MicroRNA-24/MODY Gene Regulatory Pathway Mediates Pancreatic β-cell Dysfunction

Overview

Journal Diabetes

Specialty Endocrinology

Date 2013 Jun 14

PMID 23761103

Citations 41

Authors

Yunxia Zhu

Weiyan You

Hongdong Wang

Yating Li

Nan Qiao

Yuguang Shi

Chenyu Zhang

David Bleich

Xiao Han

Affiliations

Soon will be listed here.

Abstract

Overnutrition and genetics both contribute separately to pancreatic β-cell dysfunction, but how these factors interact is unclear. This study was aimed at determining whether microRNAs (miRNAs) provide a link between these factors. In this study, miRNA-24 (miR-24) was highly expressed in pancreatic β-cells and further upregulated in islets from genetic fatty (db/db) or mice fed a high-fat diet, and islets subject to oxidative stress. Overexpression of miR-24 inhibited insulin secretion and β-cell proliferation, potentially involving 351 downregulated genes. By using bioinformatic analysis combined with luciferase-based promoter activity assays and quantitative real-time PCR assays, we identified two maturity-onset diabetes of the young (MODY) genes as direct targets of miR-24. Silencing either of these MODY genes (Hnf1a and Neurod1) mimicked the cellular phenotype caused by miR-24 overexpression, whereas restoring their expression rescued β-cell function. Our findings functionally link the miR-24/MODY gene regulatory pathway to the onset of type 2 diabetes and create a novel network between nutrient overload and genetic diabetes via miR-24.

Citing Articles

Islet-resident macrophage-derived miR-155 promotes β cell decompensation via targeting PDX1.

Zhang Y, Cong R, Lv T, Liu K, Chang X, Li Y iScience. 2024; 27(4):109540.

PMID: 38577099 PMC: 10993184. DOI: 10.1016/j.isci.2024.109540.

Placenta-derived exosomes exacerbate beta cell dysfunction in gestational diabetes mellitus through delivery of miR-320b.

Wang Y, Yuan Y, Shen S, Ge Z, Zhu D, Bi Y Front Endocrinol (Lausanne). 2024; 14:1282075.

PMID: 38260139 PMC: 10800463. DOI: 10.3389/fendo.2023.1282075.

BRSK2 in pancreatic β cells promotes hyperinsulinemia-coupled insulin resistance and its genetic variants are associated with human type 2 diabetes.

Xu R, Wang K, Yao Z, Zhang Y, Jin L, Pang J J Mol Cell Biol. 2023; 15(5).

PMID: 37188647 PMC: 10782904. DOI: 10.1093/jmcb/mjad033.

The role of noncoding RNAs in pancreatic birth defects.

Yang Z, Parchem R Birth Defects Res. 2023; 115(19):1785-1808.

PMID: 37066622 PMC: 10579456. DOI: 10.1002/bdr2.2178.

Bulk and single-cell transcriptome analyses of islet tissue unravel gene signatures associated with pyroptosis and immune infiltration in type 2 diabetes.

Song Y, He C, Jiang Y, Yang M, Xu Z, Yuan L Front Endocrinol (Lausanne). 2023; 14:1132194.

PMID: 36967805 PMC: 10034023. DOI: 10.3389/fendo.2023.1132194.

References

Flatt P, Green B . Nutrient regulation of pancreatic beta-cell function in diabetes: problems and potential solutions. Biochem Soc Trans. 2006; 34(Pt 5):774-8. DOI: 10.1042/BST0340774. View

Huang S, He X, Ding J, Liang L, Zhao Y, Zhang Z . Upregulation of miR-23a approximately 27a approximately 24 decreases transforming growth factor-beta-induced tumor-suppressive activities in human hepatocellular carcinoma cells. Int J Cancer. 2008; 123(4):972-8. DOI: 10.1002/ijc.23580. View

Hatziapostolou M, Polytarchou C, Aggelidou E, Drakaki A, Poultsides G, Jaeger S . An HNF4α-miRNA inflammatory feedback circuit regulates hepatocellular oncogenesis. Cell. 2011; 147(6):1233-47. PMC: 3251960. DOI: 10.1016/j.cell.2011.10.043. View

Alvarez-Garcia I, Miska E . MicroRNA functions in animal development and human disease. Development. 2005; 132(21):4653-62. DOI: 10.1242/dev.02073. View

Poy M, Hausser J, Trajkovski M, Braun M, Collins S, Rorsman P . miR-375 maintains normal pancreatic alpha- and beta-cell mass. Proc Natl Acad Sci U S A. 2009; 106(14):5813-8. PMC: 2656556. DOI: 10.1073/pnas.0810550106. View

LeRoith D, Accili D . Mechanisms of disease: using genetically altered mice to study concepts of type 2 diabetes. Nat Clin Pract Endocrinol Metab. 2008; 4(3):164-72. PMC: 2714226. DOI: 10.1038/ncpendmet0729. View

Tang X, Muniappan L, Tang G, Ozcan S . Identification of glucose-regulated miRNAs from pancreatic {beta} cells reveals a role for miR-30d in insulin transcription. RNA. 2008; 15(2):287-93. PMC: 2648717. DOI: 10.1261/rna.1211209. View

Hao E, Tyrberg B, Itkin-Ansari P, Lakey J, Geron I, Monosov E . Beta-cell differentiation from nonendocrine epithelial cells of the adult human pancreas. Nat Med. 2006; 12(3):310-6. DOI: 10.1038/nm1367. View

Zhu Y, Shu T, Lin Y, Wang H, Yang J, Shi Y . Inhibition of the receptor for advanced glycation endproducts (RAGE) protects pancreatic β-cells. Biochem Biophys Res Commun. 2010; 404(1):159-65. DOI: 10.1016/j.bbrc.2010.11.085. View

10.

Rubio-Cabezas O, Minton J, Kantor I, Williams D, Ellard S, Hattersley A . Homozygous mutations in NEUROD1 are responsible for a novel syndrome of permanent neonatal diabetes and neurological abnormalities. Diabetes. 2010; 59(9):2326-31. PMC: 2927956. DOI: 10.2337/db10-0011. View

11.

Zhao E, Keller M, Rabaglia M, Oler A, Stapleton D, Schueler K . Obesity and genetics regulate microRNAs in islets, liver, and adipose of diabetic mice. Mamm Genome. 2009; 20(8):476-85. PMC: 2879069. DOI: 10.1007/s00335-009-9217-2. View

12.

Yeom S, Kim G, Kim C, Jung H, Kim S, Park J . Regulation of insulin secretion and beta-cell mass by activating signal cointegrator 2. Mol Cell Biol. 2006; 26(12):4553-63. PMC: 1489122. DOI: 10.1128/MCB.01412-05. View

13.

Cnop M, Welsh N, Jonas J, Jorns A, Lenzen S, Eizirik D . Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities. Diabetes. 2005; 54 Suppl 2:S97-107. DOI: 10.2337/diabetes.54.suppl_2.s97. View

14.

Roccisana J, Reddy V, Vasavada R, Gonzalez-Pertusa J, Magnuson M, Garcia-Ocana A . Targeted inactivation of hepatocyte growth factor receptor c-met in beta-cells leads to defective insulin secretion and GLUT-2 downregulation without alteration of beta-cell mass. Diabetes. 2005; 54(7):2090-102. DOI: 10.2337/diabetes.54.7.2090. View

15.

Cheung L, Zervou S, Mattsson G, Abouna S, Zhou L, Ifandi V . c-Myc directly induces both impaired insulin secretion and loss of β-cell mass, independently of hyperglycemia in vivo. Islets. 2010; 2(1):37-45. DOI: 10.4161/isl.2.1.10196. View

16.

Schickel R, Boyerinas B, Park S, Peter M . MicroRNAs: key players in the immune system, differentiation, tumorigenesis and cell death. Oncogene. 2008; 27(45):5959-74. DOI: 10.1038/onc.2008.274. View

17.

Hagman D, Hays L, Parazzoli S, Poitout V . Palmitate inhibits insulin gene expression by altering PDX-1 nuclear localization and reducing MafA expression in isolated rat islets of Langerhans. J Biol Chem. 2005; 280(37):32413-8. PMC: 1361267. DOI: 10.1074/jbc.M506000200. View

18.

Eitel K, Staiger H, Rieger J, Mischak H, Brandhorst H, Brendel M . Protein kinase C delta activation and translocation to the nucleus are required for fatty acid-induced apoptosis of insulin-secreting cells. Diabetes. 2003; 52(4):991-7. DOI: 10.2337/diabetes.52.4.991. View

19.

Wajchenberg B . beta-cell failure in diabetes and preservation by clinical treatment. Endocr Rev. 2007; 28(2):187-218. DOI: 10.1210/10.1210/er.2006-0038. View

20.

Takagi S, Nakajima M, Kida K, Yamaura Y, Fukami T, Yokoi T . MicroRNAs regulate human hepatocyte nuclear factor 4alpha, modulating the expression of metabolic enzymes and cell cycle. J Biol Chem. 2009; 285(7):4415-22. PMC: 2836046. DOI: 10.1074/jbc.M109.085431. View