Abstract
Diabetes mellitus has become one of the most common chronic diseases, thereby posing a major challenge to global health. Characterized by high levels of blood glucose (hyperglycemia), diabetes usually results from a loss of insulin-producing β-cells in the pancreas, leading to a deficiency of insulin (type 1 diabetes), or loss of insulin sensitivity (type 2 diabetes). Both types of diabetes have serious secondary complications, such as microvascular abnormalities, cardiovascular dysfunction, and kidney failure. Various complex factors, such as genetic and environmental factors, are associated with the pathophysiology of diabetes. Over the past two decades, the role of small, single-stranded noncoding microRNAs in various metabolic disorders, especially diabetes mellitus and its complications, has gained widespread attention in the scientific community. Discovered first as an endogenous regulator of development in the nematode Caenorhabditis elegans, these small RNAs post-transcriptionally suppress mRNA target expression. In this review, we discuss the potential roles of different microRNAs in diabetes and diabetes-related complications.
Keywords: diabetes, diabetic complications, dicer, glucose, insulin, microRNA, pancreas
Contributor Information
Munish Kumar, Email: munishkp@gmail.com.
Yong Li, Email: yong.li@louisville.edu.
References
- Alessi D.R. Discovery of PDK1, one of the missing links in insulin signal transduction. Colworth Medal Lecture. Biochem Soc Trans. 2001;29:1–14. doi: 10.1042/bst0290001. [DOI] [PubMed] [Google Scholar]
- Baroukh N., Ravier M.A., Loder M.K., Hill E.V., Bounacer A., Scharfmann R., Rutter G.A., Van Obberghen E. MicroRNA-124a regulates Foxa2 expression and intracellular signaling in pancreatic β-cell lines. J Biol Chem. 2007;282:19575–19588. doi: 10.1074/jbc.M611841200. [DOI] [PubMed] [Google Scholar]
- Baroukh N.N., Van Obberghen E. Function of microRNA-375 and microRNA-124a in pancreas and brain. FEBS J. 2009;276:6509–6521. doi: 10.1111/j.1742-4658.2009.07353.x. [DOI] [PubMed] [Google Scholar]
- Bartel D.P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–297. doi: 10.1016/S0092-8674(04)00045-5. [DOI] [PubMed] [Google Scholar]
- Baskerville S., Bartel D.P. Microarray profiling of microRNAs reveals frequent coexpression with neighboring miRNAs and host genes. RNA. 2005;11:241–247. doi: 10.1261/rna.7240905. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Berezikov E., Guryev V., van de Belt J., Wienholds E., Plasterk R.H.A., Cuppen E. Phylogenetic shadowing and computational identification of human microRNA genes. Cell. 2005;120:21–24. doi: 10.1016/j.cell.2004.12.031. [DOI] [PubMed] [Google Scholar]
- Cai X.Z., Hagedorn C.H., Cullen B.R. Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs. RNA. 2004;10:1957–1966. doi: 10.1261/rna.7135204. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Caporali A., Meloni M., Vollenkle C., Bonci D., Sala-Newby G.B., Addis R., Spinetti G., Losa S., Masson R., Baker A.H., et al. Deregulation of microRNA-503 contributes to diabetes mellitus-induced impairment of endothelial function and reparative angiogenesis after limb ischemia. Circulation. 2011;123:282–291. doi: 10.1161/CIRCULATIONAHA.110.952325. [DOI] [PubMed] [Google Scholar]
- Carè A., Catalucci D., Felicetti F., Bonci D., Addario A., Gallo P., Bang M.L., Segnalini P., Gu Y.S., Dalton N.D., et al. MicroRNA-133 controls cardiac hypertrophy. Nat Med. 2007;13:613–618. doi: 10.1038/nm1582. [DOI] [PubMed] [Google Scholar]
- Conaco C., Otto S., Han J.J., Mandel G. Reciprocal actions of REST and a microRNA promote neuronal identity. Proc Natl Acad Sci U S A. 2006;103:2422–2427. doi: 10.1073/pnas.0511041103. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Coppola T., Frantz C., Perret-Menoud V., Gattesco S., Hirling H., Regazzi R. Pancreatic β-cell protein granuphilin binds Rab3 and Munc-18 and controls exocytosis. Mol Biol Cell. 2002;13:1906–1915. doi: 10.1091/mbc.02-02-0025. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dieci G., Fiorino G., Castelnuovo M., Teichmann M., Pagano A. The expanding RNA polymerase III transcriptome. Trends Genet. 2007;23:614–622. doi: 10.1016/j.tig.2007.09.001. [DOI] [PubMed] [Google Scholar]
- El Ouaamari A., Baroukh N., Martens G.A., Lebrun P., Pipeleers D., van Obberghen E. miR-375 targets 3′-phosphoinositide-dependent protein kinase-1 and regulates glucose-induced biological responses in pancreatic β-cells. Diabetes. 2008;57:2708–2717. doi: 10.2337/db07-1614. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Esau C., Davis S., Murray S.F., Yu X.X., Pandey S.K., Pear M., Watts L., Booten S.L., Graham M., McKay R., et al. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab. 2006;3:87–98. doi: 10.1016/j.cmet.2006.01.005. [DOI] [PubMed] [Google Scholar]
- Esau C., Kang X.L., Peralta E., Hanson E., Marcusson E.G., Ravichandran L.V., Sun Y.Q., Koo S., Perera R.J., Jain R., et al. MicroRNA-143 regulates adipocyte differentiation. J Biol Chem. 2004;279:52361–52365. doi: 10.1074/jbc.C400438200. [DOI] [PubMed] [Google Scholar]
- Frost R.J.A., Olson E.N. Control of glucose homeostasis and insulin sensitivity by the Let-7 family of microRNAs. Proc Natl Acad Sci U S A. 2011;108:21075–21080. doi: 10.1073/pnas.1118922109. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Geraldes P., Hiraoka-Yamamoto J., Matsumoto M., Clermont A., Leitges M., Marette A., Aiello L.P., Kern T.S., King G.L. Activation of PKC-δ and SHP-1 by hyperglycemia causes vascular cell apoptosis and diabetic retinopathy. Nat Med. 2009;15:1298–1306. doi: 10.1038/nm.2052. [DOI] [PMC free article] [PubMed] [Google Scholar]
- He A.B., Zhu L.L., Gupta N., Chang Y.S., Fang F.D. Overexpression of micro ribonucleic acid 29, highly up-regulated in diabetic rats, leads to insulin resistance in 3T3-L1 adipocytes. Mol Endocrinol. 2007;21:2785–2794. doi: 10.1210/me.2007-0167. [DOI] [PubMed] [Google Scholar]
- Hennessy E., O’Driscoll L. Molecular medicine of microRNAs: structure, function and implications for diabetes. Expert Rev Mol Med. 2008;10:e24. doi: 10.1017/S1462399408000781. [DOI] [PubMed] [Google Scholar]
- Jordan S.D., Krüger M., Willmes D.M., Redemann N., Wunderlich F.T., Brönneke H.S., Merkwirth C., Kashkar H., Olkkonen V.M., Böttger T., et al. Obesity-induced overexpression of miRNA-143 inhibits insulin-stimulated AKT activation and impairs glucose metabolism. Nat Cell Biol. 2011;13:434–446. doi: 10.1038/ncb2211. [DOI] [PubMed] [Google Scholar]
- Kalis M., Bolmeson C., Esguerra J.L.S., Gupta S., Edlund A., Tormo-Badia N., Speidel D., Holmberg D., Mayans S., Khoo N.K.S., et al. Beta-cell specific deletion of Dicer1 leads to defective insulin secretion and diabetes mellitus. PloS One. 2011;6:e29166. doi: 10.1371/journal.pone.0029166. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kantharidis P., Wang B., Carew R.M., Lan H.Y. Diabetes complications: the microRNA perspective. Diabetes. 2011;60:1832–1837. doi: 10.2337/db11-0082. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kato M., Zhang J., Wang M., Lanting L., Yuan H., Rossi J.J., Natarajan R. MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-beta-induced collagen expression via inhibition of E-box repressors. Proc Natl Acad Sci U S A. 2007;104:3432–3437. doi: 10.1073/pnas.0611192104. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kovacs B., Lumayag S., Cowan C., Xu S.B. MicroRNAs in early diabetic retinopathy in streptozotocin-induced diabetic rats. Invest Ophthalmol Vis Sci. 2011;52:4402–4409. doi: 10.1167/iovs.10-6879. [DOI] [PubMed] [Google Scholar]
- Krek A., Grün D., Poy M.N., Wolf R., Rosenberg L., Epstein E.J., MacMenamin P., da Piedade I., Gunsalus K.C., Stoffel M., et al. Combinatorial microRNA target predictions. Nat Genet. 2005;37:495–500. doi: 10.1038/ng1536. [DOI] [PubMed] [Google Scholar]
- Krichevsky A.M., Sonntag K.C., Isacson O., Kosik K.S. Specific microRNAs modulate embryonic stem cell-derived neurogenesis. Stem Cells. 2006;24:857–864. doi: 10.1634/stemcells.2005-0441. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kumar M., Lu Z., Takwi A.A.L., Chen W., Callander N.S., Ramos K.S., Young K.H., Li Y. Negative regulation of the tumor suppressor p53 gene by microRNAs. Oncogene. 2011;30:843–853. doi: 10.1038/onc.2010.457. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Labbaye C., Testa U. The emerging role of MIR-146A in the control of hematopoiesis, immune function and cancer. J Hematol Oncol. 2012;5:13. doi: 10.1186/1756-8722-5-13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lee R.C., Feinbaum R.L., Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993;75:843–854. doi: 10.1016/0092-8674(93)90529-Y. [DOI] [PubMed] [Google Scholar]
- Long J.Y., Wang Y., Wang W.J., Chang B.H.J., Danesh F.R. Identification of microRNA-93 as a novel regulator of vascular endothelial growth factor in hyperglycemic conditions. J Biol Chem. 2010;285:23457–23465. doi: 10.1074/jbc.M110.136168. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lovis P., Gattesco S., Regazzi R. Regulation of the expression of components of the exocytotic machinery of insulin-secreting cells by microRNAs. Biol Chem. 2008;389:305–312. doi: 10.1515/BC.2008.026. [DOI] [PubMed] [Google Scholar]
- Lovis P., Roggli E., Laybutt D.R., Gattesco S., Yang J.Y., Widmann C., Abderrahmani A., Regazzi R. Alterations in microRNA expression contribute to fatty acid-induced pancreatic β-cell dysfunction. Diabetes. 2008;57:2728–2736. doi: 10.2337/db07-1252. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Luo X.B., Lin H.X., Pan Z.W., Xiao J.N., Zhang Y., Lu Y.J., Yang B.F., Wang Z.G. Down-regulation of miR-1/miR-133 contributes to re-expression of pacemaker channel genes HCN2 and HCN4 in hypertrophic heart. J Biol Chem. 2008;283:20045–20052. doi: 10.1074/jbc.M801035200. [DOI] [PubMed] [Google Scholar]
- Lynn F.C., Skewes-Cox P., Kosaka Y., McManus M.T., Harfe B.D., German M.S. MicroRNA expression is required for pancreatic islet cell genesis in the mouse. Diabetes. 2007;56:2938–2945. doi: 10.2337/db07-0175. [DOI] [PubMed] [Google Scholar]
- Michels G., Er F., Khan I., Sudkamp M., Herzig S., Hoppe U.C. Single-channel properties support a potential contribution of hyperpolarization-activated cyclic nucleotide-gated channels and If to cardiac arrhythmias. Circulation. 2005;111:399–404. doi: 10.1161/01.CIR.0000153799.65783.3A. [DOI] [PubMed] [Google Scholar]
- Mishra P.K., Tyagi N., Kumar M., Tyagi S.C. MicroRNAs as a therapeutic target for cardiovascular diseases. J Cell Mol Med. 2009;13:778–789. doi: 10.1111/j.1582-4934.2009.00744.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Moosmang S., Stieber J., Zong X.G., Biel M., Hofmann F., Ludwig A. Cellular expression and functional characterization of four hyperpolarization-activated pacemaker channels in cardiac and neuronal tissues. Eur J Biochem. 2001;268:1646–1652. doi: 10.1046/j.1432-1327.2001.02036.x. [DOI] [PubMed] [Google Scholar]
- Muhonen P., Holthofer H. Epigenetic and microRNA-mediated regulation in diabetes. Nephrol Dial Transplant. 2009;24:1088–1096. doi: 10.1093/ndt/gfn728. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Okamura K., Hagen J.W., Duan H., Tyler D.M., Lai E.C. The mirtron pathway generates microRNA-class regulatory RNAs in Drosophila. Cell. 2007;130:89–100. doi: 10.1016/j.cell.2007.06.028. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pandey A.K., Agarwal P., Kaur K., Datta M. MicroRNAs in diabetes: tiny players in big disease. Cell Physiol Biochem. 2009;23:221–232. doi: 10.1159/000218169. [DOI] [PubMed] [Google Scholar]
- Plaisance V., Abderrahmani A., Perret-Menoud V., Jacquemin P., Lemaigre F., Regazzi R. MicroRNA-9 controls the expression of Granuphilin/Slp4 and the secretory response of insulin-producing cells. J Biol Chem. 2006;281:26932–26942. doi: 10.1074/jbc.M601225200. [DOI] [PubMed] [Google Scholar]
- Poy M.N., Eliasson L., Krutzfeldt J., Kuwajima S., Ma X.S., Macdonald P.E., Pfeffer S., Tuschl T., Rajewsky N., Rorsman P., et al. A pancreatic islet-specific microRNA regulates insulin secretion. Nature. 2004;432:226–230. doi: 10.1038/nature03076. [DOI] [PubMed] [Google Scholar]
- Poy M.N., Hausser J., Trajkovski M., Braun M., Collins S., Rorsman P., Zavolan M., Stoffel M. miR-375 maintains normal pancreatic α- and β-cell mass. Proc Natl Acad Sci U S A. 2009;106:5813–5818. doi: 10.1073/pnas.0810550106. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Poy M.N., Spranger M., Stoffel M. microRNAs and the regulation of glucose and lipid metabolism. Diabetes Obes Metab. 2007;9(Suppl2):67–73. doi: 10.1111/j.1463-1326.2007.00775.x. [DOI] [PubMed] [Google Scholar]
- Roggli E., Britan A., Gattesco S., Lin-Marq N., Abderrahmani A., Meda P., Regazzi R. Involvement of microRNAs in the cytotoxic effects exerted by proinflammatory cytokines on pancreatic β-cells. Diabetes. 2010;59:978–986. doi: 10.2337/db09-0881. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ruby J.G., Jan C.H., Bartel D.P. Intronic microRNA precursors that bypass Drosha processing. Nature. 2007;448:83–86. doi: 10.1038/nature05983. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Saal S., Harvey S.J. MicroRNAs and the kidney: coming of age. Curr Opin Nephrol Hypertens. 2009;18:317–323. doi: 10.1097/MNH.0b013e32832c9da2. [DOI] [PubMed] [Google Scholar]
- Saltiel A.R., Kahn C.R. Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 2001;414:799–806. doi: 10.1038/414799a. [DOI] [PubMed] [Google Scholar]
- Scherer P.E., Okamoto T., Chun M., Nishimoto I., Lodish H.F., Lisanti M.P. Identification, sequence, and expression of caveolin-2 defines a caveolin gene family. Proc Natl Acad Sci U S A. 1996;93:131–135. doi: 10.1073/pnas.93.1.131. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shaw J.E., Sicree R.A., Zimmet P.Z. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract. 2010;87:4–14. doi: 10.1016/j.diabres.2009.10.007. [DOI] [PubMed] [Google Scholar]
- Shi B., Sepp-Lorenzino L., Prisco M., Linsley P., deAngelis T., Baserga R. Micro RNA 145 targets the insulin receptor substrate-1 and inhibits the growth of colon cancer cells. J Biol Chem. 2007;282:32582–32590. doi: 10.1074/jbc.M702806200. [DOI] [PubMed] [Google Scholar]
- Stitt-Cavanagh E., MacLeod L., Kennedy C.R.J. The podocyte in diabetic kidney disease. Scientific World Journal. 2009;l9:1127–1139. doi: 10.1100/tsw.2009.133. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tang X.Q., Tang G.L., Özcan S. Role of microRNAs in diabetes. Biochim Biophys Acta. 2008;1779:697–701. doi: 10.1016/j.bbagrm.2008.06.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Teleman A.A., Cohen S.M. Drosophila lacking microRNA miR-278 are defective in energy homeostasis. Genes Dev. 2006;20:417–422. doi: 10.1101/gad.374406. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Trajkovski M., Hausser J., Soutschek J., Bhat B., Akin A., Zavolan M., Heim M.H., Stoffel M. MicroRNAs 103 and 107 regulate insulin sensitivity. Nature. 2011;474:649–653. doi: 10.1038/nature10112. [DOI] [PubMed] [Google Scholar]
- Uchida T., Myers M.G., Jr., White M.F. IRS-4 mediates protein kinase B signaling during insulin stimulation without promoting antiapoptosis. Mol Cell Biol. 2000;20:126–138. doi: 10.1128/MCB.20.1.126-138.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Vikman J., Ma X.S., Hockerman G.H., Rorsman P., Eliasson L. Antibody inhibition of synaptosomal protein of 25 kDa (SNAP-25) and syntaxin 1 reduces rapid exocytosis in insulin-secreting cells. J Mol Endocrinol. 2006;36:503–515. doi: 10.1677/jme.1.01978. [DOI] [PubMed] [Google Scholar]
- Wang H.Y., Gauthier B.R., Hagenfeldt-Johansson K.A., Iezzi M., Wollheim C.B. Foxa2 (HNF3β) controls multiple genes implicated in metabolism-secretion coupling of glucose-induced insulin release. J Biol Chem. 2002;277:17564–17570. doi: 10.1074/jbc.M111037200. [DOI] [PubMed] [Google Scholar]
- Wang Q., Wang Y.L., Minto A.W., Wang J.H., Shi Q., Li X.M., Quigg R.J. MicroRNA-377 is up-regulated and can lead to increased fibronectin production in diabetic nephropathy. FASEB J. 2008;22:4126–4135. doi: 10.1096/fj.08-112326. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wang X.H., Qian R.Z., Zhang W., Chen S.F., Jin H.M., Hu R.M. MicroRNA-320 expression in myocardial microvascular endothelial cells and its relationship with insulin-like growth factor-1 in type 2 diabetic rats. Clin Exp Pharmacol Physiol. 2009;36:181–188. doi: 10.1111/j.1440-1681.2008.05057.x. [DOI] [PubMed] [Google Scholar]
- White M.F. IRS proteins and the common path to diabetes. Am J Physiol Endocrinol Metab. 2002;283:E413–E422. doi: 10.1152/ajpendo.00514.2001. [DOI] [PubMed] [Google Scholar]
- Wilcox G. Insulin and insulin resistance. Clin Biochem Rev. 2005;26:19–39. [PMC free article] [PubMed] [Google Scholar]
- Wilfred B.R., Wang W.X., Nelson P.T. Energizing miRNA research: a review of the role of miRNAs in lipid metabolism, with a prediction that miR-103/107 regulates human metabolic pathways. Mol Genet Metab. 2007;91:209–217. doi: 10.1016/j.ymgme.2007.03.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wolfrum C., Besser D., Luca E., Stoffel M. Insulin regulates the activity of forkhead transcription factor Hnf-3β/Foxa-2 by Akt-mediated phosphorylation and nuclear/cytosolic localization. Proc Natl Acad Sci U S A. 2003;100:11624–11629. doi: 10.1073/pnas.1931483100. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Xu P.Z., Vernooy S.Y., Guo M., Hay B.A. The Drosophila microRNA Mir-14 suppresses cell death and is required for normal fat metabolism. Curr Biol. 2003;13:790–795. doi: 10.1016/S0960-9822(03)00250-1. [DOI] [PubMed] [Google Scholar]
- Yang B.F., Lin H.X., Xiao J.N., Lu Y.J., Luo X.B., Li B.X., Zhang Y., Xu C.Q., Bai Y.L., Wang H.Z., et al. The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2. Nat Med. 2007;13:486–491. doi: 10.1038/nm1569. [DOI] [PubMed] [Google Scholar]
- Zampetaki A., Kiechl S., Drozdov I., Willeit P., Mayr U., Prokopi M., Mayr A., Weger S., Oberhollenzer F., Bonora E., et al. Plasma microRNA profiling reveals loss of endothelial miR-126 and other microRNAs in type 2 diabetes. Circ Res. 2010;107:810–817. doi: 10.1161/CIRCRESAHA.110.226357. [DOI] [PubMed] [Google Scholar]
- Zhao E.P., Keller M.P., Rabaglia M.E., Oler A.T., Stapleton D.S., Schueler K.L., Neto E.C., Moon J.Y., Wang P., Wang I.M., et al. Obesity and genetics regulate microRNAs in islets, liver, and adipose of diabetic mice. Mamm Genome. 2009;20:476–485. doi: 10.1007/s00335-009-9217-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zhu H., Shyh-Chang N., Segrè A.V., Shinoda G., Shah S.P., Einhorn W.S., Takeuchi A., Engreitz J.M., Hagan J.P., Kharas M.G., et al. The Lin28/let-7 axis regulates glucose metabolism. Cell1. 2011;47:81–94. doi: 10.1016/j.cell.2011.08.033. [DOI] [PMC free article] [PubMed] [Google Scholar]