MiRNA-30a-5p-mediated Silencing of Beta2/NeuroD Expression is an Important Initial Event of Glucotoxicity-induced Beta Cell Dysfunction in Rodent Models

Overview

Journal Diabetologia

Specialty Endocrinology

Date 2013 Jan 23

PMID 23338554

Citations 29

Authors

J-W Kim

Y-H You

S Jung

H Suh-Kim

I-K Lee

J-H Cho

K-H Yoon

Affiliations

Soon will be listed here.

Abstract

Aims/hypothesis: The loss of beta cell function is a critical factor in the development of type 2 diabetes. Glucotoxicity plays a major role in the progressive deterioration of beta cell function and development of type 2 diabetes mellitus. Here we demonstrate that microRNA (miR)-30a-5p is a key player in early-stage glucotoxicity-induced beta cell dysfunction.

Methods: We performed northern blots, RT-PCR and western blots in glucotoxicity-exposed primary rat islets and INS-1 cells. We also measured glucose-stimulated insulin secretion and insulin content. In vivo approaches were used to evaluate the role of miR-30a-5p in beta cell dysfunction.

Results: miR-30a-5p expression was increased in beta cells after exposure to glucotoxic conditions, and exogenous miR-30a-5p overexpression also induced beta cell dysfunction in vitro. miR-30a-5p directly suppressed expression of Beta2/NeuroD (also known as Neurod1) by binding to a specific binding site in its 3'-untranslated region. After restoration of Beta2/NeuroD expression by knockdown miR-30a-5p or transfection of the Beta2/NeuroD gene, beta cell dysfunction, including decreased insulin content, gene expression and glucose-stimulated insulin secretion, recovered. Glucose tolerance and beta cell dysfunction improved on direct injection of Ad-si30a-5p into the pancreas of diabetic mice.

Conclusions/interpretation: Our data demonstrate that miR-30a-5p-mediated direct suppression of Beta2/NeuroD gene expression is an important initiation step of glucotoxicity-induced beta cell dysfunction.

Citing Articles

Dysregulated microRNAs in type 2 diabetes and breast cancer: Potential associated molecular mechanisms.

Improta-Caria A, Ferrari F, Gomes J, Villalta P, Soci U, Stein R World J Diabetes. 2024; 15(6):1187-1198.

PMID: 38983808 PMC: 11229979. DOI: 10.4239/wjd.v15.i6.1187.

MicroRNAs Targeting Critical Molecular Pathways in Diabetic Cardiomyopathy Emerging Valuable for Therapy.

Mathur P, Saxena S, Saxena B, Rani V Cardiovasc Hematol Agents Med Chem. 2024; 22(3):298-307.

PMID: 38265401 DOI: 10.2174/0118715257265947231129074526.

Circulating MicroRNA-30a, Beclin1 and Their Association with Different Variables in Females with Metabolically Healthy /Unhealthy Obesity.

Naguib M, Magdy M, Yousef O, Ibrahim W, Mostafa Gharib D Diabetes Metab Syndr Obes. 2023; 16:3065-3074.

PMID: 37810570 PMC: 10559787. DOI: 10.2147/DMSO.S428844.

Glycemia-Induced miRNA Changes: A Review.

Al-Mahayni S, Ali M, Khan M, Jamsheer F, Moin A, Butler A Int J Mol Sci. 2023; 24(8).

PMID: 37108651 PMC: 10144997. DOI: 10.3390/ijms24087488.

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.

References

Weir G, Marselli L, Marchetti P, Katsuta H, Jung M, Bonner-Weir S . Towards better understanding of the contributions of overwork and glucotoxicity to the beta-cell inadequacy of type 2 diabetes. Diabetes Obes Metab. 2009; 11 Suppl 4:82-90. DOI: 10.1111/j.1463-1326.2009.01113.x. View

Lynn F, Skewes-Cox P, Kosaka Y, McManus M, Harfe B, German M . MicroRNA expression is required for pancreatic islet cell genesis in the mouse. Diabetes. 2007; 56(12):2938-45. DOI: 10.2337/db07-0175. View

Jonas J, Bensellam M, Duprez J, Elouil H, Guiot Y, Pascal S . Glucose regulation of islet stress responses and beta-cell failure in type 2 diabetes. Diabetes Obes Metab. 2009; 11 Suppl 4:65-81. DOI: 10.1111/j.1463-1326.2009.01112.x. View

Griffiths-Jones S . The microRNA Registry. Nucleic Acids Res. 2003; 32(Database issue):D109-11. PMC: 308757. DOI: 10.1093/nar/gkh023. View

Kaneto H, Matsuoka T, Kawashima S, Yamamoto K, Kato K, Miyatsuka T . Role of MafA in pancreatic beta-cells. Adv Drug Deliv Rev. 2009; 61(7-8):489-96. DOI: 10.1016/j.addr.2008.12.015. View

Melloul D, Marshak S, Cerasi E . Regulation of pdx-1 gene expression. Diabetes. 2002; 51 Suppl 3:S320-5. DOI: 10.2337/diabetes.51.2007.s320. View

He A, Zhu L, Gupta N, Chang Y, Fang F . Overexpression of micro ribonucleic acid 29, highly up-regulated in diabetic rats, leads to insulin resistance in 3T3-L1 adipocytes. Mol Endocrinol. 2007; 21(11):2785-94. DOI: 10.1210/me.2007-0167. View

Pullen T, da Silva Xavier G, Kelsey G, Rutter G . miR-29a and miR-29b contribute to pancreatic beta-cell-specific silencing of monocarboxylate transporter 1 (Mct1). Mol Cell Biol. 2011; 31(15):3182-94. PMC: 3147603. DOI: 10.1128/MCB.01433-10. View

Joglekar M, Patil D, Joglekar V, Rao G, Reddy D, Mitnala S . The miR-30 family microRNAs confer epithelial phenotype to human pancreatic cells. Islets. 2010; 1(2):137-47. DOI: 10.4161/isl.1.2.9578. View

10.

Ozcan S . MiR-30 family and EMT in human fetal pancreatic islets. Islets. 2010; 1(3):283-5. DOI: 10.4161/isl.1.3.9968. View

11.

Hay C, Docherty K . Comparative analysis of insulin gene promoters: implications for diabetes research. Diabetes. 2006; 55(12):3201-13. DOI: 10.2337/db06-0788. View

12.

Melloul D . Transcription factors in islet development and physiology: role of PDX-1 in beta-cell function. Ann N Y Acad Sci. 2004; 1014:28-37. DOI: 10.1196/annals.1294.003. View

13.

Gupta D, Krueger C, Lastra G . Over-nutrition, obesity and insulin resistance in the development of β-cell dysfunction. Curr Diabetes Rev. 2012; 8(2):76-83. DOI: 10.2174/157339912799424564. View

14.

Kim J, Seghers V, Cho J, Kang Y, Kim S, Ryu Y . Transactivation of the mouse sulfonylurea receptor I gene by BETA2/NeuroD. Mol Endocrinol. 2002; 16(5):1097-107. DOI: 10.1210/mend.16.5.0934. View

15.

Chen H, Charlat O, Tartaglia L, Woolf E, Weng X, Ellis S . Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell. 1996; 84(3):491-5. DOI: 10.1016/s0092-8674(00)81294-5. View

16.

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

17.

Rauhut R, Lendeckel W, Tuschl T . Identification of novel genes coding for small expressed RNAs. Science. 2001; 294(5543):853-8. DOI: 10.1126/science.1064921. View

18.

Poy M, Eliasson L, Krutzfeldt J, Kuwajima S, Ma X, MacDonald P . A pancreatic islet-specific microRNA regulates insulin secretion. Nature. 2004; 432(7014):226-30. DOI: 10.1038/nature03076. View

19.

Hennessy E, Clynes M, Jeppesen P, ODriscoll L . Identification of microRNAs with a role in glucose stimulated insulin secretion by expression profiling of MIN6 cells. Biochem Biophys Res Commun. 2010; 396(2):457-62. DOI: 10.1016/j.bbrc.2010.04.116. View

20.

Hamid M, McCluskey J, McClenaghan N, Flatt P . Comparison of the secretory properties of four insulin-secreting cell lines. Endocr Res. 2002; 28(1-2):35-47. DOI: 10.1081/erc-120004536. View