerging therapeutic target in diabetic microvascular damage. Nat. Rev. Endocrinol. 2010 6 8 454 463 10.1038/nrendo.2010.89 20567246
    [Google Scholar]
  36. Ren Y. Shen H.M. Critical role of AMPK in redox regulation under glucose starvation. Redox Biol. 2019 25 101154 10.1016/j.redox.2019.101154 30853530
    [Google Scholar]
  37. Zeng B. Su M. Chen Q. Chang Q. Wang W. Li H. Anoectochilus roxburghii polysaccharide prevents carbon tetrachloride-induced liver injury in mice by metabolomic analysis. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2020 1152 122202 10.1016/j.jchromb.2020.122202 32534261
    [Google Scholar]
  38. Chen B. Du Y.R. Zhu H. Sun M.L. Wang C. Cheng Y. Pang H. Ding G. Gao J. Tan Y. Tong X. Lv P. Zhou F. Zhan Q. Xu Z.M. Wang L. Luo D. Ye Y. Jin L. Zhang S. Zhu Y. Lin X. Wu Y. Jin L. Zhou Y. Yan C. Sheng J. Flatt P.R. Xu G.L. Huang H. Maternal inheritance of glucose intolerance via oocyte TET3 insufficiency. Nature 2022 605 7911 761 766 10.1038/s41586‑022‑04756‑4 35585240
    [Google Scholar]
  39. Jia W. Li Y. Cheung K.C.P. Zheng X. Bile acid signaling in the regulation of whole body metabolic and immunological homeostasis. Sci. China Life Sci. 2024 67 5 865 878 10.1007/s11427‑023‑2353‑0 37515688
    [Google Scholar]
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Analysis of the Mechanism of PGLP-1 Inhibiting Gluconeogenesis Based on Whole Transcriptome Sequencing
Bentham Science Publishers ; https://doi.org/10.2174/0113892010382822250516034835
/content/journals/cpb/10.2174/0113892010382822250516034835
/content/journals/cpb/10.2174/0113892010382822250516034835
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  • Article Type:     Research Article
Keywords: PI3K-Akt signaling ; ceRNA network ; Whole transcriptome sequencing ; PGLP-1 ; gluconeogenesis

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