BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

Lin28a ameliorates glucotoxicity-induced β-cell dysfunction and apoptosis

  • Hwang, Yeo Jin (Division of Electronics & Information System, Daegu Gyeongbuk Institute of Science and Technology) ;
  • Jung, Gwon-Soo (New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation) ;
  • Jeon, WonBae (Division of Biotechnology, Daegu Gyeongbuk Institute of Science and Technology) ;
  • Lee, Kyeong-Min (Division of Biotechnology, Daegu Gyeongbuk Institute of Science and Technology)
  • Received : 2020.11.13
  • Accepted : 2021.03.09
  • Published : 2021.04.30
Download PDF
⟨ Previous Next ⟩

Abstract

An excessive and prolonged increase in glucose levels causes β-cell dysregulation, which is accompanied by impaired insulin synthesis and secretion, a condition known as glucotoxicity. Although it is known that both Lin28a and Lin28b regulate glucose metabolism, other molecular mechanisms that may protect against glucotoxicity are poorly understood. We investigated whether Lin28a overexpression can improve glucotoxicity-induced β-cell dysregulation in INS-1 and primary rat islet cells. INS-1, a rat insulinoma cell line was cultured and primary rat islet cells were isolated from SD-rats. To define the effect of Lin28a in chronic high glucose-induced β-cell dysregulation, we performed several in vitro and ex-vivo experiments. Chronic exposure to high glucose led to a downregulation of Lin28a mRNA and protein expression, followed by a decrease in insulin mRNA expression and secretion in β-cells. The mRNA and protein expression levels of PDX-1 and BETA2, were reduced; The levels of apoptotic factors, including c-caspase3 and the Bax/Bcl-2 ratio, were increased due to glucotoxicity. Adenovirus-mediated Lin28a overexpression in β-cells reversed the glucotoxicity-induced reduction of insulin secretion and insulin mRNA expression via regulation of β-cell-enriched transcription factors such as PDX-1 and BETA2. Adenovirus-mediated overexpression of Lin28a downregulated the glucotoxicity-induced upregulation of c-caspase3 levels and the Bax/Bcl-2 ratio, while inhibition of endogenous Lin28a by small interfering RNA resulted in their up-regulation. Lin28a counteracted glucotoxicity-induced downregulation of p-Akt and p-mTOR. Our results suggest that Lin28a protects pancreatic β-cells from glucotoxicity through inhibition of apoptotic factors via the PI3 kinase/Akt/mT pathway.

Keywords

Acknowledgement

This work was supported by DGIST projects 21-BT-06, NRF-2021R1A2C1011314 and NRF-2018R1C1B6008955 from the National Research Foundation of Korea funded by the Ministry of Science, ICT of the Republic of Korea.

References

  1. Korsgren O, Jansson L, Sandler S et al (1990) Hyperglycemia-induced B cell toxicity. The fate of pancreatic islets transplanted into diabetic mice is dependent on their genetic background. J Clin Invest 86, 2161-2168 https://doi.org/10.1172/JCI114955
  2. Unger RH and Grundy S (1985) Hyperglycaemia as an inducer as well as a consequence of impaired islet cell function and insulin resistance: implications for the management of diabetes. Diabetologia 28, 119-121 https://doi.org/10.1007/BF00273856
  3. Marshak S, Leibowitz G, Bertuzzi F et al (1999) Impaired beta-cell functions induced by chronic exposure of cultured human pancreatic islets to high glucose. Diabetes 48, 1230-1236 https://doi.org/10.2337/diabetes.48.6.1230
  4. Donath MY, Gross DJ, Cerasi E et al (1999) Hyperglycemia-induced beta-cell apoptosis in pancreatic islets of Psammomys obesus during development of diabetes. Diabetes 48, 738-744 https://doi.org/10.2337/diabetes.48.4.738
  5. Poitout V and Robertson RP (2008) Glucolipotoxicity: fuel excess and β-cell dysfunction. Endocr Rev 29, 351-366 https://doi.org/10.1210/er.2007-0023
  6. Kahn SE, Hull RL and Utzschneider KM (2006) Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444, 840-846 https://doi.org/10.1038/nature05482
  7. Bonner-Weir S, Trent DF and Weir GC (1983) Partial pancreatectomy in the rat and subsequent defect in glucose-induced insulin release. J Clin Invest 71, 1544-1553 https://doi.org/10.1172/JCI110910
  8. Del Prato S (2009) Role of glucotoxicity and lipotoxicity in the pathophysiology of type 2 diabetes mellitus and emerging treatment strategies. Diabetic Med 26, 1185-1192 https://doi.org/10.1111/j.1464-5491.2009.02847.x
  9. Mandrup-Poulsen T (2001) Beta-cell apoptosis: stimuli and signaling. Diabetes 50 Suppl 1, S58-S63 https://doi.org/10.2337/diabetes.50.2007.S58
  10. Kim WH, Lee JW, Suh YH et al (2005) Exposure to chronic high glucose induces β-cell apoptosis through decreased interaction of glucokinase with mitochondria. Diabetes 54, 2602-2611 https://doi.org/10.2337/diabetes.54.9.2602
  11. Piro S, Anello M, Di Pietro C et al (2002) Chronic exposure to free fatty acids or high glucose induces apoptosis in rat pancreatic islets: possible role of oxidative stress. Metabolism 51, 1340-1347 https://doi.org/10.1053/meta.2002.35200
  12. Viswanathan SR, Daley GQ and Gregory RI (2008) Selective blockade of microRNA processing by Lin28. Science 320, 97-100 https://doi.org/10.1126/science.1154040
  13. Viswanathan SR and Daley GQ (2010) Lin28a: a microRNA regulator with a macro role. Cell 140, 445-449 https://doi.org/10.1016/j.cell.2010.02.007
  14. Newman MA, Thomson JM and Hammond SM (2008) Lin-28 interaction with the Let-7 precursor loop mediates regulated microRNA processing. RNA 47, 1539-1549
  15. Zhu H, Shyh-Chang N, Segre AV et al (2011) The Lin28/let7 axis regulates glucose metabolism. Cell 147, 81-94 https://doi.org/10.1016/j.cell.2011.08.033
  16. Yang DH and Moss EG (2003) Temporally regulated expression of Lin-28 in diverse tissues of the developing mouse. Gene Expr Patterns 3, 719-726 https://doi.org/10.1016/S1567-133X(03)00140-6
  17. Piskounova E, Polytarchou C, Thornton JE et al (2001) Lin28A and Lin28B inhibit let-7 microRNA biogenesis by distinct mechanisms. Cell 147, 1066-1079 https://doi.org/10.1016/j.cell.2011.10.039
  18. Frost RJ and Olson EN (2011) Control of glucose homeostasis and insulin sensitivity by the Let-7 family of microRNAs. Proc Natl Acad Sci U S A 108, 21075-21080 https://doi.org/10.1073/pnas.1118922109
  19. Balcazar Morales N and Aguilar de Plata C (2012) Role of AKT/mTORC1 pathway in pancreatic β-cell proliferation. Colomb Med 43, 235-243 https://doi.org/10.25100/cm.v43i3.783
  20. Tuttle RL, Gill NS, Pugh W et al (2001) Regulation of pancreatic β-cell growth and survival by the serine/threonine protein kinase Akt1/PKB. Nature Med 10, 71133-71137
  21. Kim DJ, Toda C, Ramirez CM et al (2017) Hypothalamic ventromedial Lin28a enhances glucose metabolism in diet-induced obesity. Diabetes 66, 2102-2111 https://doi.org/10.2337/db16-1558
  22. Park KG, Lee KM, Seo HY et al (2007) Glucotoxicity in the INS-1 rat insulinoma cell line is mediated by the orphan nuclear receptor small heterodimer partner. Diabetes 56, 431-437 https://doi.org/10.2337/db06-0753
  23. Kooptiwut S, Kaewin S and Semprasert N (2018) Estradiol prevents high glucose induced β-cell apoptosis by decreased BTG2 expression. Sci Rep 16, 12256 https://doi.org/10.1038/s41598-018-30698-x
  24. Chao DT and Korsmeyer SJ (1998) BCL-2 family: regulators of cell death. Annu Rev Immunol 16, 395-419 https://doi.org/10.1146/annurev.immunol.16.1.395
  25. Mizuno N, Yoshitomi H, Ishida H et al (1998) Altered BCL-2 and Bax expression and intracellular Ca2+ signaling in apoptosis of pancreatic cells and the impairment of glucose-induced insulin secretion. Endocrinology 139, 1429-1439 https://doi.org/10.1210/en.139.3.1429
  26. Brown JE and Dunmore SJ (2007) Leptin decreases apoptosis and alters BCL-2: Bax ratio in clonal rodent pancreatic beta-cells. Diabetes Metab Res Rev 23, 497-502 https://doi.org/10.1002/dmrr.726
  27. Wrede CE, Dickson LM, Lingohr MK et al (2002) Protein kinase B/Akt prevents fatty acid-induced apoptosis in pancreatic beta-cells (INS-1). J Biol Chem 277, 49676-49684 https://doi.org/10.1074/jbc.M208756200
  28. Wijesekara N, Krishnamurthy M, Bhattacharjee A et al (2010) Adiponectin-induced ERK and Akt phosphorylation protects against pancreatic beta cell apoptosis and increases insulin gene expression and secretion. J Biol Chem 285, 33623-33631 https://doi.org/10.1074/jbc.M109.085084
  29. Bernal-Mizrachi E, Wen W, Stahlhut S et al (2001) Islet beta cell expression of constitutively active Akt1/PKB alpha induces striking hypertrophy, hyperplasia, and hyperinsulinemia. J Clin Invest 108, 1631-1638 https://doi.org/10.1172/JCI200113785
  30. Sung Y, Jeong J, Kang RJ et al (2019) Lin28a expression protects against streptozotocin-induced β-cell destruction and prevents diabetes in mice. Cell Biochem Funct 37, 139-147 https://doi.org/10.1002/cbf.3376
  31. Zhang M, Niu X, Hu J et al (2014) Lin28a protects against hypoxia/reoxygenation induced cardiomyocytes apoptosis by alleviating mitochondrial dysfunction under high glucose/high fat conditions. PLoS One 9, e110580 https://doi.org/10.1371/journal.pone.0110580
  32. Jung GS, Hwang YJ, Choi JH et al (2020) Lin28a attenuates TGF- β-induced renal fibrosis. BMB Rep 53, 594-599 https://doi.org/10.5483/BMBRep.2020.53.11.153