Skip to main content
SpringerLink
Log in

Abnormal Expression of microRNA-296-3p in Type 2 Diabetes Patients and its Role in Pancreatic β-Cells Function by Targeting Tensin Homolog Deleted on Chromosome Ten

  • Original Article
  • Published:
Biochemical Genetics Aims and scope Submit manuscript

Abstract

Diabetes mellitus (DM), a familiar disease, is characterized by high blood glucose levels owing to insulin deficiency. Researches have suggested that the incidence rate of diabetes is increasing and it has become an important global epidemic. The type 2 diabetes mellitus (T2DM) is featured with pancreatic β-cell loss and lack of insulin release. Nevertheless, the therapeutic methods that was helpful to improve pancreatic β-cell damage still unclear. Previous report have revealed that tensin homolog deleted on chromosome ten (PTEN) was remarkably enhanced in serum of patients with T2DM, and the lack of PTEN may prevent function deficiency of pancreatic β-cells in DM. However, the underlying mechanisms are rarely illustrated. Our purpose in this report was to illustrated the roles and potential mechanism of microRNA-296-3p (miR-296-3p) in uric acid (UA)-induced pancreatic β-cell injury. The direct target of miR-296-3p was predicted and verified by dual-luciferase reporter system and TargetScan assay. Moreover, Min6 cells were induced by 5 mg/dl UA and the cell proliferation, apoptosis, and insulin release were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometry and glucose-stimulated insulin secretion (GSIS), respectively. Quantitative reverse transcription PCR (qRT-PCR) and western blot assay were adopted to analyze the levels of miR-296-3p, PTEN and apoptosis-related proteins. TargetScan and Dual-luciferase reporter system confirmed that PTEN directly target miR-296-3p. MiR-296-3p was downregulated in UA-induced Min6 cells and the serum of type 2 diabetes patients, while PTEN was upregulated in UA-induced Min6 cells. Upregulation of miR-296-3p by mimic dramatically promoted miR-296-3p level and decreased PTEN level. Besides, PTEN was over-expressed after PTEN-plasmid transfection. UA treatment prominently decreased cell viability, promoted apoptotic cells, enhanced Bax levels, declined Bcl-2 level as well as decreased insulin release in Min6 cells. MiR-296-3p mimic significantly alleviated UA-induced pancreatic β-cells dysfunction, and PTEN-plasmid eliminated the protective effect of miR-296-3p on insulin release, cell viability, and apoptosis of pancreatic β-cells in UA-stimulated Min6 cells. In summary, our findings revealed that upregulation of miR-296-3p protected pancreatic β-cells functions against UA-induced dysfunction by targeting PTEN, which provides a novel agent for type 2 diabetes treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Alotaibi A, Perry L, Gholizadeh L, Al-Ganmi A (2017) Incidence and prevalence rates of diabetes mellitus in Saudi Arabia: An overview. J Epidemiol Glob Health 7:211–218

    Article  Google Scholar 

  • Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136:215–233

    Article  CAS  Google Scholar 

  • Birnbaum Y, Nanhwan MK, Ling S, Perez-Polo JR, Ye Y, Bajaj M (2014) PTEN upregulation may explain the development of insulin resistance and type 2 diabetes with high dose statins. Cardiovasc Drugs Ther 28:447–457

    Article  CAS  Google Scholar 

  • Boraie MB, Elnaggar YA, Ahmed MO, Mahmoud AM (2019) Effect of direct acting antiviral therapy of chronic Hepatitis C virus on insulin resistance and Type2 DM in Egyptian patients (prospective study). Diabetes Metab Syndr 13:2641–2646

    Article  Google Scholar 

  • Bordbar M, Darvishzadeh R, Pazhouhandeh M, Kahrizi D (2020) An overview of genome editing methods based on endonucleases. Mod Genet J 15:75–92

    Google Scholar 

  • Chakraborty C, Doss CG, Bandyopadhyay S, Agoramoorthy G (2014) Influence of miRNA in insulin signaling pathway and insulin resistance: micro-molecules with a major role in type-2 diabetes. Wiley Interdiscip Rev RNA 5:697–712

    Article  CAS  Google Scholar 

  • Dassano A, Loretelli C, Fiorina P (2019) Idebenone and T2D: A new insulin-sensitizing drug for personalized therapy. Pharmacol Res 139:469–470

    Article  CAS  Google Scholar 

  • David RB, Almeida ED, Cruz LV et al (2014) Diabetes mellitus and glucose as predictors of mortality in primary coronary percutaneous intervention. Arq Bras Cardiol 103:323–330

    CAS  PubMed  PubMed Central  Google Scholar 

  • De Cosmo S, Viazzi F, Pacilli A et al (2015) Serum uric acid and risk of CKD in type 2 diabetes. Clin J Am Soc Nephrol 10:1921–1929

    Article  Google Scholar 

  • Dihingia A, Ozah D, Ghosh S et al (2018) Vitamin K1 inversely correlates with glycemia and insulin resistance in patients with type 2 diabetes (T2D) and positively regulates SIRT1/AMPK pathway of glucose metabolism in liver of T2D mice and hepatocytes cultured in high glucose. J Nutr Biochem 52:103–114

    Article  CAS  Google Scholar 

  • Elizabeth MM, Alarcon-Aguilar JF, Clara OC, Escobar-Villanueva DCM (2017) Pancreatic beta-Cells and Type 2 Diabetes Development. Curr Diabetes Rev 13:108–121

    Article  CAS  Google Scholar 

  • Ge T, Wu HC, Zhou YY, Shen SM, Zhu LG, You GX (2019) MiR-296-3p may affect the proliferation and migration of non-small cell lung cancer cells via regulating RABL3. Eur Rev Med Pharmacol Sci 23:5823–5830

    CAS  PubMed  Google Scholar 

  • Gong Z, Yang J, Bai S, Wei S (2020) MicroRNAs regulate granulosa cells apoptosis and follicular development: a review. Asian-Australas J Anim Sci 33:1714–1724

    Article  CAS  Google Scholar 

  • Howard-Thompson A, Khan M, Jones M, George CM (2018) Type 2 diabetes mellitus: outpatient insulin management. Am Fam Physician 97:29–37

    PubMed  Google Scholar 

  • Hu Y, Zhao H, Lu J, Xie D, Wang Q, Huang T, Xin H, Hisatome I, Yamamoto T, Wang W, Cheng J (2021) High uric acid promotes dysfunction in pancreatic beta cells by blocking IRS2/AKT signalling. Mol Cell Endocrinol 520:111070

    Article  CAS  Google Scholar 

  • Inoue-Narita T, Hamada K, Sasaki T et al (2008) Pten deficiency in melanocytes results in resistance to hair graying and susceptibility to carcinogen-induced melanomagenesis. Cancer Res 68:5760–5768

    Article  CAS  Google Scholar 

  • Jiang J, Gao Q, Gong Y et al (2018) MiR-486 promotes proliferation and suppresses apoptosis in myeloid cells by targeting Cebpa in vitro. Cancer Med 7:4627–4638

    Article  CAS  Google Scholar 

  • Jung JY, Choi Y, Suh CH, Yoon D, Kim HA (2018) Effect of fenofibrate on uric acid level in patients with gout. Sci Rep 8:16767

    Article  Google Scholar 

  • Kazemi E, Zargooshi J, Kaboudi M et al (2020) A genome-wide association study to identify candidate genes for erectile dysfunction. Brief Bioinform. https://doi.org/10.1093/bib/bbaa338

    Article  Google Scholar 

  • Kim MJ, Hopfer H (2016) Mayr M [Uric acid, kidney disease and nephrolithiasis]. Ther Umsch 73:159–165

    Article  Google Scholar 

  • Kim EM, Jung CH, Song JY, Park JK, Um HD (2018) Pro-apoptotic Bax promotes mesenchymal-epithelial transition by binding to respiratory complex-I and antagonizing the malignant actions of pro-survival Bcl-2 proteins. Cancer Lett 424:127–135

    Article  CAS  Google Scholar 

  • Li H, Wu J, Zhu L et al (2018) Insulin degrading enzyme contributes to the pathology in a mixed model of Type 2 diabetes and Alzheimer’s disease: possible mechanisms of IDE in T2D and AD. Biosci Rep. https://doi.org/10.1042/BSR20170862

  • Liu B, Li J, Cairns MJ (2014) Identifying miRNAs, targets and functions. Brief Bioinform 15:1–19

    Article  Google Scholar 

  • Lu TX, Rothenberg ME (2018) MicroRNA. J Allergy Clin Immunol 141:1202–1217

    Article  CAS  Google Scholar 

  • Lytvyn Y, Perkins BA, Cherney DZ (2015) Uric acid as a biomarker and a therapeutic target in diabetes. Can J Diabetes 39:239–246

    Article  Google Scholar 

  • Pordzik J, Jakubik D, Jarosz-Popek J, Wicik Z, Eyileten C, De Rosa S, Indolfi C, Siller-Matula JM, Czajka P, Postula M (2019) Significance of circulating microRNAs in diabetes mellitus type 2 and platelet reactivity: bioinformatic analysis and review. Cardiovasc Diabetol 18:113

    Article  Google Scholar 

  • Samad A, James A, Wong J et al (2014) Insulin protects pancreatic acinar cells from palmitoleic acid-induced cellular injury. J Biol Chem 289:23582–23595

    Article  CAS  Google Scholar 

  • Segerstrom AB, Glans F, Eriksson KF, Holmback AM, Groop L, Thorsson O, Wollmer P (2010) Impact of exercise intensity and duration on insulin sensitivity in women with T2D. Eur J Intern Med 21:404–408

    Article  Google Scholar 

  • Shirjang S, Mansoori B, Asghari S, Duijf P, Mohammadi A, Gjerstorff M, Baradaran B (2019) MicroRNAs in cancer cell death pathways: Apoptosis and necroptosis. Free Radic Biol Med 139:1–15

    Article  CAS  Google Scholar 

  • Thong EP, Codner E, Laven J, Teede H (2020) Diabetes: a metabolic and reproductive disorder in women. Lancet Diabetes Endocrinol 8:134–149

    Article  CAS  Google Scholar 

  • Titov SE, Ivanov MK, Demenkov PS et al (2019) Combined quantitation of HMGA2 mRNA, microRNAs, and mitochondrial-DNA content enables the identification and typing of thyroid tumors in fine-needle aspiration smears. BMC Cancer 19:1010

    Article  Google Scholar 

  • Viazzi F, Piscitelli P, Giorda C et al (2017) Metabolic syndrome, serum uric acid and renal risk in patients with T2D. PLoS ONE 12:e0176058

    Article  Google Scholar 

  • Vilchis-Flores LH, Barajas-Medina GA, Villa-Martinez AK et al (2019) Pancreatic β-cell dysfunction in normoglycemic patients and risk factors. Acta Diabetol 56:1305–1314

    Article  CAS  Google Scholar 

  • Wang L, Liu Y, Yan LS, Nguyen KT, Schroer SA, Suzuki A, Mak TW, Gaisano H, Woo M (2010) Deletion of Pten in pancreatic β-cells protects against deficient β-cell mass and function in mouse models of type 2 diabetes. Diabetes 59:3117–3126

    Article  CAS  Google Scholar 

  • Wang Y, Hai B, Niu X, Ai L, Cao Y, Li R, Li Y (2017) Chronic intermittent hypoxia disturbs insulin secretion and causes pancreatic injury via the MAPK signaling pathway. Biochem Cell Biol 95:415–420

    Article  CAS  Google Scholar 

  • Wang L, Chen R, Zhang Y (2019) miR-296-3p targets APEX1 to suppress cell migration and invasion of non-small-cell lung cancer. Oncol Lett 18:2612–2618

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wu X, Yu T, Ji N et al (2019) IL6R inhibits viability and apoptosis of pancreatic β-cells in type 2 diabetes mellitus via regulation by miR-22 of the JAK/STAT signaling pathway. Diabetes Metab Syndr Obes 12:1645–1657

    Article  CAS  Google Scholar 

  • Xin Y, Zhang H, Jia Z, Ding X, Sun Y, Wang Q, Xu T (2018a) Resveratrol improves uric acid-induced pancreatic beta-cells injury and dysfunction through regulation of miR-126. Biomed Pharmacother 102:1120–1126

    Article  CAS  Google Scholar 

  • Xin Y, Wang K, Jia Z, Xu T, Xu Q, Zhang C, Liu J, Chen R, Du Z, Sun J (2018b) Zurampic protects pancreatic beta-Cells from high uric acid induced-damage by inhibiting URAT1 and inactivating the ROS/AMPK/ERK pathways. Cell Physiol Biochem 47:1074–1083

    Article  CAS  Google Scholar 

  • Yang F, Chen Y, Xue Z, Lv Y, Shen L, Li K, Zheng P, Pan P, Feng T, Jin L, Yao Y (2020) High-throughput sequencing and exploration of the lncRNA-circRNA-miRNA-mRNA network in type 2 diabetes mellitus. Biomed Res Int 2020:8162524

    PubMed  PubMed Central  Google Scholar 

  • Zhang T, Qiu F (2020) Icariin Protects Mouse Insulinoma Min6 Cell Function by Activating the PI3K/AKT Pathway. Med Sci Monit 26:e924453

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This project was supported by the Science and Technology Innovation Fund Project of Longhua District, Shenzhen; Chinese character of Shenzhen Longhua science and technology (2017) NO.2 (Grant No. 20160831A1030200).

Author information

Author notes

  1. Minggang Cheng and Yichen Guo have contributed equally to the work

Authors and Affiliations

  1. Department of Clinical Laboratory, the Affiliated Shenzhen Baoan Hospital of the Southern Medical University, Shenzhen, 518000, Guangdong Province, China

    Minggang Cheng

  2. Endocrinology Department, Peking University Shenzhen Hospital, Shenzhen, 518036, Guangdong Province, China

    Yichen Guo

  3. Department of Clinical Laboratory, The People’s Hospital of Longhua District, Shenzhen, 518109, Guangdong Province, China

    Weichuan Zhong, Xueyan Chen & Guangzhou Guo

Authors
  1. Minggang Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yichen Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Weichuan Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xueyan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Guangzhou Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Guangzhou Guo.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cheng, M., Guo, Y., Zhong, W. et al. Abnormal Expression of microRNA-296-3p in Type 2 Diabetes Patients and its Role in Pancreatic β-Cells Function by Targeting Tensin Homolog Deleted on Chromosome Ten. Biochem Genet 60, 39–53 (2022). https://doi.org/10.1007/s10528-021-10083-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10528-021-10083-6

Keywords

Search

Navigation