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Exp Clin Endocrinol Diabetes 2022; 130(01): 22-29
DOI: 10.1055/a-1261-5282
Article

Let7b-5p is Upregulated in the Serum of Emirati Patients with Type 2 Diabetes and Regulates Insulin Secretion in INS-1 Cells

Hayat Aljaibeji‡
1   Sharjah Institute for Medical Research, University of Sharjah
,
Noha Mousaad Elemam‡
1   Sharjah Institute for Medical Research, University of Sharjah
,
Abdul Khader Mohammed
1   Sharjah Institute for Medical Research, University of Sharjah
,
Hind Hasswan
1   Sharjah Institute for Medical Research, University of Sharjah
,
Mahammad Al Thahyabat
2   Mediclinic Parkview Hospital, Dubai
,
Noura Alkhayyal
1   Sharjah Institute for Medical Research, University of Sharjah
,
Nabil Sulaiman
3   Department of Family Medicine, College of Medicine, University of Sharjah
4   Baker/IDI Heart and Diabetes Institute, Melbourne, Victoria
,
Jalal Taneera
1   Sharjah Institute for Medical Research, University of Sharjah
5   Department of Basic Medical Sciences, College of Medicine, University of Sharjah
› Author Affiliations Funding: This study is supported by the University of Sharjah grants (1701090119-P and 1701090121-P) and AL-Jalila foundation (AJF201723 and AJF201724).
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Abstract

Let7b-5p is a member of the Let-7 miRNA family and one of the top expressed miRNAs in human islets that implicated in glucose homeostasis. The levels of Let7b-5p in type 2 diabetes (T2DM) patients or its role in β-cell function is still unclear. In the current study, we measured the serum levels of let7b-5p in Emirati patients with T2DM (with/without complications) and control subjects. Overexpression or silencing of let7b-5p in INS-1 (832/13) cells was performed to investigate the impact on insulin secretion, content, cell viability, apoptosis, and key functional genes. We found that serum levels of let7b-5p are significantly (p<0.05) higher in T2DM-patients or T2DM with complications compared to control subjects. Overexpression of let7b-5p increased insulin content and decreased glucose-stimulated insulin secretion, whereas silencing of let7b-5p reduced insulin content and secretion. Modulation of the expression levels of let7b-5p did not influence cell viability nor apoptosis. Analysis of mRNA and protein expression of hallmark genes in let7b-5p transfected cells revealed a marked dysregulation of Insulin, Pancreatic And Duodenal Homeobox 1 (PDX1), glucokinase (GCK), glucose transporter 2 (GLUT2), and INSR. In conclusion, an appropriate level of let7b-5p is essential to maintain β-cell function and may be regarded as a biomarker for T2DM.

Key words

Diabetes - Autoimmunity - Let7b-5p. - INS-1 (832/31) - miRNA

Supplementary Material



Publication History

Received: 17 March 2020
Received: 09 June 2020

Accepted: 11 September 2020

Article published online:
09 October 2020

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 van de Bunt M, Gaulton KJ, Parts L. et al. The miRNA profile of human pancreatic islets and beta-cells and relationship to type 2 diabetes pathogenesis. PLoS One 2013; 8: e55272
    CrossrefPubMedGoogle Scholar
  • 2 Boyerinas B, Park SM, Hau A. et al. The role of let-7 in cell differentiation and cancer. Endocr Relat Cancer 2010; 17: F19-F36
    CrossrefPubMedGoogle Scholar
  • 3 Johnson SM, Grosshans H, Shingara J. et al. RAS is regulated by the let-7 microRNA family. Cell 2005; 120: 635-647
    CrossrefPubMedGoogle Scholar
  • 4 Kumar MS, Erkeland SJ, Pester RE. et al. Suppression of non-small cell lung tumor development by the let-7 microRNA family. Proc Natl Acad Sci USA 2008; 105: 3903-3908
    CrossrefPubMedGoogle Scholar
  • 5 Lee YS, Dutta A. The tumor suppressor microRNA let-7 represses the HMGA2 oncogene. Genes Dev 2007; 21: 1025-1030
    CrossrefPubMedGoogle Scholar
  • 6 Mayr C, Hemann MT, Bartel DP. Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation. Science 2007; 315: 1576-1579
    CrossrefPubMedGoogle Scholar
  • 7 Pasquinelli AE, Reinhart BJ, Slack F. et al. Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature 2000; 408: 86-89
    CrossrefPubMedGoogle Scholar
  • 8 Ruby JG, Jan C, Player C. et al. Large-scale sequencing reveals 21U-RNAs and additional microRNAs and endogenous siRNAs in C. elegans. Cell 2006; 127: 1193-1207
    CrossrefPubMedGoogle Scholar
  • 9 LaPierre MP, Stoffel M. MicroRNAs as stress regulators in pancreatic beta cells and diabetes. Mol Metab 2017; 6: 1010-1023
    CrossrefPubMedGoogle Scholar
  • 10 Nesca V, Guay C, Jacovetti C. et al. Identification of particular groups of microRNAs that positively or negatively impact on beta cell function in obese models of type 2 diabetes. Diabetologia 2013; 56: 2203-2212
    CrossrefPubMedGoogle Scholar
  • 11 Roggli E, Britan A, Gattesco S. et al. Involvement of microRNAs in the cytotoxic effects exerted by proinflammatory cytokines on pancreatic β-Cells. Diabetes 2010; 59: 978-986
    CrossrefPubMedGoogle Scholar
  • 12 van de Bunt M, Gloyn AL. A tale of two glucose transporters: how GLUT2 re-emerged as a contender for glucose transport into the human beta cell. Diabetologia 2012; 55: 2312-2315
    CrossrefPubMedGoogle Scholar
  • 13 Frost RJ, Olson EN. Control of glucose homeostasis and insulin sensitivity by the Let-7 family of microRNAs. Proc Natl Acad Sci USA 2011; 108: 21075-21080
    CrossrefPubMedGoogle Scholar
  • 14 Williams MD, Mitchell GM. MicroRNAs in insulin resistance and obesity. Exp Diabetes Res 2012; 2012: 484696
    CrossrefPubMedGoogle Scholar
  • 15 Zhu H, Shyh-Chang N, Segrè AV. et al. The Lin28/let-7 axis regulates glucose metabolism. Cell 2011; 147: 81-94
    CrossrefPubMedGoogle Scholar
  • 16 Ideozu JE, Zhang X, Rangaraj V. et al. Microarray profiling identifies extracellular circulating miRNAs dysregulated in cystic fibrosis. Sci Rep 2019; 9: 15483
    CrossrefPubMedGoogle Scholar
  • 17 Qattan A, Intabli H, Alkhayal W. et al. Robust expression of tumor suppressor miRNA’s let-7 and miR-195 detected in plasma of Saudi female breast cancer patients. BMC Cancer 2017; 17: 799
    CrossrefPubMedGoogle Scholar
  • 18 Zedan AH, Hansen TF, Assenholt J. et al. microRNA expression in tumour tissue and plasma in patients with newly diagnosed metastatic prostate cancer. Tumour Biol 2018; 40: 1010428318775864
    CrossrefPubMedGoogle Scholar
  • 19 Zou X, Wei J, Huang Z. et al. Identification of a six-miRNA panel in serum benefiting pancreatic cancer diagnosis. Cancer Med 2019; 8: 2810-2822
    CrossrefPubMedGoogle Scholar
  • 20 Meerson A, Najjar A, Saad E. et al. Sex differences in plasma microrna biomarkers of early and complicated diabetes mellitus in Israeli Arab and Jewish Patients. Noncoding RNA 2019; 5: 32-43
    CrossrefPubMedGoogle Scholar
  • 21 Pasquier J, Ramachandran V, Abu-Qaoud MdR. et al. Differentially expressed circulating microRNAs in the development of acute diabetic Charcot foot. Epigenomics 2018; 10: 1267-1278
    CrossrefPubMedGoogle Scholar
  • 22 Catanzaro G, Besharat ZM, Chiacchiarini M. et al. Circulating microRNAs in elderly type 2 diabetic patients. Int J Endocrinol 2018; 2018: 6872635-6872635
    CrossrefPubMedGoogle Scholar
  • 23 Kokkinopoulou I, Maratou E, Mitrou P. et al. Decreased expression of microRNAs targeting type-2 diabetes susceptibility genes in peripheral blood of patients and predisposed individuals. Endocrine 2019; 66: 226-239
    CrossrefPubMedGoogle Scholar
  • 24 Elhelw DS, Mekky RY, El-Ekiaby N. et al. Predictive prognostic role of miR‑181a with discrepancy in the liver and serum of genotype 4 hepatitis C virus patients. Biomed Rep 2014; 2: 843-848
    CrossrefPubMedGoogle Scholar
  • 25 Taneera J, Dhaiban S, Hachim M et al. Reduced expression of Chl1 gene impairs insulin secretion by down-regulating the expression of key molecules of β-cell function. Exp Clin Endocrinol Diabetes 2019: (EFirst)
    PubMed
  • 26 Xu H, Liu C, Zhang Y. et al. Let-7b-5p regulates proliferation and apoptosis in multiple myeloma by targeting IGF1R. Acta Biochim Biophys Sin 2014; 46: 965-972
    CrossrefPubMedGoogle Scholar
  • 27 Huang RS, Gamazon ER, Ziliak D. et al. Population differences in microRNA expression and biological implications. RNA Biol 2011; 8: 692-701
    CrossrefPubMedGoogle Scholar
  • 28 Osella M, Riba A, Testori A. et al. Interplay of microRNA and epigenetic regulation in the human regulatory network. Front Genet 2014; 5: 345-355
    CrossrefPubMedGoogle Scholar
  • 29 Theodore SC, Rhim JS, Turner T. et al. MiRNA 26a expression in a novel panel of African American prostate cancer cell lines. Ethn Dis 2010; 20: S1
    PubMedGoogle Scholar
  • 30 Saito Y, Liang G, Egger G. et al. Specific activation of microRNA-127 with downregulation of the proto-oncogene BCL6 by chromatin-modifying drugs in human cancer cells. Cancer Cell 2006; 9: 435-443
    CrossrefPubMedGoogle Scholar
  • 31 Castellano L, Giamas G, Jacob J. et al. The estrogen receptor-α-induced microRNA signature regulates itself and its transcriptional response. Proc Natl Acad Sci USA 2009; 106: 15732-15737
    CrossrefPubMedGoogle Scholar
  • 32 Fletcher CE, Dart DA, Bevan CL. Interplay between steroid signalling and microRNAs: Implications for hormone-dependent cancers. Endocr Relat Cancer 2014; 21: R409-R429
    CrossrefPubMedGoogle Scholar
  • 33 Greenblatt RB, Oettinger M, Bohler CS. Estrogen-androgen levels in aging men and women: Therapeutic considerations. J Am Geriatr Soc 1976; 24: 173-178
    CrossrefPubMedGoogle Scholar
  • 34 Klinge CM. Estrogen regulation of microRNA expression. Curr Genomics 2009; 10: 169-183
    CrossrefPubMedGoogle Scholar
  • 35 Klinge CM. miRNAs and estrogen action. Trends Endocrinol Metab 2012; 23: 223-233
    CrossrefPubMedGoogle Scholar
  • 36 Wang Y-T, Tsai P-C, Liao Y-C. et al. Circulating microRNAs have a sex-specific association with metabolic syndrome. J Biomed Sci 2013; 20: 72
    CrossrefPubMedGoogle Scholar
  • 37 Cho S, Mutlu L, Grechukhina O. et al. Circulating microRNAs as potential biomarkers for endometriosis. Fertil Steril 2015; 103: 1252.e1251-1260.e1251
    PubMedGoogle Scholar
  • 38 Seifer BJ, Su D, Taylor HS. Circulating miRNAs in murine experimental endometriosis: decreased abundance of let-7a. Reprod Sci 2017; 24: 376-381
    CrossrefPubMedGoogle Scholar
  • 39 Bollheimer LC, Skelly RH, Chester MW. et al. Chronic exposure to free fatty acid reduces pancreatic beta cell insulin content by increasing basal insulin secretion that is not compensated for by a corresponding increase in proinsulin biosynthesis translation. J Clin Invest 1998; 101: 1094-1101
    CrossrefPubMedGoogle Scholar
  • 40 Eto K, Yamashita T, Tsubamoto Y. et al. Phosphatidylinositol 3-kinase suppresses glucose-stimulated insulin secretion by affecting post-cytosolic [Ca2+] elevation signals. Diabetes 2002; 51: 87-97
    CrossrefPubMedGoogle Scholar
  • 41 Lenzen S. A fresh view of glycolysis and glucokinase regulation: history and current status. J Biol Chem 2014; 289: 12189-12194
    CrossrefPubMedGoogle Scholar
  • 42 Schuit FC, Huypens P, Heimberg H. et al. Glucose sensing in pancreatic beta-cells: a model for the study of other glucose-regulated cells in gut, pancreas, and hypothalamus. Diabetes 2001; 50: 1-11
    CrossrefPubMedGoogle Scholar
  • 43 Thorens B, Guillam MT, Beermann F. et al. Transgenic reexpression of GLUT1 or GLUT2 in pancreatic beta cells rescues GLUT2-null mice from early death and restores normal glucose-stimulated insulin secretion. J Biol Chem 2000; 275: 23751-23758
    CrossrefPubMedGoogle Scholar