Comprehensive Physiology Wiley Online Library

Roles of Noncoding RNAs in Islet Biology

Full Article on Wiley Online Library



Abstract

The discovery that most mammalian genome sequences are transcribed to ribonucleic acids (RNA) has revolutionized our understanding of the mechanisms governing key cellular processes and of the causes of human diseases, including diabetes mellitus. Pancreatic islet cells were found to contain thousands of noncoding RNAs (ncRNAs), including micro‐RNAs (miRNAs), PIWI‐associated RNAs, small nucleolar RNAs, tRNA‐derived fragments, long non‐coding RNAs, and circular RNAs. While the involvement of miRNAs in islet function and in the etiology of diabetes is now well documented, there is emerging evidence indicating that other classes of ncRNAs are also participating in different aspects of islet physiology. The aim of this article will be to provide a comprehensive and updated view of the studies carried out in human samples and rodent models over the past 15 years on the role of ncRNAs in the control of α‐ and β‐cell development and function and to highlight the recent discoveries in the field. We not only describe the role of ncRNAs in the control of insulin and glucagon secretion but also address the contribution of these regulatory molecules in the proliferation and survival of islet cells under physiological and pathological conditions. It is now well established that most cells release part of their ncRNAs inside small extracellular vesicles, allowing the delivery of genetic material to neighboring or distantly located target cells. The role of these secreted RNAs in cell‐to‐cell communication between β‐cells and other metabolic tissues as well as their potential use as diabetes biomarkers will be discussed. © 2020 American Physiological Society. Compr Physiol 10:893‐932, 2020.

Figure 1. Figure 1. Regulation of β‐cell mass over lifetime. The functional β‐cell mass is regulated by different processes over the course of a lifetime. During embryonic development and the neonatal period, expansion of the β‐cells is critical for the acquisition and the maintenance of a fully functional β‐cell mass. Adverse conditions limiting β‐mass expansion during these critical periods predispose individuals to diabetes later in life. Pancreatic β‐cells can be the target of an autoimmune attack. Immune cells infiltrate the islets and selectively kill the β‐cells, leading to a near complete loss of insulin‐secreting cells and the appearance of type 1 diabetes. Throughout life, several mechanisms favor the expansion of the functional β‐cell mass during pregnancy or in obese individuals to compensate for insulin resistance of peripheral tissues. Type 2 diabetes develops if the functional β‐cell mass fails to adapt to cover the increased insulin needs. Lastly, aging and β‐cell senescence can reduce the capacity to compensate for insulin resistance.
Figure 2. Figure 2. Relative amounts of RNA transcripts in human and mouse cells. Pie chart representing the proportion of different RNA classes compared to the total number of annotated genes in (A) human (60,603 genes) or (B) mouse (55,487 genes). Data obtained from Gencode 31. Abbreviations: lncRNAs, long‐noncoding ribonucleic acids; miRNAs, micro‐ribonucleic acids; snoRNAs, small nucleolar ribonucleic acids; snRNAs, small nuclear ribonucleic acids; ncRNAs, noncoding ribonucleic acids.
Figure 3. Figure 3. Classification of RNAs. RNA molecules can be divided into two categories, depending on their ability to code (coding RNA) or not (noncoding RNA) for proteins. Noncoding RNA transcripts are classified based on their function (rRNA, ribosomal ribonucleic acid; tRNA, transfer ribonucleic acid) or on their length (shorter or longer than 200 nucleotides). The short RNA families include snoRNAs (small nucleolar ribonucleic acids), snRNAs (small nuclear ribonucleic acids), siRNAs (small interfering ribonucleic acids), miRNAs (micro‐ribonucleic acids), and piRNAs (PIWI‐interacting ribonucleic acids). The long‐noncoding ribonucleic acid (lncRNA) family is further subdivided based on the shape of the RNA molecules: linear lncRNA or circular ribonucleic acid (circRNA). Of note, tRNA molecules can be cleaved to generate fragments (tRF) that share some properties with other short ncRNAs.
Figure 4. Figure 4. Generation and classification of tRFs. Endonucleic cleavage of mature tRNAs generates a diverse range of tRFs. Various endonucleases including Dicer generate short tRFs (12–20 nucleotides) at either arms of the tRNAs. Alternatively, angiogenin cleaves tRNAs at the anticodon loop, generating tRNA halves (32–50 nucleotides, also known as tiRNAs). A double cleavage along the length of tRNAs can generate internal tRNA fragments (16 nucleotides or longer, also known as i‐tRFs).
Figure 5. Figure 5. Classification of lncRNAs based on their genomic proximity to protein‐coding genes. (A) Long intergenic noncoding ribonucleic acids (lincRNAs) are located in intergenic regions. They are situated at more than 1 kb distance from the nearest protein‐coding genes. (B) The other classes of long noncoding ribonucleic acids (lncRNAs) are located in the vicinity of protein‐coding genes and are named based on how their exons are positioned on the genome with respect to the exons of the mRNA and on the direction of transcription: overlapping, intronic, cis‐antisense, or bidirectional.
Figure 6. Figure 6. Examples of mode of action of lncRNAs in β‐cells. (A) The lncRNA PLUTO acts on 3D chromatin organization to favor the transcription of PDX1 by bringing in close proximity the PDX1 promoter with its enhancer cluster. (B) The lncRNA Meg3 inhibits EZH2‐mediated methylation of Rad21, Smc3, and Sin3α promoters, triggering the expression of these transcription factors and, therefore, resulting in the inhibition of MafA expression. (C) The lncRNA H19 sequesters let‐7 members to prevent the repression of target genes of these miRNAs, leading to activation of the PI3K/AKT pathway. Abbreviations: lncRNA, long noncoding ribonucleic acid; miRNA, micro‐ribonucleic acid; PI3K, phosphatidylinositol 3‐kinase.
Figure 7. Figure 7. Formation of circular RNAs in eukaryotic cells. Eukaryotic circRNAs can be generated from introns (gray) and/or exons (colored) of pre‐mRNAs. Circular intronic RNAs (left) arise from introns circularized at the 5′ and branchpoint (bp) nucleotides by a 2′ to 5′ junction during linear splicing. These branched circular introns have a linear 3′ tail and are known as lariats. Intron lariats can be debranched and rapidly degraded or escape debranching, lose their tail, and turn into stable circular intronic RNAs. Instead, circular exonic and exonic‐intronic RNAs (right) can contain one or more exons and/or introns and are produced by backsplicing of an upstream 3′ splice site and a downstream 5′ splice site circularized by a 3′ to 5′ junction.
Figure 8. Figure 8. Exosome cross talk in the context of type 1 and type 2 diabetes. (A) In the context of T1D, islet mesenchymal stem cells (i‐MSC) and β‐cells secrete exosomes that activate T‐ and B‐cells. Pancreatic islet cells produce exosomes that can horizontally transfer genetic material to adjacent islet cells and endothelial cells. Infiltrated T‐cells transfer specific miRNAs via exosomes to β‐cells. (B) In the context of T2D, muscle and hepatic exosomes deliver miRNAs to pancreatic islet cells. Exosomes secreted from adipose tissue macrophages (ATMs) transfer miRNAs to insulin target tissues. Adipose tissue release exosomes containing miRNAs to liver and skeletal muscle. (A,B) Pancreatic islet exosomes and ncRNAs that are released in the blood stream represent potential biomarkers for T1D and T2D.


Figure 1. Regulation of β‐cell mass over lifetime. The functional β‐cell mass is regulated by different processes over the course of a lifetime. During embryonic development and the neonatal period, expansion of the β‐cells is critical for the acquisition and the maintenance of a fully functional β‐cell mass. Adverse conditions limiting β‐mass expansion during these critical periods predispose individuals to diabetes later in life. Pancreatic β‐cells can be the target of an autoimmune attack. Immune cells infiltrate the islets and selectively kill the β‐cells, leading to a near complete loss of insulin‐secreting cells and the appearance of type 1 diabetes. Throughout life, several mechanisms favor the expansion of the functional β‐cell mass during pregnancy or in obese individuals to compensate for insulin resistance of peripheral tissues. Type 2 diabetes develops if the functional β‐cell mass fails to adapt to cover the increased insulin needs. Lastly, aging and β‐cell senescence can reduce the capacity to compensate for insulin resistance.


Figure 2. Relative amounts of RNA transcripts in human and mouse cells. Pie chart representing the proportion of different RNA classes compared to the total number of annotated genes in (A) human (60,603 genes) or (B) mouse (55,487 genes). Data obtained from Gencode 31. Abbreviations: lncRNAs, long‐noncoding ribonucleic acids; miRNAs, micro‐ribonucleic acids; snoRNAs, small nucleolar ribonucleic acids; snRNAs, small nuclear ribonucleic acids; ncRNAs, noncoding ribonucleic acids.


Figure 3. Classification of RNAs. RNA molecules can be divided into two categories, depending on their ability to code (coding RNA) or not (noncoding RNA) for proteins. Noncoding RNA transcripts are classified based on their function (rRNA, ribosomal ribonucleic acid; tRNA, transfer ribonucleic acid) or on their length (shorter or longer than 200 nucleotides). The short RNA families include snoRNAs (small nucleolar ribonucleic acids), snRNAs (small nuclear ribonucleic acids), siRNAs (small interfering ribonucleic acids), miRNAs (micro‐ribonucleic acids), and piRNAs (PIWI‐interacting ribonucleic acids). The long‐noncoding ribonucleic acid (lncRNA) family is further subdivided based on the shape of the RNA molecules: linear lncRNA or circular ribonucleic acid (circRNA). Of note, tRNA molecules can be cleaved to generate fragments (tRF) that share some properties with other short ncRNAs.


Figure 4. Generation and classification of tRFs. Endonucleic cleavage of mature tRNAs generates a diverse range of tRFs. Various endonucleases including Dicer generate short tRFs (12–20 nucleotides) at either arms of the tRNAs. Alternatively, angiogenin cleaves tRNAs at the anticodon loop, generating tRNA halves (32–50 nucleotides, also known as tiRNAs). A double cleavage along the length of tRNAs can generate internal tRNA fragments (16 nucleotides or longer, also known as i‐tRFs).


Figure 5. Classification of lncRNAs based on their genomic proximity to protein‐coding genes. (A) Long intergenic noncoding ribonucleic acids (lincRNAs) are located in intergenic regions. They are situated at more than 1 kb distance from the nearest protein‐coding genes. (B) The other classes of long noncoding ribonucleic acids (lncRNAs) are located in the vicinity of protein‐coding genes and are named based on how their exons are positioned on the genome with respect to the exons of the mRNA and on the direction of transcription: overlapping, intronic, cis‐antisense, or bidirectional.


Figure 6. Examples of mode of action of lncRNAs in β‐cells. (A) The lncRNA PLUTO acts on 3D chromatin organization to favor the transcription of PDX1 by bringing in close proximity the PDX1 promoter with its enhancer cluster. (B) The lncRNA Meg3 inhibits EZH2‐mediated methylation of Rad21, Smc3, and Sin3α promoters, triggering the expression of these transcription factors and, therefore, resulting in the inhibition of MafA expression. (C) The lncRNA H19 sequesters let‐7 members to prevent the repression of target genes of these miRNAs, leading to activation of the PI3K/AKT pathway. Abbreviations: lncRNA, long noncoding ribonucleic acid; miRNA, micro‐ribonucleic acid; PI3K, phosphatidylinositol 3‐kinase.


Figure 7. Formation of circular RNAs in eukaryotic cells. Eukaryotic circRNAs can be generated from introns (gray) and/or exons (colored) of pre‐mRNAs. Circular intronic RNAs (left) arise from introns circularized at the 5′ and branchpoint (bp) nucleotides by a 2′ to 5′ junction during linear splicing. These branched circular introns have a linear 3′ tail and are known as lariats. Intron lariats can be debranched and rapidly degraded or escape debranching, lose their tail, and turn into stable circular intronic RNAs. Instead, circular exonic and exonic‐intronic RNAs (right) can contain one or more exons and/or introns and are produced by backsplicing of an upstream 3′ splice site and a downstream 5′ splice site circularized by a 3′ to 5′ junction.


Figure 8. Exosome cross talk in the context of type 1 and type 2 diabetes. (A) In the context of T1D, islet mesenchymal stem cells (i‐MSC) and β‐cells secrete exosomes that activate T‐ and B‐cells. Pancreatic islet cells produce exosomes that can horizontally transfer genetic material to adjacent islet cells and endothelial cells. Infiltrated T‐cells transfer specific miRNAs via exosomes to β‐cells. (B) In the context of T2D, muscle and hepatic exosomes deliver miRNAs to pancreatic islet cells. Exosomes secreted from adipose tissue macrophages (ATMs) transfer miRNAs to insulin target tissues. Adipose tissue release exosomes containing miRNAs to liver and skeletal muscle. (A,B) Pancreatic islet exosomes and ncRNAs that are released in the blood stream represent potential biomarkers for T1D and T2D.
References
 1.Ackermann AM, Wang Z, Schug J, Naji A, Kaestner KH. Integration of ATAC‐seq and RNA‐seq identifies human alpha cell and beta cell signature genes. Mol Metab 5: 233‐244, 2016.
 2.Agarwal V, Bell GW, Nam JW, Bartel DP. Predicting effective microRNA target sites in mammalian mRNAs. Elife 4: e05005, 2015.
 3.Aguayo‐Mazzucato C, Andle J, Lee TB Jr, Midha A, Talemal L, Chipashvili V, Hollister‐Lock J, van Deursen J, Weir G, Bonner‐Weir S. Acceleration of beta cell aging determines diabetes and senolysis improves disease outcomes. Cell Metab 30: 129‐142 e124, 2019.
 4.Aguayo‐Mazzucato C, Koh A, El Khattabi I, Li WC, Toschi E, Jermendy A, Juhl K, Mao K, Weir GC, Sharma A, Bonner‐Weir S. Mafa expression enhances glucose‐responsive insulin secretion in neonatal rat beta cells. Diabetologia 54: 583‐593, 2011.
 5.Aguayo‐Mazzucato C, Sanchez‐Soto C, Godinez‐Puig V, Gutierrez‐Ospina G, Hiriart M. Restructuring of pancreatic islets and insulin secretion in a postnatal critical window. PLoS One 1: e35, 2006.
 6.Ahren B. Glucagon – Early breakthroughs and recent discoveries. Peptides 67: 74‐81, 2015.
 7.Akerman I, Tu Z, Beucher A, Rolando DMY, Sauty‐Colace C, Benazra M, Nakic N, Yang J, Wang H, Pasquali L, Moran I, Garcia‐Hurtado J, Castro N, Gonzalez‐Franco R, Stewart AF, Bonner C, Piemonti L, Berney T, Groop L, Kerr‐Conte J, Pattou F, Argmann C, Schadt E, Ravassard P, Ferrer J. Human pancreatic beta cell lncRNAs control cell‐specific regulatory networks. Cell Metab 25: 400‐411, 2017.
 8.Alejandro EU, Gregg B, Wallen T, Kumusoglu D, Meister D, Chen A, Merrins MJ, Satin LS, Liu M, Arvan P, Bernal‐Mizrachi E. Maternal diet‐induced microRNAs and mTOR underlie beta cell dysfunction in offspring. J Clin Invest 124: 4395‐4410, 2014.
 9.Ameres SL, Zamore PD. Diversifying microRNA sequence and function. Nat Rev 14: 475‐488, 2013.
 10.Angulo MA, Butler MG, Cataletto ME. Prader‐Willi syndrome: A review of clinical, genetic, and endocrine findings. J Endocrinol Investig 38: 1249‐1263, 2015.
 11.Araujo EP, Amaral ME, Souza CT, Bordin S, Ferreira F, Saad MJ, Boschero AC, Magalhaes EC, Velloso LA. Blockade of IRS1 in isolated rat pancreatic islets improves glucose‐induced insulin secretion. FEBS Lett 531: 437‐442, 2002.
 12.Arnes L, Akerman I, Balderes DA, Ferrer J, Sussel L. betalinc1 encodes a long noncoding RNA that regulates islet beta‐cell formation and function. Genes Dev 30: 502‐507, 2016.
 13.Arroyo JD, Chevillet JR, Kroh EM, Ruf IK, Pritchard CC, Gibson DF, Mitchell PS, Bennett CF, Pogosova‐Agadjanyan EL, Stirewalt DL, Tait JF, Tewari M. Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc Natl Acad Sci U S A 108: 5003‐5008, 2011.
 14.Atkinson MA, Eisenbarth GS, Michels AW. Type 1 diabetes. Lancet 383: 69‐82, 2014.
 15.Backe MB, Novotny GW, Christensen DP, Grunnet LG, Mandrup‐Poulsen T. Altering beta‐cell number through stable alteration of miR‐21 and miR‐34a expression. Islets 6: e27754, 2014.
 16.Backes C, Meese E, Keller A. Specific miRNA disease biomarkers in blood, serum and plasma: Challenges and prospects. Mol Diagn Ther 20: 509‐518, 2016.
 17.Baird JD, Farquhar JW. Insulin‐secreting capacity in newborn infants of normal and diabetic women. Lancet 1: 71‐74, 1962.
 18.Barbagallo D, Piro S, Condorelli AG, Mascali LG, Urbano F, Parrinello N, Monello A, Statello L, Ragusa M, Rabuazzo AM, Di Pietro C, Purrello F, Purrello M. miR‐296‐3p, miR‐298‐5p and their downstream networks are causally involved in the higher resistance of mammalian pancreatic alpha cells to cytokine‐induced apoptosis as compared to beta cells. BMC Genomics 14: 62, 2013.
 19.Baroukh N, Ravier MA, Loder MK, Hill EV, Bounacer A, Scharfmann R, Rutter GA, Van Obberghen E. MicroRNA‐124a regulates Foxa2 expression and intracellular signaling in pancreatic beta‐cell lines. J Biol Chem 282: 19575‐19588, 2007.
 20.Bartel DP. MicroRNAs: Target recognition and regulatory functions. Cell 136: 215‐233, 2009.
 21.Bartel DP. Metazoan microRNAs. Cell 173: 20‐51, 2018.
 22.Bashratyan R, Sheng H, Regn D, Rahman MJ, Dai YD. Insulinoma‐released exosomes activate autoreactive marginal zone‐like B cells that expand endogenously in prediabetic NOD mice. Eur J Immunol 43: 2588‐2597, 2013.
 23.Belgardt BF, Ahmed K, Spranger M, Latreille M, Denzler R, Kondratiuk N, von Meyenn F, Villena FN, Herrmanns K, Bosco D, Kerr‐Conte J, Pattou F, Rulicke T, Stoffel M. The microRNA‐200 family regulates pancreatic beta cell survival in type 2 diabetes. Nat Med 21: 619‐627, 2015.
 24.Benner C, van der Meulen T, Caceres E, Tigyi K, Donaldson CJ, Huising MO. The transcriptional landscape of mouse beta cells compared to human beta cells reveals notable species differences in long non‐coding RNA and protein‐coding gene expression. BMC Genomics 15: 620, 2014.
 25.Betel D, Sheridan R, Marks DS, Sander C. Computational analysis of mouse piRNA sequence and biogenesis. PLoS Comput Biol 3: e222, 2007.
 26.Bijkerk R, Esguerra JLS, Ellenbroek JH, Au YW, Hanegraaf MAJ, de Koning EJ, Eliasson L, van Zonneveld AJ. In vivo silencing of microRNA‐132 reduces blood glucose and improves insulin secretion. Nucleic Acid Ther 29: 67‐72, 2019.
 27.Bratkovic T, Bozic J, Rogelj B. Functional diversity of small nucleolar RNAs. Nucleic Acids Res 48 (4): 1627‐1651, 2020.
 28.Bravo‐Egana V, Rosero S, Klein D, Jiang Z, Vargas N, Tsinoremas N, Doni M, Podetta M, Ricordi C, Molano RD, Pileggi A, Pastori RL. Inflammation‐mediated regulation of microRNA expression in transplanted pancreatic islets. J Transplant 2012: 723614, 2012.
 29.Burnett LC, Hubner G, LeDuc CA, Morabito MV, Carli JFM, Leibel RL. Loss of the imprinted, non‐coding Snord116 gene cluster in the interval deleted in the Prader Willi syndrome results in murine neuronal and endocrine pancreatic developmental phenotypes. Hum Mol Genet 26: 4606‐4616, 2017.
 30.Burnett LC, LeDuc CA, Sulsona CR, Paull D, Rausch R, Eddiry S, Carli JF, Morabito MV, Skowronski AA, Hubner G, Zimmer M, Wang L, Day R, Levy B, Fennoy I, Dubern B, Poitou C, Clement K, Butler MG, Rosenbaum M, Salles JP, Tauber M, Driscoll DJ, Egli D, Leibel RL. Deficiency in prohormone convertase PC1 impairs prohormone processing in Prader‐Willi syndrome. J Clin Invest 127: 293‐305, 2017.
 31.Cantaluppi V, Biancone L, Figliolini F, Beltramo S, Medica D, Deregibus MC, Galimi F, Romagnoli R, Salizzoni M, Tetta C, Segoloni GP, Camussi G. Microvesicles derived from endothelial progenitor cells enhance neoangiogenesis of human pancreatic islets. Cell Transplant 21: 1305‐1320, 2012.
 32.Carrieri C, Cimatti L, Biagioli M, Beugnet A, Zucchelli S, Fedele S, Pesce E, Ferrer I, Collavin L, Santoro C, Forrest AR, Carninci P, Biffo S, Stupka E, Gustincich S. Long non‐coding antisense RNA controls Uchl1 translation through an embedded SINEB2 repeat. Nature 491: 454‐457, 2012.
 33.Carter G, Miladinovic B, Patel AA, Deland L, Mastorides S, Patel NA. Circulating long noncoding RNA GAS5 levels are correlated to prevalence of type 2 diabetes mellitus. BBA Clin 4: 102‐107, 2015.
 34.Castano C, Kalko S, Novials A, Parrizas M. Obesity‐associated exosomal miRNAs modulate glucose and lipid metabolism in mice. Proc Natl Acad Sci U S A 115: 12158‐12163, 2018.
 35.Castano C, Novials A, Parrizas M. Exosomes and diabetes. Diabetes Metab Res Rev 35: e3107, 2018.
 36.Cech TR, Steitz JA. The noncoding RNA revolution‐trashing old rules to forge new ones. Cell 157: 77‐94, 2014.
 37.Cesana M, Cacchiarelli D, Legnini I, Santini T, Sthandier O, Chinappi M, Tramontano A, Bozzoni I. A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA. Cell 147: 358‐369, 2011.
 38.Chen H, Gu X, Liu Y, Wang J, Wirt SE, Bottino R, Schorle H, Sage J, Kim SK. PDGF signalling controls age‐dependent proliferation in pancreatic beta‐cells. Nature 478: 349‐355, 2011.
 39.Chen Q, Yan M, Cao Z, Li X, Zhang Y, Shi J, Feng GH, Peng H, Zhang X, Zhang Y, Qian J, Duan E, Zhai Q, Zhou Q. Sperm tsRNAs contribute to intergenerational inheritance of an acquired metabolic disorder. Science 351: 397‐400, 2016.
 40.Chen Z, Qi M, Shen B, Luo G, Wu Y, Li J, Lu Z, Zheng Z, Dai Q, Wang H. Transfer RNA demethylase ALKBH3 promotes cancer progression via induction of tRNA‐derived small RNAs. Nucleic Acids Res 47: 2533‐2545, 2019.
 41.Cheng J, Metge F, Dieterich C. Specific identification and quantification of circular RNAs from sequencing data. Bioinformatics 32: 1094‐1096, 2016.
 42.Chiou NT, Kageyama R, Ansel KM. Selective export into extracellular vesicles and function of tRNA fragments during T cell activation. Cell Rep 25: 3356‐3370 e3354, 2018.
 43.Chitnis NS, Pytel D, Bobrovnikova‐Marjon E, Pant D, Zheng H, Maas NL, Frederick B, Kushner JA, Chodosh LA, Koumenis C, Fuchs SY, Diehl JA. miR‐211 is a prosurvival microRNA that regulates chop expression in a PERK‐dependent manner. Mol Cell 48: 353‐364, 2012.
 44.Cho JH, Chen L, Kim MH, Chow RH, Hille B, Koh DS. Characteristics and functions of {alpha}‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionate receptors expressed in mouse pancreatic {alpha}‐cells. Endocrinology 151: 1541‐1550, 2010.
 45.Cho YS, Chen CH, Hu C, Long J, Ong RT, Sim X, Takeuchi F, Wu Y, Go MJ, Yamauchi T, Chang YC, Kwak SH, Ma RC, Yamamoto K, Adair LS, Aung T, Cai Q, Chang LC, Chen YT, Gao Y, Hu FB, Kim HL, Kim S, Kim YJ, Lee JJ, Lee NR, Li Y, Liu JJ, Lu W, Nakamura J, Nakashima E, Ng DP, Tay WT, Tsai FJ, Wong TY, Yokota M, Zheng W, Zhang R, Wang C, So WY, Ohnaka K, Ikegami H, Hara K, Cho YM, Cho NH, Chang TJ, Bao Y, Hedman AK, Morris AP, McCarthy MI, Consortium D, Mu TC, Takayanagi R, Park KS, Jia W, Chuang LM, Chan JC, Maeda S, Kadowaki T, Lee JY, Wu JY, Teo YY, Tai ES, Shu XO, Mohlke KL, Kato N, Han BG, Seielstad M. Meta‐analysis of genome‐wide association studies identifies eight new loci for type 2 diabetes in east Asians. Nat Genet 44: 67‐72, 2011.
 46.Conine CC, Sun F, Song L, Rivera‐Perez JA, Rando OJ. Small RNAs gained during epididymal transit of sperm are essential for embryonic development in mice. Dev Cell 46: 470‐480 e473, 2018.
 47.Conrad E, Stein R, Hunter CS. Revealing transcription factors during human pancreatic beta cell development. Trends Endocrinol Metab 25: 407‐414, 2014.
 48.Correa‐Medina M, Bravo‐Egana V, Rosero S, Ricordi C, Edlund H, Diez J, Pastori RL. MicroRNA miR‐7 is preferentially expressed in endocrine cells of the developing and adult human pancreas. Gene Expr Patterns 9: 193‐199, 2009.
 49.Cosentino C, Toivonen S, Diaz Villamil E, Atta M, Ravanat JL, Demine S, Schiavo AA, Pachera N, Deglasse JP, Jonas JC, Balboa D, Otonkoski T, Pearson ER, Marchetti P, Eizirik DL, Cnop M, Igoillo‐Esteve M. Pancreatic beta‐cell tRNA hypomethylation and fragmentation link TRMT10A deficiency with diabetes. Nucleic Acids Res 46: 10302‐10318, 2018.
 50.Cozen AE, Quartley E, Holmes AD, Hrabeta‐Robinson E, Phizicky EM, Lowe TM. ARM‐seq: AlkB‐facilitated RNA methylation sequencing reveals a complex landscape of modified tRNA fragments. Nat Methods 12: 879‐884, 2015.
 51.Cunha DA, Igoillo‐Esteve M, Gurzov EN, Germano CM, Naamane N, Marhfour I, Fukaya M, Vanderwinden JM, Gysemans C, Mathieu C, Marselli L, Marchetti P, Harding HP, Ron D, Eizirik DL, Cnop M. Death protein 5 and p53‐upregulated modulator of apoptosis mediate the endoplasmic reticulum stress‐mitochondrial dialog triggering lipotoxic rodent and human beta‐cell apoptosis. Diabetes 61: 2763‐2775, 2012.
 52.da Rocha ST, Edwards CA, Ito M, Ogata T, Ferguson‐Smith AC. Genomic imprinting at the mammalian Dlk1‐Dio3 domain. Trends Genet 24: 306‐316, 2008.
 53.De Tata V. Age‐related impairment of pancreatic beta‐cell function: Pathophysiological and cellular mechanisms. Front Endocrinol (Lausanne) 5: 138, 2014.
 54.Deatherage BL, Cookson BT. Membrane vesicle release in bacteria, eukaryotes, and archaea: A conserved yet underappreciated aspect of microbial life. Infect Immun 80: 1948‐1957, 2012.
 55.Derrien T, Johnson R, Bussotti G, Tanzer A, Djebali S, Tilgner H, Guernec G, Martin D, Merkel A, Knowles DG, Lagarde J, Veeravalli L, Ruan X, Ruan Y, Lassmann T, Carninci P, Brown JB, Lipovich L, Gonzalez JM, Thomas M, Davis CA, Shiekhattar R, Gingeras TR, Hubbard TJ, Notredame C, Harrow J, Guigo R. The GENCODE v7 catalog of human long noncoding RNAs: Analysis of their gene structure, evolution, and expression. Genome Res 22: 1775‐1789, 2012.
 56.Dibble CC, Cantley LC. Regulation of mTORC1 by PI3K signaling. Trends Cell Biol 25: 545‐555, 2015.
 57.Djebali S, Davis CA, Merkel A, Dobin A, Lassmann T, Mortazavi A, Tanzer A, Lagarde J, Lin W, Schlesinger F, Xue C, Marinov GK, Khatun J, Williams BA, Zaleski C, Rozowsky J, Roder M, Kokocinski F, Abdelhamid RF, Alioto T, Antoshechkin I, Baer MT, Bar NS, Batut P, Bell K, Bell I, Chakrabortty S, Chen X, Chrast J, Curado J, Derrien T, Drenkow J, Dumais E, Dumais J, Duttagupta R, Falconnet E, Fastuca M, Fejes‐Toth K, Ferreira P, Foissac S, Fullwood MJ, Gao H, Gonzalez D, Gordon A, Gunawardena H, Howald C, Jha S, Johnson R, Kapranov P, King B, Kingswood C, Luo OJ, Park E, Persaud K, Preall JB, Ribeca P, Risk B, Robyr D, Sammeth M, Schaffer L, See LH, Shahab A, Skancke J, Suzuki AM, Takahashi H, Tilgner H, Trout D, Walters N, Wang H, Wrobel J, Yu Y, Ruan X, Hayashizaki Y, Harrow J, Gerstein M, Hubbard T, Reymond A, Antonarakis SE, Hannon G, Giddings MC, Ruan Y, Wold B, Carninci P, Guigo R, Gingeras TR. Landscape of transcription in human cells. Nature 489: 101‐108, 2012.
 58.Dooley J, Garcia‐Perez JE, Sreenivasan J, Schlenner SM, Vangoitsenhoven R, Papadopoulou AS, Tian L, Schonefeldt S, Serneels L, Deroose C, Staats KA, Van der Schueren B, De Strooper B, McGuinness OP, Mathieu C, Liston A. The microRNA‐29 family dictates the balance between homeostatic and pathological glucose handling in diabetes and obesity. Diabetes 65: 53‐61, 2016.
 59.Dumortier O, Hinault C, Gautier N, Patouraux S, Casamento V, Van Obberghen E. Maternal protein restriction leads to pancreatic failure in offspring: Role of misexpressed microRNA‐375. Diabetes 63: 3416‐3427, 2014.
 60.Durcin M, Fleury A, Taillebois E, Hilairet G, Krupova Z, Henry C, Truchet S, Trotzmuller M, Kofeler H, Mabilleau G, Hue O, Andriantsitohaina R, Martin P, Le Lay S. Characterisation of adipocyte‐derived extracellular vesicle subtypes identifies distinct protein and lipid signatures for large and small extracellular vesicles. J Extracell Vesicles 6: 1305677, 2017.
 61.Dusaulcy R, Handgraaf S, Visentin F, Vesin C, Philippe J, Gosmain Y. miR‐132‐3p is a positive regulator of alpha‐cell mass and is downregulated in obese hyperglycemic mice. Mol Metab 22: 84‐95, 2019.
 62.Ebert MS, Neilson JR, Sharp PA. MicroRNA sponges: Competitive inhibitors of small RNAs in mammalian cells. Nat Methods 4: 721‐726, 2007.
 63.Eizirik DL, Colli ML, Ortis F. The role of inflammation in insulitis and beta‐cell loss in type 1 diabetes. Nat Rev Endocrinol 5: 219‐226, 2009.
 64.El Ouaamari A, Baroukh N, Martens GA, Lebrun P, Pipeleers D, van Obberghen E. miR‐375 targets 3′‐phosphoinositide‐dependent protein kinase‐1 and regulates glucose‐induced biological responses in pancreatic beta‐cells. Diabetes 57: 2708‐2717, 2008.
 65.ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 489: 57‐74, 2012.
 66.Enright AJ, John B, Gaul U, Tuschl T, Sander C, Marks DS. MicroRNA targets in Drosophila. Genome Biol 5: R1, 2003.
 67.Erener S, Marwaha A, Tan R, Panagiotopoulos C, Kieffer TJ. Profiling of circulating microRNAs in children with recent onset of type 1 diabetes. JCI Insight 2: e89656, 2017.
 68.Erener S, Mojibian M, Fox JK, Denroche HC, Kieffer TJ. Circulating miR‐375 as a biomarker of beta‐cell death and diabetes in mice. Endocrinology 154: 603‐608, 2013.
 69.Esguerra JL, Bolmeson C, Cilio CM, Eliasson L. Differential glucose‐regulation of microRNAs in pancreatic islets of non‐obese type 2 diabetes model Goto‐Kakizaki rat. PLoS One 6: e18613, 2011.
 70.Esguerra JL, Eliasson L. Functional implications of long non‐coding RNAs in the pancreatic islets of Langerhans. Front Genet 5: 209, 2014.
 71.Esguerra JL, Mollet IG, Salunkhe VA, Wendt A, Eliasson L. Regulation of pancreatic beta cell stimulus‐secretion coupling by microRNAs. Genes (Basel) 5: 1018‐1031, 2014.
 72.Esguerra JLS, Nagao M, Ofori JK, Wendt A, Eliasson L. MicroRNAs in islet hormone secretion. Diabetes Obes Metab 20 (Suppl 2): 11‐19, 2018.
 73.Fadista J, Vikman P, Laakso EO, Mollet IG, Esguerra JL, Taneera J, Storm P, Osmark P, Ladenvall C, Prasad RB, Hansson KB, Finotello F, Uvebrant K, Ofori JK, Di Camillo B, Krus U, Cilio CM, Hansson O, Eliasson L, Rosengren AH, Renstrom E, Wollheim CB, Groop L. Global genomic and transcriptomic analysis of human pancreatic islets reveals novel genes influencing glucose metabolism. Proc Natl Acad Sci U S A 111: 13924‐13929, 2014.
 74.Faghihi MA, Modarresi F, Khalil AM, Wood DE, Sahagan BG, Morgan TE, Finch CE, St Laurent G 3rd, Kenny PJ, Wahlestedt C. Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed‐forward regulation of beta‐secretase. Nat Med 14: 723‐730, 2008.
 75.Fajas L, Annicotte JS, Miard S, Sarruf D, Watanabe M, Auwerx J. Impaired pancreatic growth, beta cell mass, and beta cell function in E2F1 (‐/‐)mice. J Clin Invest 113: 1288‐1295, 2004.
 76.Fernandez‐Twinn DS, Hjort L, Novakovic B, Ozanne SE, Saffery R. Intrauterine programming of obesity and type 2 diabetes. Diabetologia 62: 1789‐1801, 2019.
 77.Figliolini F, Cantaluppi V, De Lena M, Beltramo S, Romagnoli R, Salizzoni M, Melzi R, Nano R, Piemonti L, Tetta C, Biancone L, Camussi G. Isolation, characterization and potential role in beta cell‐endothelium cross‐talk of extracellular vesicles released from human pancreatic islets. PLoS One 9: e102521, 2014.
 78.Filios SR, Shalev A. beta‐Cell MicroRNAs: small but powerful. Diabetes 64: 3631‐3644, 2015.
 79.Filios SR, Xu G, Chen J, Hong K, Jing G, Shalev A. MicroRNA‐200 is induced by thioredoxin‐interacting protein and regulates Zeb1 protein signaling and beta cell apoptosis. J Biol Chem 289: 36275‐36283, 2014.
 80.Francis N, Moore M, Rutter GA, Burns C. The role of microRNAs in the pancreatic differentiation of pluripotent stem cells. MicroRNA 3: 54‐63, 2014.
 81.Friedlander MR, Chen W, Adamidi C, Maaskola J, Einspanier R, Knespel S, Rajewsky N. Discovering microRNAs from deep sequencing data using miRDeep. Nat Biotechnol 26: 407‐415, 2008.
 82.Friedlander MR, Mackowiak SD, Li N, Chen W, Rajewsky N. miRDeep2 accurately identifies known and hundreds of novel microRNA genes in seven animal clades. Nucleic Acids Res 40: 37‐52, 2012.
 83.Friedman RC, Farh KK, Burge CB, Bartel DP. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 19: 92‐105, 2009.
 84.Frost RJ, Olson EN. Control of glucose homeostasis and insulin sensitivity by the Let‐7 family of microRNAs. Proc Natl Acad Sci U S A 108: 21075‐21080, 2011.
 85.Fu Q, Li Y, Jiang H, Shen Z, Gao R, He Y, Liu Y, Xu K, Yang T. Hepatocytes derived extracellular vesicles from high‐fat diet induced obese mice modulate genes expression and proliferation of islet beta cells. Biochem Biophys Res Commun 516: 1159‐1166, 2019.
 86.Fu Q, Wang PJ. Mammalian piRNAs: Biogenesis, function, and mysteries. Spermatogenesis 4: e27889, 2014.
 87.Furman BL. Streptozotocin‐induced diabetic models in mice and rats. Curr Protoc Pharmacol 70: 5.47.1‐5.47.20, 2015.
 88.Gabory A, Ripoche MA, Le Digarcher A, Watrin F, Ziyyat A, Forne T, Jammes H, Ainscough JF, Surani MA, Journot L, Dandolo L. H19 acts as a trans regulator of the imprinted gene network controlling growth in mice. Development 136: 3413‐3421, 2009.
 89.Gao Y, Zhang J, Zhao F. Circular RNA identification based on multiple seed matching. Brief Bioinform 19: 803‐810, 2018.
 90.Gentilella R, Pechtner V, Corcos A, Consoli A. Glucagon‐like peptide‐1 receptor agonists in type 2 diabetes treatment: Are they all the same? Diabetes Metab Res Rev 35: e3070, 2019.
 91.Gkirtzou K, Tsamardinos I, Tsakalides P, Poirazi P. MatureBayes: A probabilistic algorithm for identifying the mature miRNA within novel precursors. PLoS One 5: e11843, 2010.
 92.Glazar P, Papavasileiou P, Rajewsky N. circBase: A database for circular RNAs. RNA 20: 1666‐1670, 2014.
 93.Gong C, Maquat LE. lncRNAs transactivate STAU1‐mediated mRNA decay by duplexing with 3′UTRs via Alu elements. Nature 470: 284‐288, 2011.
 94.Goodarzi H, Liu X, Nguyen HC, Zhang S, Fish L, Tavazoie SF. Endogenous tRNA‐derived fragments suppress breast cancer progression via YBX1 displacement. Cell 161: 790‐802, 2015.
 95.Gou LT, Dai P, Yang JH, Xue Y, Hu YP, Zhou Y, Kang JY, Wang X, Li H, Hua MM, Zhao S, Hu SD, Wu LG, Shi HJ, Li Y, Fu XD, Qu LH, Wang ED, Liu MF. Pachytene piRNAs instruct massive mRNA elimination during late spermiogenesis. Cell Res 25: 266, 2015.
 96.Grasso S, Messina A, Saporito N, Reitano G. Serum‐insulin response to glucose and aminoacids in the premature infant. Lancet 2: 755‐756, 1968.
 97.Grieco FA, Schiavo AA, Brozzi F, Juan‐Mateu J, Bugliani M, Marchetti P, Eizirik D. The microRNAs miR‐211‐5p and miR‐204‐5p modulate ER stress in human beta cells. J Mol Endocrinol 63: 139‐149, 2019.
 98.Grieco FA, Sebastiani G, Juan‐Mateu J, Villate O, Marroqui L, Ladriere L, Tugay K, Regazzi R, Bugliani M, Marchetti P, Dotta F, Eizirik DL. MicroRNAs miR‐23a‐3p, miR‐23b‐3p, and miR‐149‐5p regulate the expression of proapoptotic BH3‐only proteins DP5 and PUMA in human pancreatic beta‐cells. Diabetes 66: 100‐112, 2017.
 99.Guay C, Jacovetti C, Nesca V, Motterle A, Tugay K, Regazzi R. Emerging roles of non‐coding RNAs in pancreatic beta‐cell function and dysfunction. Diabetes Obes Metab 14 (Suppl 3): 12‐21, 2012.
 100.Guay C, Kruit JK, Rome S, Menoud V, Mulder NL, Jurdzinski A, Mancarella F, Sebastiani G, Donda A, Gonzalez BJ, Jandus C, Bouzakri K, Pinget M, Boitard C, Romero P, Dotta F, Regazzi R. Lymphocyte‐derived exosomal microRNAs promote pancreatic beta cell death and may contribute to type 1 diabetes development. Cell Metab 29: 348‐361 e346, 2019.
 101.Guay C, Menoud V, Rome S, Regazzi R. Horizontal transfer of exosomal microRNAs transduce apoptotic signals between pancreatic beta‐cells. Cell Commun Signal 13: 17, 2015.
 102.Guay C, Regazzi R. MicroRNAs and the functional beta cell mass: For better or worse. Diabetes Metab 41: 369‐377, 2015.
 103.Guay C, Regazzi R. Role of islet microRNAs in diabetes: Which model for which question? Diabetologia 58: 456‐463, 2015.
 104.Guay C, Regazzi R. Exosomes as new players in metabolic organ cross‐talk. Diabetes Obes Metab 19 (Suppl 1): 137‐146, 2017.
 105.Guttman M, Donaghey J, Carey BW, Garber M, Grenier JK, Munson G, Young G, Lucas AB, Ach R, Bruhn L, Yang X, Amit I, Meissner A, Regev A, Rinn JL, Root DE, Lander ES. lincRNAs act in the circuitry controlling pluripotency and differentiation. Nature 477: 295‐300, 2011.
 106.Guttman M, Rinn JL. Modular regulatory principles of large non‐coding RNAs. Nature 482: 339‐346, 2012.
 107.Gyuris A, Navarrete‐Perea J, Jo A, Cristea S, Zhou S, Fraser K, Wei Z, Krichevsky AM, Weissleder R, Lee H, Gygi SP, Charest A. Physical and molecular landscapes of mouse glioma extracellular vesicles define heterogeneity. Cell Rep 27: 3972‐3987 e3976, 2019.
 108.Hacisuleyman E, Goff LA, Trapnell C, Williams A, Henao‐Mejia J, Sun L, McClanahan P, Hendrickson DG, Sauvageau M, Kelley DR, Morse M, Engreitz J, Lander ES, Guttman M, Lodish HF, Flavell R, Raj A, Rinn JL. Topological organization of multichromosomal regions by the long intergenic noncoding RNA Firre. Nat Struct Mol Biol 21: 198‐206, 2014.
 109.Hackenberg M, Rodriguez‐Ezpeleta N, Aransay AM. miRanalyzer: An update on the detection and analysis of microRNAs in high‐throughput sequencing experiments. Nucleic Acids Res 39: W132‐W138, 2011.
 110.Hackenberg M, Sturm M, Langenberger D, Falcon‐Perez JM, Aransay AM. miRanalyzer: A microRNA detection and analysis tool for next‐generation sequencing experiments. Nucleic Acids Res 37: W68‐W76, 2009.
 111.Hansen TB. Improved circRNA identification by combining prediction algorithms. Front Cell Dev Biol 6: 20, 2018.
 112.Helwak A, Kudla G, Dudnakova T, Tollervey D. Mapping the human miRNA interactome by CLASH reveals frequent noncanonical binding. Cell 153: 654‐665, 2013.
 113.Henaoui IS, Jacovetti C, Guerra Mollet I, Guay C, Sobel J, Eliasson L, Regazzi R. PIWI‐interacting RNAs as novel regulators of pancreatic beta cell function. Diabetologia 60: 1977‐1986, 2017.
 114.Holdt LM, Kohlmaier A, Teupser D. Molecular roles and function of circular RNAs in eukaryotic cells. Cell Mol Life Sci 75: 1071‐1098, 2018.
 115.Hong K, Xu G, Grayson TB, Shalev A. Cytokines regulate beta‐cell thioredoxin‐interacting protein (TXNIP) via distinct mechanisms and pathways. J Biol Chem 291: 8428‐8439, 2016.
 116.Huang TH, Fan B, Rothschild MF, Hu ZL, Li K, Zhao SH. MiRFinder: An improved approach and software implementation for genome‐wide fast microRNA precursor scans. BMC Bioinformatics 8: 341, 2007.
 117.Huang‐Doran I, Zhang CY, Vidal‐Puig A. Extracellular vesicles: Novel mediators of cell communication in metabolic disease. Trends Endocrinol Metab 28: 3‐18, 2017.
 118.Hunter MP, Ismail N, Zhang X, Aguda BD, Lee EJ, Yu L, Xiao T, Schafer J, Lee ML, Schmittgen TD, Nana‐Sinkam SP, Jarjoura D, Marsh CB. Detection of microRNA expression in human peripheral blood microvesicles. PLoS One 3: e3694, 2008.
 119.Igoillo‐Esteve M, Genin A, Lambert N, Desir J, Pirson I, Abdulkarim B, Simonis N, Drielsma A, Marselli L, Marchetti P, Vanderhaeghen P, Eizirik DL, Wuyts W, Julier C, Chakera AJ, Ellard S, Hattersley AT, Abramowicz M, Cnop M. tRNA methyltransferase homolog gene TRMT10A mutation in young onset diabetes and primary microcephaly in humans. PLoS Genet 9: e1003888, 2013.
 120.Ivanov P. Emerging roles of tRNA‐derived fragments in viral infections: The case of respiratory syncytial virus. Mol Ther 23: 1557‐1558, 2015.
 121.Ivanov P, Emara MM, Villen J, Gygi SP, Anderson P. Angiogenin‐induced tRNA fragments inhibit translation initiation. Mol Cell 43: 613‐623, 2011.
 122.Jacovetti C, Abderrahmani A, Parnaud G, Jonas JC, Peyot ML, Cornu M, Laybutt R, Meugnier E, Rome S, Thorens B, Prentki M, Bosco D, Regazzi R. MicroRNAs contribute to compensatory beta cell expansion during pregnancy and obesity. J Clin Invest 122: 3541‐3551, 2012.
 123.Jacovetti C, Jimenez V, Ayuso E, Laybutt R, Peyot ML, Prentki M, Bosch F, Regazzi R. Contribution of intronic miR‐338‐3p and its hosting gene AATK to compensatory beta‐cell mass expansion. Mol Endocrinol 29: 693‐702, 2015.
 124.Jacovetti C, Matkovich SJ, Rodriguez‐Trejo A, Guay C, Regazzi R. Postnatal beta‐cell maturation is associated with islet‐specific microRNA changes induced by nutrient shifts at weaning. Nat Commun 6: 8084, 2015.
 125.Jacovetti C, Rodriguez‐Trejo A, Guay C, Sobel J, Gattesco S, Petrenko V, Saini C, Dibner C, Regazzi R. MicroRNAs modulate core‐clock gene expression in pancreatic islets during early postnatal life in rats. Diabetologia 60: 2011‐2020, 2017.
 126.Jalabert A, Vial G, Guay C, Wiklander OP, Nordin JZ, Aswad H, Forterre A, Meugnier E, Pesenti S, Regazzi R, Danty‐Berger E, Ducreux S, Vidal H, El‐Andaloussi S, Rieusset J, Rome S. Exosome‐like vesicles released from lipid‐induced insulin‐resistant muscles modulate gene expression and proliferation of beta recipient cells in mice. Diabetologia 59: 1049‐1058, 2016.
 127.Jeppesen DK, Fenix AM, Franklin JL, Higginbotham JN, Zhang Q, Zimmerman LJ, Liebler DC, Ping J, Liu Q, Evans R, Fissell WH, Patton JG, Rome LH, Burnette DT, Coffey RJ. Reassessment of exosome composition. Cell 177: 428‐445 e418, 2019.
 128.Jha A, Shankar R. miReader: Discovering novel miRNAs in species without sequenced genome. PLoS One 8: e66857, 2013.
 129.Ji J, Dai X, Yeung SJ, He X. The role of long non‐coding RNA GAS5 in cancers. Cancer Manag Res 11: 2729‐2737, 2019.
 130.Jimenez‐Palomares M, Lopez‐Acosta JF, Villa‐Perez P, Moreno‐Amador JL, Munoz‐Barrera J, Fernandez‐Luis S, Heras‐Pozas B, Perdomo G, Bernal‐Mizrachi E, Cozar‐Castellano I. Cyclin C stimulates beta‐cell proliferation in rat and human pancreatic beta‐cells. Am J Phys Endocrinol Metab 308: E450‐E459, 2015.
 131.Jin F, Wang N, Zhu Y, You L, Wang L, De W, Tang W. Downregulation of long noncoding RNA Gas5 affects cell cycle and insulin secretion in mouse pancreatic beta cells. Cell Physiol Biochem 43: 2062‐2073, 2017.
 132.Jo S, Chen J, Xu G, Grayson TB, Thielen LA, Shalev A. miR‐204 controls glucagon‐like peptide 1 receptor expression and agonist function. Diabetes 67: 256‐264, 2018.
 133.Joglekar MV, Joglekar VM, Hardikar AA. Expression of islet‐specific microRNAs during human pancreatic development. Gene Expr Patterns 9: 109‐113, 2009.
 134.Jonsson J, Carlsson L, Edlund T, Edlund H. Insulin‐promoter‐factor 1 is required for pancreas development in mice. Nature 371: 606‐609, 1994.
 135.Kadri S, Hinman V, Benos PV. HHMMiR: Efficient de novo prediction of microRNAs using hierarchical hidden Markov models. BMC Bioinformatics 10 (Suppl 1): S35, 2009.
 136.Kahn SE, Cooper ME, Del Prato S. Pathophysiology and treatment of type 2 diabetes: Perspectives on the past, present, and future. Lancet 383: 1068‐1083, 2014.
 137.Kalis M, Bolmeson C, Esguerra JL, Gupta S, Edlund A, Tormo‐Badia N, Speidel D, Holmberg D, Mayans S, Khoo NK, Wendt A, Eliasson L, Cilio CM. Beta‐cell specific deletion of dicer1 leads to defective insulin secretion and diabetes mellitus. PLoS One 6: e29166, 2011.
 138.Kameswaran V, Bramswig NC, McKenna LB, Penn M, Schug J, Hand NJ, Chen Y, Choi I, Vourekas A, Won KJ, Liu C, Vivek K, Naji A, Friedman JR, Kaestner KH. Epigenetic regulation of the DLK1‐MEG3 microRNA cluster in human type 2 diabetic islets. Cell Metab 19: 135‐145, 2014.
 139.Kameswaran V, Kaestner KH. The Missing lnc(RNA) between the pancreatic beta‐cell and diabetes. Front Genet 5: 200, 2014.
 140.Kanji MS, Martin MG, Bhushan A. Dicer1 is required to repress neuronal fate during endocrine cell maturation. Diabetes 62: 1602‐1611, 2013.
 141.Kapranov P, Cheng J, Dike S, Nix DA, Duttagupta R, Willingham AT, Stadler PF, Hertel J, Hackermuller J, Hofacker IL, Bell I, Cheung E, Drenkow J, Dumais E, Patel S, Helt G, Ganesh M, Ghosh S, Piccolboni A, Sementchenko V, Tammana H, Gingeras TR. RNA maps reveal new RNA classes and a possible function for pervasive transcription. Science 316: 1484‐1488, 2007.
 142.Karaiskos S, Grigoriev A. Dynamics of tRNA fragments and their targets in aging mammalian brain. F1000Research 5: 2758, 2016.
 143.Kaspi H, Pasvolsky R, Hornstein E. Could microRNAs contribute to the maintenance of beta cell identity? Trends Endocrinol Metab 25: 285‐292, 2014.
 144.Kato T, Tanaka D, Muro S, Jambaljav B, Mori E, Yonemitsu S, Oki S, Inagaki N. A novel p.L145Q mutation in the HNF1B gene in a case of maturity‐onset diabetes of the young type 5 (MODY5). Intern Med 57: 2035‐2039, 2018.
 145.Kaur S, Mirza AH, Pociot F. Cell type‐selective expression of circular RNAs in human pancreatic islets. Noncoding RNA 4: 38, 2018.
 146.Kaviani M, Azarpira N, Karimi MH, Al‐Abdullah I. The role of microRNAs in islet beta‐cell development. Cell Biol Int 40: 1248‐1255, 2016.
 147.Kertesz M, Iovino N, Unnerstall U, Gaul U, Segal E. The role of site accessibility in microRNA target recognition. Nat Genet 39: 1278‐1284, 2007.
 148.Khalil AM, Guttman M, Huarte M, Garber M, Raj A, Rivea Morales D, Thomas K, Presser A, Bernstein BE, van Oudenaarden A, Regev A, Lander ES, Rinn JL. Many human large intergenic noncoding RNAs associate with chromatin‐modifying complexes and affect gene expression. Proc Natl Acad Sci U S A 106: 11667‐11672, 2009.
 149.Kim HK, Fuchs G, Wang S, Wei W, Zhang Y, Park H, Roy‐Chaudhuri B, Li P, Xu J, Chu K, Zhang F, Chua MS, So S, Zhang QC, Sarnow P, Kay MA. A transfer‐RNA‐derived small RNA regulates ribosome biogenesis. Nature 552: 57‐62, 2017.
 150.Kjorholt C, Akerfeldt MC, Biden TJ, Laybutt DR. Chronic hyperglycemia, independent of plasma lipid levels, is sufficient for the loss of beta‐cell differentiation and secretory function in the db/db mouse model of diabetes. Diabetes 54: 2755‐2763, 2005.
 151.Klein D, Misawa R, Bravo‐Egana V, Vargas N, Rosero S, Piroso J, Ichii H, Umland O, Zhijie J, Tsinoremas N, Ricordi C, Inverardi L, Dominguez‐Bendala J, Pastori RL. MicroRNA expression in alpha and beta cells of human pancreatic islets. PLoS One 8: e55064, 2013.
 152.Kloosterman WP, Lagendijk AK, Ketting RF, Moulton JD, Plasterk RH. Targeted inhibition of miRNA maturation with morpholinos reveals a role for miR‐375 in pancreatic islet development. PLoS Biol 5: e203, 2007.
 153.Kong Y, Sharma RB, Ly S, Stamateris RE, Jesdale WM, Alonso LC. CDKN2A/B T2D genome‐wide association study risk SNPs impact locus gene expression and proliferation in human islets. Diabetes 67: 872‐884, 2018.
 154.Kornfeld JW, Baitzel C, Konner AC, Nicholls HT, Vogt MC, Herrmanns K, Scheja L, Haumaitre C, Wolf AM, Knippschild U, Seibler J, Cereghini S, Heeren J, Stoffel M, Bruning JC. Obesity‐induced overexpression of miR‐802 impairs glucose metabolism through silencing of Hnf1b. Nature 494: 111‐115, 2013.
 155.Kowal J, Arras G, Colombo M, Jouve M, Morath JP, Primdal‐Bengtson B, Dingli F, Loew D, Tkach M, Thery C. Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes. Proc Natl Acad Sci U S A 113: E968‐E977, 2016.
 156.Kowal J, Tkach M, Thery C. Biogenesis and secretion of exosomes. Curr Opin Cell Biol 29: 116‐125, 2014.
 157.Kozomara A, Birgaoanu M, Griffiths‐Jones S. miRBase: From microRNA sequences to function. Nucleic Acids Res 47: D155‐D162, 2019.
 158.Kredo‐Russo S, Mandelbaum AD, Ness A, Alon I, Lennox KA, Behlke MA, Hornstein E. Pancreas‐enriched miRNA refines endocrine cell differentiation. Development 139: 3021‐3031, 2012.
 159.Kredo‐Russo S, Ness A, Mandelbaum AD, Walker MD, Hornstein E. Regulation of pancreatic microRNA‐7 expression. Exp Diabetes Res 2012: 695214, 2012.
 160.Kristensen LS, Andersen MS, Stagsted LVW, Ebbesen KK, Hansen TB, Kjems J. The biogenesis, biology and characterization of circular RNAs. Nat Rev Genet 20: 675‐691, 2019.
 161.Kruger J, Rehmsmeier M. RNAhybrid: microRNA target prediction easy, fast and flexible. Nucleic Acids Res 34: W451‐W454, 2006.
 162.Ku GM, Kim H, Vaughn IW, Hangauer MJ, Myung Oh C, German MS, McManus MT. Research resource: RNA‐Seq reveals unique features of the pancreatic beta‐cell transcriptome. Mol Endocrinol 26: 1783‐1792, 2012.
 163.Kumar P, Kuscu C, Dutta A. Biogenesis and function of transfer RNA‐related fragments (tRFs). Trends Biochem Sci 41: 679‐689, 2016.
 164.Kuscu C, Kumar P, Kiran M, Su Z, Malik A, Dutta A. tRNA fragments (tRFs) guide Ago to regulate gene expression post‐transcriptionally in a Dicer‐independent manner. RNA 24: 1093‐1105, 2018.
 165.Lai EC, Tomancak P, Williams RW, Rubin GM. Computational identification of Drosophila microRNA genes. Genome Biol 4: R42, 2003.
 166.Lakhter AJ, Pratt RE, Moore RE, Doucette KK, Maier BF, DiMeglio LA, Sims EK. Beta cell extracellular vesicle miR‐21‐5p cargo is increased in response to inflammatory cytokines and serves as a biomarker of type 1 diabetes. Diabetologia 61: 1124‐1134, 2018.
 167.Lalaouna D, Carrier MC, Semsey S, Brouard JS, Wang J, Wade JT, Masse E. A 3′ external transcribed spacer in a tRNA transcript acts as a sponge for small RNAs to prevent transcriptional noise. Mol Cell 58: 393‐405, 2015.
 168.Lall S, Grun D, Krek A, Chen K, Wang YL, Dewey CN, Sood P, Colombo T, Bray N, Macmenamin P, Kao HL, Gunsalus KC, Pachter L, Piano F, Rajewsky N. A genome‐wide map of conserved microRNA targets in C. elegans. Curr Biol 16: 460‐471, 2006.
 169.LaPierre MP, Stoffel M. MicroRNAs as stress regulators in pancreatic beta cells and diabetes. Mol Metab 6: 1010‐1023, 2017.
 170.Lasda E, Parker R. Circular RNAs: Diversity of form and function. RNA 20: 1829‐1842, 2014.
 171.Lasser C, Shelke GV, Yeri A, Kim DK, Crescitelli R, Raimondo S, Sjostrand M, Gho YS, Van Keuren Jensen K, Lotvall J. Two distinct extracellular RNA signatures released by a single cell type identified by microarray and next‐generation sequencing. RNA Biol 14: 58‐72, 2017.
 172.Latreille M, Hausser J, Stutzer I, Zhang Q, Hastoy B, Gargani S, Kerr‐Conte J, Pattou F, Zavolan M, Esguerra JL, Eliasson L, Rulicke T, Rorsman P, Stoffel M. MicroRNA‐7a regulates pancreatic beta cell function. J Clin Invest 124: 2722‐2735, 2014.
 173.Latreille M, Herrmanns K, Renwick N, Tuschl T, Malecki MT, McCarthy MI, Owen KR, Rulicke T, Stoffel M. miR‐375 gene dosage in pancreatic beta‐cells: Implications for regulation of beta‐cell mass and biomarker development. J Mol Med (Berl) 93: 1159‐1169, 2015.
 174.Lecerf C, Le Bourhis X, Adriaenssens E. The long non‐coding RNA H19: An active player with multiple facets to sustain the hallmarks of cancer. Cell Mol Life Sci 76: 4673‐4687, 2019.
 175.Lee EJ, Banerjee S, Zhou H, Jammalamadaka A, Arcila M, Manjunath BS, Kosik KS. Identification of piRNAs in the central nervous system. RNA 17: 1090‐1099, 2011.
 176.Lee HS, Jeong J, Lee KJ. Characterization of vesicles secreted from insulinoma NIT‐1 cells. J Proteome Res 8: 2851‐2862, 2009.
 177.Lee J, Harris AN, Holley CL, Mahadevan J, Pyles KD, Lavagnino Z, Scherrer DE, Fujiwara H, Sidhu R, Zhang J, Huang SC, Piston DW, Remedi MS, Urano F, Ory DS, Schaffer JE. Rpl13a small nucleolar RNAs regulate systemic glucose metabolism. J Clin Invest 126: 4616‐4625, 2016.
 178.Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin‐4 encodes small RNAs with antisense complementarity to lin‐14. Cell 75: 843‐854, 1993.
 179.Lemaire K, Thorrez L, Schuit F. Disallowed and allowed gene expression: Two faces of mature islet beta cells. Annu Rev Nutr 36: 45‐71, 2016.
 180.Lerner AG, Upton JP, Praveen PV, Ghosh R, Nakagawa Y, Igbaria A, Shen S, Nguyen V, Backes BJ, Heiman M, Heintz N, Greengard P, Hui S, Tang Q, Trusina A, Oakes SA, Papa FR. IRE1alpha induces thioredoxin‐interacting protein to activate the NLRP3 inflammasome and promote programmed cell death under irremediable ER stress. Cell Metab 16: 250‐264, 2012.
 181.Li D, Luo L, Zhang W, Liu F, Luo F. A genetic algorithm‐based weighted ensemble method for predicting transposon‐derived piRNAs. BMC Bioinformatics 17: 329, 2016.
 182.Li J, Liu C. Coding or noncoding, the converging concepts of RNAs. Front Genet 10: 496, 2019.
 183.Li W, Notani D, Rosenfeld MG. Enhancers as non‐coding RNA transcription units: Recent insights and future perspectives. Nat Rev Genet 17: 207‐223, 2016.
 184.Li Y, Luo T, Wang L, Wu J, Guo S. MicroRNA‐19a‐3p enhances the proliferation and insulin secretion, while it inhibits the apoptosis of pancreatic beta cells via the inhibition of SOCS3. Int J Mol Med 38: 1515‐1524, 2016.
 185.Liang D, Zhang Y, Han J, Wang W, Liu Y, Li J, Jiang X. Embryonic stem cell‐derived pancreatic endoderm transplant with MCT1‐suppressing miR‐495 attenuates type II diabetes in mice. Endocr J 62: 907‐920, 2015.
 186.Lim LP, Lau NC, Weinstein EG, Abdelhakim A, Yekta S, Rhoades MW, Burge CB, Bartel DP. The microRNAs of Caenorhabditis elegans. Genes Dev 17: 991‐1008, 2003.
 187.Lindstrom P. The physiology of obese‐hyperglycemic mice [ob/ob mice]. Sci World J 7: 666‐685, 2007.
 188.Liu B, Yang F, Chou KC. 2L‐piRNA: A two‐layer ensemble classifier for identifying piwi‐interacting RNAs and their function. Mol Ther Nucleic Acids 7: 267‐277, 2017.
 189.Locke JM, da Silva Xavier G, Dawe HR, Rutter GA, Harries LW. Increased expression of miR‐187 in human islets from individuals with type 2 diabetes is associated with reduced glucose‐stimulated insulin secretion. Diabetologia 57: 122‐128, 2014.
 190.Loher P, Rigoutsos I. Interactive exploration of RNA22 microRNA target predictions. Bioinformatics 28: 3322‐3323, 2012.
 191.Loher P, Telonis AG, Rigoutsos I. MINTmap: Fast and exhaustive profiling of nuclear and mitochondrial tRNA fragments from short RNA‐seq data. Sci Rep 7: 41184, 2017.
 192.Lopez‐Beas J, Capilla‐Gonzalez V, Aguilera Y, Mellado N, Lachaud CC, Martin F, Smani T, Soria B, Hmadcha A. miR‐7 modulates hESC differentiation into insulin‐producing beta‐like cells and contributes to cell maturation. Mol Ther Nucleic Acids 12: 463‐477, 2018.
 193.Lovis P, Gattesco S, Regazzi R. Regulation of the expression of components of the exocytotic machinery of insulin‐secreting cells by microRNAs. Biol Chem 389: 305‐312, 2008.
 194.Lovis P, Roggli E, Laybutt DR, Gattesco S, Yang JY, Widmann C, Abderrahmani A, Regazzi R. Alterations in microRNA expression contribute to fatty acid‐induced pancreatic beta‐cell dysfunction. Diabetes 57: 2728‐2736, 2008.
 195.Lu Y, Fei XQ, Yang SF, Xu BK, Li YY. Glucose‐induced microRNA‐17 promotes pancreatic beta cell proliferation through down‐regulation of Menin. Eur Rev Med Pharmacol Sci 19: 624‐629, 2015.
 196.Luo L, Li D, Zhang W, Tu S, Zhu X, Tian G. Accurate prediction of transposon‐derived piRNAs by integrating various sequential and physicochemical features. PLoS One 11: e0153268, 2016.
 197.Lynn FC, Skewes‐Cox P, Kosaka Y, McManus MT, Harfe BD, German MS. MicroRNA expression is required for pancreatic islet cell genesis in the mouse. Diabetes 56: 2938‐2945, 2007.
 198.Lyons SM, Fay MM, Ivanov P. The role of RNA modifications in the regulation of tRNA cleavage. FEBS Lett 592: 2828‐2844, 2018.
 199.Mak KY, Rajapaksha IG, Angus PW, Herath CB. The adeno‐associated virus ‐ A safe and promising vehicle for liverspecific gene therapy of inherited and non‐inherited disorders. Curr Gene Ther 17: 4‐16, 2017.
 200.Malm HA, Mollet IG, Berggreen C, Orho‐Melander M, Esguerra JL, Goransson O, Eliasson L. Transcriptional regulation of the miR‐212/miR‐132 cluster in insulin‐secreting beta‐cells by cAMP‐regulated transcriptional co‐activator 1 and salt‐inducible kinases. Mol Cell Endocrinol 424: 23‐33, 2016.
 201.Malone CD, Brennecke J, Dus M, Stark A, McCombie WR, Sachidanandam R, Hannon GJ. Specialized piRNA pathways act in germline and somatic tissues of the Drosophila ovary. Cell 137: 522‐535, 2009.
 202.Mandelbaum AD, Kredo‐Russo S, Aronowitz D, Myers N, Yanowski E, Klochendler A, Swisa A, Dor Y, Hornstein E. miR‐17‐92 and miR‐106b‐25 clusters regulate beta cell mitotic checkpoint and insulin secretion in mice. Diabetologia 62: 1653‐1666, 2019.
 203.Mandelbaum AD, Melkman‐Zehavi T, Oren R, Kredo‐Russo S, Nir T, Dor Y, Hornstein E. Dysregulation of Dicer1 in beta cells impairs islet architecture and glucose metabolism. Exp Diabetes Res 2012: 470302, 2012.
 204.Marchand L, Jalabert A, Meugnier E, Van den Hende K, Fabien N, Nicolino M, Madec AM, Thivolet C, Rome S. miRNA‐375 a sensor of glucotoxicity is altered in the serum of children with newly diagnosed type 1 diabetes. J Diabetes Res 2016: 1869082, 2016.
 205.Martianov I, Ramadass A, Serra Barros A, Chow N, Akoulitchev A. Repression of the human dihydrofolate reductase gene by a non‐coding interfering transcript. Nature 445: 666‐670, 2007.
 206.Martinez‐Sanchez A, Nguyen‐Tu MS, Cebola I, Yavari A, Marchetti P, Piemonti L, de Koning E, Shapiro AMJ, Johnson P, Sakamoto K, Smith DM, Leclerc I, Ashrafian H, Ferrer J, Rutter GA. MiR‐184 expression is regulated by AMPK in pancreatic islets. FASEB J 32: 2587‐2600, 2018.
 207.Martinez‐Sanchez A, Nguyen‐Tu MS, Rutter GA. DICER inactivation identifies pancreatic beta‐cell “disallowed” genes targeted by microRNAs. Mol Endocrinol 29: 1067‐1079, 2015.
 208.Martinez‐Sanchez A, Rutter GA, Latreille M. MiRNAs in beta‐cell development, identity, and disease. Front Genet 7: 226, 2016.
 209.Martin‐Gronert MS, Ozanne SE. Metabolic programming of insulin action and secretion. Diabetes Obes Metab 14 (Suppl 3): 29‐39, 2012.
 210.Mathieu M, Martin‐Jaular L, Lavieu G, Thery C. Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell‐to‐cell communication. Nat Cell Biol 21: 9‐17, 2019.
 211.Maute RL, Schneider C, Sumazin P, Holmes A, Califano A, Basso K, Dalla‐Favera R. tRNA‐derived microRNA modulates proliferation and the DNA damage response and is down‐regulated in B cell lymphoma. Proc Natl Acad Sci U S A 110: 1404‐1409, 2013.
 212.McKenzie MD, Jamieson E, Jansen ES, Scott CL, Huang DC, Bouillet P, Allison J, Kay TW, Strasser A, Thomas HE. Glucose induces pancreatic islet cell apoptosis that requires the BH3‐only proteins Bim and Puma and multi‐BH domain protein Bax. Diabetes 59: 644‐652, 2010.
 213.Meier JJ, Butler AE, Saisho Y, Monchamp T, Galasso R, Bhushan A, Rizza RA, Butler PC. Beta‐cell replication is the primary mechanism subserving the postnatal expansion of beta‐cell mass in humans. Diabetes 57: 1584‐1594, 2008.
 214.Melkman‐Zehavi T, Oren R, Kredo‐Russo S, Shapira T, Mandelbaum AD, Rivkin N, Nir T, Lennox KA, Behlke MA, Dor Y, Hornstein E. miRNAs control insulin content in pancreatic beta‐cells via downregulation of transcriptional repressors. EMBO J 30: 835‐845, 2011.
 215.Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A, Maier L, Mackowiak SD, Gregersen LH, Munschauer M, Loewer A, Ziebold U, Landthaler M, Kocks C, le Noble F, Rajewsky N. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 495: 333‐338, 2013.
 216.Mercer TR, Dinger ME, Mattick JS. Long non‐coding RNAs: Insights into functions. Nat Rev Genet 10: 155‐159, 2009.
 217.Michel CI, Holley CL, Scruggs BS, Sidhu R, Brookheart RT, Listenberger LL, Behlke MA, Ory DS, Schaffer JE. Small nucleolar RNAs U32a, U33, and U35a are critical mediators of metabolic stress. Cell Metab 14: 33‐44, 2011.
 218.Miyoshi N, Wagatsuma H, Wakana S, Shiroishi T, Nomura M, Aisaka K, Kohda T, Surani MA, Kaneko‐Ishino T, Ishino F. Identification of an imprinted gene, Meg3/Gtl2 and its human homologue MEG3, first mapped on mouse distal chromosome 12 and human chromosome 14q. Genes Cells 5: 211‐220, 2000.
 219.Mohan R, Mao Y, Zhang S, Zhang YW, Xu CR, Gradwohl G, Tang X. Differentially expressed microRNA‐483 confers distinct functions in pancreatic beta‐ and alpha‐cells. J Biol Chem 290: 19955‐19966, 2015.
 220.Montani F, Bianchi F. Circulating cancer biomarkers: The macro‐revolution of the micro‐RNA. EBioMedicine 5: 4‐6, 2016.
 221.Moran I, Akerman I, van de Bunt M, Xie R, Benazra M, Nammo T, Arnes L, Nakic N, Garcia‐Hurtado J, Rodriguez‐Segui S, Pasquali L, Sauty‐Colace C, Beucher A, Scharfmann R, van Arensbergen J, Johnson PR, Berry A, Lee C, Harkins T, Gmyr V, Pattou F, Kerr‐Conte J, Piemonti L, Berney T, Hanley N, Gloyn AL, Sussel L, Langman L, Brayman KL, Sander M, McCarthy MI, Ravassard P, Ferrer J. Human beta cell transcriptome analysis uncovers lncRNAs that are tissue‐specific, dynamically regulated, and abnormally expressed in type 2 diabetes. Cell Metab 16: 435‐448, 2012.
 222.Mori MA, Ludwig RG, Garcia‐Martin R, Brandao BB, Kahn CR. Extracellular miRNAs: From biomarkers to mediators of physiology and disease. Cell Metab 30: 656‐673, 2019.
 223.Morita S, Horii T, Kimura M, Hatada I. MiR‐184 regulates insulin secretion through repression of Slc25a22. PeerJ 1: e162, 2013.
 224.Morris KV, Mattick JS. The rise of regulatory RNA. Nat Rev Genet 15: 423‐437, 2014.
 225.Motterle A, Gattesco S, Caille D, Meda P, Regazzi R. Involvement of long non‐coding RNAs in beta cell failure at the onset of type 1 diabetes in NOD mice. Diabetologia 58: 1827‐1835, 2015.
 226.Motterle A, Gattesco S, Peyot ML, Esguerra JLS, Gomez‐Ruiz A, Laybutt DR, Gilon P, Burdet F, Ibberson M, Eliasson L, Prentki M, Regazzi R. Identification of islet‐enriched long non‐coding RNAs contributing to beta‐cell failure in type 2 diabetes. Mol Metab 6: 1407‐1418, 2017.
 227.Motterle A, Sanchez‐Parra C, Regazzi R. Role of long non‐coding RNAs in the determination of beta‐cell identity. Diabetes Obes Metab 18 (Suppl 1): 41‐50, 2016.
 228.Mulder NL, Havinga R, Kluiver J, Groen AK, Kruit JK. AAV8‐mediated gene transfer of microRNA‐132 improves beta cell function in mice fed a high‐fat diet. J Endocrinol 240: 123‐132, 2019.
 229.Mziaut H, Henniger G, Ganss K, Hempel S, Wolk S, McChord J, Chowdhury K, Ravassard P, Knoch K‐P, Krautz C, Weitz J, Grützmann R, Pilarsky C, Solimena M, Kersting S. MiR‐132 controls pancreatic beta cell proliferation and survival through Pten/Akt/Foxo3 signaling. Mol Metab 31: 150‐162, 2020.
 230.Nam JW, Kim J, Kim SK, Zhang BT. ProMiR II: A web server for the probabilistic prediction of clustered, nonclustered, conserved and nonconserved microRNAs. Nucleic Acids Res 34: W455‐W458, 2006.
 231.Nesca V, Guay C, Jacovetti C, Menoud V, Peyot ML, Laybutt DR, Prentki M, Regazzi R. Identification of particular groups of microRNAs that positively or negatively impact on beta cell function in obese models of type 2 diabetes. Diabetologia 56: 2203‐2212, 2013.
 232.Newman MA, Hammond SM. Lin‐28: An early embryonic sentinel that blocks Let‐7 biogenesis. Int J Biochem Cell Biol 42: 1330‐1333, 2010.
 233.Ng KW, Anderson C, Marshall EA, Minatel BC, Enfield KS, Saprunoff HL, Lam WL, Martinez VD. Piwi‐interacting RNAs in cancer: Emerging functions and clinical utility. Mol Cancer 15: 5, 2016.
 234.Nieto M, Hevia P, Garcia E, Klein D, Alvarez‐Cubela S, Bravo‐Egana V, Rosero S, Damaris Molano R, Vargas N, Ricordi C, Pileggi A, Diez J, Dominguez‐Bendala J, Pastori RL. Antisense miR‐7 impairs insulin expression in developing pancreas and in cultured pancreatic buds. Cell Transplant 21: 1761‐1774, 2012.
 235.Nishibu T, Hayashida Y, Tani S, Kurono S, Kojima‐Kita K, Ukekawa R, Kurokawa T, Kuramochi‐Miyagawa S, Nakano T, Inoue K, Honda S. Identification of MIWI‐associated Poly(A) RNAs by immunoprecipitation with an anti‐MIWI monoclonal antibody. Biosci Trends 6: 248‐261, 2012.
 236.Nolan CJ, Damm P, Prentki M. Type 2 diabetes across generations: From pathophysiology to prevention and management. Lancet 378: 169‐181, 2011.
 237.Offield MF, Jetton TL, Labosky PA, Ray M, Stein RW, Magnuson MA, Hogan BL, Wright CV. PDX‐1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development 122: 983‐995, 1996.
 238.Ofori JK, Salunkhe VA, Bagge A, Vishnu N, Nagao M, Mulder H, Wollheim CB, Eliasson L, Esguerra JL. Elevated miR‐130a/miR130b/miR‐152 expression reduces intracellular ATP levels in the pancreatic beta cell. Sci Rep 7: 44986, 2017.
 239.Osmai M, Osmai Y, Bang‐Berthelsen CH, Pallesen EM, Vestergaard AL, Novotny GW, Pociot F, Mandrup‐Poulsen T. MicroRNAs as regulators of beta‐cell function and dysfunction. Diabetes Metab Res Rev 32: 334‐349, 2016.
 240.Oulas A, Boutla A, Gkirtzou K, Reczko M, Kalantidis K, Poirazi P. Prediction of novel microRNA genes in cancer‐associated genomic regions—a combined computational and experimental approach. Nucleic Acids Res 37: 3276‐3287, 2009.
 241.Oulas A, Poirazi P. Utilization of SSCprofiler to predict a new miRNA gene. Methods Mol Biol 676: 243‐252, 2011.
 242.Ozata DM, Gainetdinov I, Zoch A, O'Carroll D, Zamore PD. PIWI‐interacting RNAs: Small RNAs with big functions. Nat Rev Genet 20: 89‐108, 2019.
 243.Pan T. Modifications and functional genomics of human transfer RNA. Cell Res 28: 395‐404, 2018.
 244.Pandey RR, Homolka D, Olotu O, Sachidanandam R, Kotaja N, Pillai RS. Exonuclease domain‐containing 1 enhances MIWI2 piRNA biogenesis via its interaction with TDRD12. Cell Rep 24: 3423‐3432 e3424, 2018.
 245.Pasquali L, Gaulton KJ, Rodriguez‐Segui SA, Mularoni L, Miguel‐Escalada I, Akerman I, Tena JJ, Moran I, Gomez‐Marin C, van de Bunt M, Ponsa‐Cobas J, Castro N, Nammo T, Cebola I, Garcia‐Hurtado J, Maestro MA, Pattou F, Piemonti L, Berney T, Gloyn AL, Ravassard P, Skarmeta JLG, Muller F, McCarthy MI, Ferrer J. Pancreatic islet enhancer clusters enriched in type 2 diabetes risk‐associated variants. Nat Genet 46: 136‐143, 2014.
 246.Pearson JA, Wong FS, Wen L. The importance of the non obese diabetic (NOD) mouse model in autoimmune diabetes. J Autoimmun 66: 76‐88, 2016.
 247.Petry CJ. Gestational diabetes: Risk factors and recent advances in its genetics and treatment. Br J Nutr 104: 775‐787, 2010.
 248.Peyot ML, Pepin E, Lamontagne J, Latour MG, Zarrouki B, Lussier R, Pineda M, Jetton TL, Madiraju SR, Joly E, Prentki M. Beta‐cell failure in diet‐induced obese mice stratified according to body weight gain: Secretory dysfunction and altered islet lipid metabolism without steatosis or reduced beta‐cell mass. Diabetes 59: 2178‐2187, 2010.
 249.Poitout V, Satin LS, Kahn SE, Stoffers DA, Marchetti P, Gannon M, Verchere CB, Herold KC, Myers MG Jr, Marshall SM. A call for improved reporting of human islet characteristics in research articles. Diabetologia 62: 209‐211, 2019.
 250.Poitout V, Satin LS, Kahn SE, Stoffers DA, Marchetti P, Gannon M, Verchere CB, Herold KC, Myers MG Jr, Marshall SM. A call for improved reporting of human islet characteristics in research articles. Diabetes 68: 239‐240, 2019.
 251.Poliseno L, Salmena L, Zhang J, Carver B, Haveman WJ, Pandolfi PP. A coding‐independent function of gene and pseudogene mRNAs regulates tumour biology. Nature 465: 1033‐1038, 2010.
 252.Ponting CP, Oliver PL, Reik W. Evolution and functions of long noncoding RNAs. Cell 136: 629‐641, 2009.
 253.Portha B, Lacraz G, Kergoat M, Homo‐Delarche F, Giroix MH, Bailbe D, Gangnerau MN, Dolz M, Tourrel‐Cuzin C, Movassat J. The GK rat beta‐cell: A prototype for the diseased human beta‐cell in type 2 diabetes? Mol Cell Endocrinol 297: 73‐85, 2009.
 254.Poy MN, Eliasson L, Krutzfeldt J, Kuwajima S, Ma X, Macdonald PE, Pfeffer S, Tuschl T, Rajewsky N, Rorsman P, Stoffel M. A pancreatic islet‐specific microRNA regulates insulin secretion. Nature 432: 226‐230, 2004.
 255.Poy MN, Hausser J, Trajkovski M, Braun M, Collins S, Rorsman P, Zavolan M, Stoffel M. miR‐375 maintains normal pancreatic alpha‐ and beta‐cell mass. Proc Natl Acad Sci U S A 106: 5813‐5818, 2009.
 256.Pullen TJ, da Silva Xavier G, Kelsey G, Rutter GA. miR‐29a and miR‐29b contribute to pancreatic beta‐cell‐specific silencing of monocarboxylate transporter 1 (Mct1). Mol Cell Biol 31: 3182‐3194, 2011.
 257.Pullen TJ, Rutter GA. Roles of lncRNAs in pancreatic beta cell identity and diabetes susceptibility. Front Genet 5: 193, 2014.
 258.Pullen TJ, Sylow L, Sun G, Halestrap AP, Richter EA, Rutter GA. Overexpression of monocarboxylate transporter‐1 (SLC16A1) in mouse pancreatic beta‐cells leads to relative hyperinsulinism during exercise. Diabetes 61: 1719‐1725, 2012.
 259.Rahman MJ, Regn D, Bashratyan R, Dai YD. Exosomes released by islet‐derived mesenchymal stem cells trigger autoimmune responses in NOD mice. Diabetes 63: 1008‐1020, 2014.
 260.Raposo G, Stoorvogel W. Extracellular vesicles: Exosomes, microvesicles, and friends. J Cell Biol 200: 373‐383, 2013.
 261.Regazzi R. MicroRNAs as therapeutic targets for the treatment of diabetes mellitus and its complications. Expert Opin Ther Targets 22: 153‐160, 2018.
 262.Ridder K, Keller S, Dams M, Rupp AK, Schlaudraff J, Del Turco D, Starmann J, Macas J, Karpova D, Devraj K, Depboylu C, Landfried B, Arnold B, Plate KH, Hoglinger G, Sultmann H, Altevogt P, Momma S. Extracellular vesicle‐mediated transfer of genetic information between the hematopoietic system and the brain in response to inflammation. PLoS Biol 12: e1001874, 2014.
 263.Robinson DG, Ding Y, Jiang L. Unconventional protein secretion in plants: A critical assessment. Protoplasma 253: 31‐43, 2016.
 264.Rodriguez‐Comas J, Moreno‐Asso A, Moreno‐Vedia J, Martin M, Castano C, Marza‐Florensa A, Bofill‐De Ros X, Mir‐Coll J, Montane J, Fillat C, Gasa R, Novials A, Servitja JM. Stress‐induced microRNA‐708 impairs beta‐cell function and growth. Diabetes 66: 3029‐3040, 2017.
 265.Roels S, Costa OR, Tersey SA, Stange G, De Smet D, Balti EV, Gillard P, Keymeulen B, Ling Z, Pipeleers DG, Gorus FK, Mirmira RG, Martens GA. Combined analysis of GAD65, miR‐375, and unmethylated insulin DNA following islet transplantation in patients with T1D. J Clin Endocrinol Metab 104: 451‐460, 2019.
 266.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 beta‐cells. Diabetes 59: 978‐986, 2010.
 267.Roggli E, Gattesco S, Caille D, Briet C, Boitard C, Meda P, Regazzi R. Changes in microRNA expression contribute to pancreatic beta‐cell dysfunction in prediabetic NOD mice. Diabetes 61: 1742‐1751, 2012.
 268.Ross RJ, Weiner MM, Lin H. PIWI proteins and PIWI‐interacting RNAs in the soma. Nature 505: 353‐359, 2014.
 269.Ruan Q, Wang T, Kameswaran V, Wei Q, Johnson DS, Matschinsky F, Shi W, Chen YH. The microRNA‐21‐PDCD4 axis prevents type 1 diabetes by blocking pancreatic beta cell death. Proc Natl Acad Sci U S A 108: 12030‐12035, 2011.
 270.Ruan Y, Lin N, Ma Q, Chen R, Zhang Z, Wen W, Chen H, Sun J. Circulating lncRNAs analysis in patients with type 2 diabetes reveals novel genes influencing glucose metabolism and islet beta‐cell function. Cell Physiol Biochem 46: 335‐350, 2018.
 271.Rupaimoole R, Slack FJ. MicroRNA therapeutics: Towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov 16: 203‐222, 2017.
 272.Rutman AK, Negi S, Gasparrini M, Hasilo CP, Tchervenkov J, Paraskevas S. Immune response to extracellular vesicles from human islets of langerhans in patients with type 1 diabetes. Endocrinology 159: 3834‐3847, 2018.
 273.Saikia M, Jobava R, Parisien M, Putnam A, Krokowski D, Gao XH, Guan BJ, Yuan Y, Jankowsky E, Feng Z, Hu GF, Pusztai‐Carey M, Gorla M, Sepuri NB, Pan T, Hatzoglou M. Angiogenin‐cleaved tRNA halves interact with cytochrome c, protecting cells from apoptosis during osmotic stress. Mol Cell Biol 34: 2450‐2463, 2014.
 274.Salunkhe VA, Ofori JK, Gandasi NR, Salo SA, Hansson S, Andersson ME, Wendt A, Barg S, Esguerra JLS, Eliasson L. MiR‐335 overexpression impairs insulin secretion through defective priming of insulin vesicles. Phys Rep 5: e13493, 2017.
 275.Samandari N, Mirza AH, Nielsen LB, Kaur S, Hougaard P, Fredheim S, Mortensen HB, Pociot F. Circulating microRNA levels predict residual beta cell function and glycaemic control in children with type 1 diabetes mellitus. Diabetologia 60: 354‐363, 2017.
 276.Sanchez‐Parra C, Jacovetti C, Dumortier O, Lee K, Peyot ML, Guay C, Prentki M, Laybutt DR, Van Obberghen E, Regazzi R. Contribution of the long noncoding RNA H19 to beta‐cell mass expansion in neonatal and adult rodents. Diabetes 67: 2254‐2267, 2018.
 277.Saravanan PB, Kanak MA, Chang CA, Darden C, Yoshimatsu G, Lawrence MC, Naziruddin B. Islet damage during isolation as assessed by miRNAs and the correlation of miRNA levels with posttransplantation outcome in islet autotransplantation. Am J Transplant 18: 982‐989, 2018.
 278.Saravanan PB, Vasu S, Yoshimatsu G, Darden CM, Wang X, Gu J, Lawrence MC, Naziruddin B. Differential expression and release of exosomal miRNAs by human islets under inflammatory and hypoxic stress. Diabetologia 62: 1901‐1914, 2019.
 279.Schorey JS, Cheng Y, Singh PP, Smith VL. Exosomes and other extracellular vesicles in host‐pathogen interactions. EMBO Rep 16: 24‐43, 2015.
 280.Schorn AJ, Gutbrod MJ, LeBlanc C, Martienssen R. LTR‐retrotransposon control by tRNA‐derived small RNAs. Cell 170: 61‐71 e11, 2017.
 281.Sebastiani G, Nigi L, Grieco GE, Mancarella F, Ventriglia G, Dotta F. Circulating microRNAs and diabetes mellitus: A novel tool for disease prediction, diagnosis, and staging? J Endocrinol Investig 40: 591‐610, 2017.
 282.Sebastiani G, Po A, Miele E, Ventriglia G, Ceccarelli E, Bugliani M, Marselli L, Marchetti P, Gulino A, Ferretti E, Dotta F. MicroRNA‐124a is hyperexpressed in type 2 diabetic human pancreatic islets and negatively regulates insulin secretion. Acta Diabetol 52: 523‐530, 2015.
 283.Sedgeman LR, Beysen C, Ramirez Solano MA, Michell DL, Sheng Q, Zhao S, Turner S, Linton MF, Vickers KC. Beta cell secretion of miR‐375 to HDL is inversely associated with insulin secretion. Sci Rep 9: 3803, 2019.
 284.Selbach M, Schwanhausser B, Thierfelder N, Fang Z, Khanin R, Rajewsky N. Widespread changes in protein synthesis induced by microRNAs. Nature 455: 58‐63, 2008.
 285.Shang J, Li J, Keller MP, Hohmeier HE, Wang Y, Feng Y, Zhou HH, Shen X, Rabaglia M, Soni M, Attie AD, Newgard CB, Thornberry NA, Howard AD, Zhou YP. Induction of miR‐132 and miR‐212 Expression by Glucagon‐Like Peptide 1 (GLP‐1) in Rodent and Human Pancreatic beta‐Cells. Mol Endocrinol 29: 1243‐1253, 2015.
 286.Sharma U, Sun F, Conine CC, Reichholf B, Kukreja S, Herzog VA, Ameres SL, Rando OJ. Small RNAs are trafficked from the epididymis to developing mammalian sperm. Dev Cell 46: 481‐494 e486, 2018.
 287.Shen EZ, Chen H, Ozturk AR, Tu S, Shirayama M, Tang W, Ding YH, Dai SY, Weng Z, Mello CC. Identification of piRNA binding sites reveals the argonaute regulatory landscape of the C. elegans germline. Cell 172: 937‐951 e918, 2018.
 288.Sheng H, Hassanali S, Nugent C, Wen L, Hamilton‐Williams E, Dias P, Dai YD. Insulinoma‐released exosomes or microparticles are immunostimulatory and can activate autoreactive T cells spontaneously developed in nonobese diabetic mice. J Immunol 187: 1591‐1600, 2011.
 289.Shi Q, Yang X. Circulating microRNA and long noncoding RNA as biomarkers of cardiovascular diseases. J Cell Physiol 231: 751‐755, 2016.
 290.Simons M, Raposo G. Exosomes—vesicular carriers for intercellular communication. Curr Opin Cell Biol 21: 575‐581, 2009.
 291.Sims EK, Lakhter AJ, Anderson‐Baucum E, Kono T, Tong X, Evans‐Molina C. MicroRNA 21 targets BCL2 mRNA to increase apoptosis in rat and human beta cells. Diabetologia 60: 1057‐1065, 2017.
 292.Singer RA, Sussel L. Islet long noncoding RNAs: A playbook for discovery and characterization. Diabetes 67: 1461‐1470, 2018.
 293.Sisino G, Zhou AX, Dahr N, Sabirsh A, Soundarapandian MM, Perera R, Larsson‐Lekholm E, Magnone MC, Althage M, Tyrberg B. Long noncoding RNAs are dynamically regulated during beta‐cell mass expansion in mouse pregnancy and control beta‐cell proliferation in vitro. PLoS One 12: e0182371, 2017.
 294.Skog J, Wurdinger T, van Rijn S, Meijer DH, Gainche L, Sena‐Esteves M, Curry WT Jr, Carter BS, Krichevsky AM, Breakefield XO. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 10: 1470‐1476, 2008.
 295.Smith CM, Steitz JA. Classification of gas5 as a multi‐small‐nucleolar‐RNA (snoRNA) host gene and a member of the 5′‐terminal oligopyrimidine gene family reveals common features of snoRNA host genes. Mol Cell Biol 18: 6897‐6909, 1998.
 296.Smith MA, Mattick JS. Structural and functional annotation of long noncoding RNAs. Methods Mol Biol 1526: 65‐85, 2017.
 297.Song X, Zhang N, Han P, Moon BS, Lai RK, Wang K, Lu W. Circular RNA profile in gliomas revealed by identification tool UROBORUS. Nucleic Acids Res 44: e87, 2016.
 298.Soni MS, Rabaglia ME, Bhatnagar S, Shang J, Ilkayeva O, Mynatt R, Zhou YP, Schadt EE, Thornberry NA, Muoio DM, Keller MP, Attie AD. Downregulation of carnitine acyl‐carnitine translocase by miRNAs 132 and 212 amplifies glucose‐stimulated insulin secretion. Diabetes 63: 3805‐3814, 2014.
 299.St Laurent G, Wahlestedt C, Kapranov P. The landscape of long noncoding RNA classification. Trends Genet 31: 239‐251, 2015.
 300.Stoll L, Sobel J, Rodriguez‐Trejo A, Guay C, Lee K, Veno MT, Kjems J, Laybutt DR, Regazzi R. Circular RNAs as novel regulators of beta‐cell functions in normal and disease conditions. Mol Metab 9: 69‐83, 2018.
 301.Stolovich‐Rain M, Enk J, Vikesa J, Nielsen FC, Saada A, Glaser B, Dor Y. Weaning triggers a maturation step of pancreatic beta cells. Dev Cell 32: 535‐545, 2015.
 302.Sun C, Fu Z, Wang S, Li J, Li Y, Zhang Y, Yang F, Chu J, Wu H, Huang X, Li W, Yin Y. Roles of tRNA‐derived fragments in human cancers. Cancer Lett 414: 16‐25, 2018.
 303.Szabo L, Morey R, Palpant NJ, Wang PL, Afari N, Jiang C, Parast MM, Murry CE, Laurent LC, Salzman J. Statistically based splicing detection reveals neural enrichment and tissue‐specific induction of circular RNA during human fetal development. Genome Biol 16: 126, 2015.
 304.Talchai C, Xuan S, Lin HV, Sussel L, Accili D. Pancreatic beta cell dedifferentiation as a mechanism of diabetic beta cell failure. Cell 150: 1223‐1234, 2012.
 305.Tattikota SG, Rathjen T, Hausser J, Khedkar A, Kabra UD, Pandey V, Sury M, Wessels HH, Mollet IG, Eliasson L, Selbach M, Zinzen RP, Zavolan M, Kadener S, Tschop MH, Jastroch M, Friedlander MR, Poy MN. miR‐184 regulates pancreatic beta‐cell function according to glucose metabolism. J Biol Chem 290: 20284‐20294, 2015.
 306.Tattikota SG, Rathjen T, McAnulty SJ, Wessels HH, Akerman I, van de Bunt M, Hausser J, Esguerra JL, Musahl A, Pandey AK, You X, Chen W, Herrera PL, Johnson PR, O'Carroll D, Eliasson L, Zavolan M, Gloyn AL, Ferrer J, Shalom‐Feuerstein R, Aberdam D, Poy MN. Argonaute2 mediates compensatory expansion of the pancreatic beta cell. Cell Metab 19: 122‐134, 2014.
 307.Terai G, Komori T, Asai K, Kin T. miRRim: A novel system to find conserved miRNAs with high sensitivity and specificity. RNA 13: 2081‐2090, 2007.
 308.Terauchi Y, Takamoto I, Kubota N, Matsui J, Suzuki R, Komeda K, Hara A, Toyoda Y, Miwa I, Aizawa S, Tsutsumi S, Tsubamoto Y, Hashimoto S, Eto K, Nakamura A, Noda M, Tobe K, Aburatani H, Nagai R, Kadowaki T. Glucokinase and IRS‐2 are required for compensatory beta cell hyperplasia in response to high‐fat diet‐induced insulin resistance. J Clin Invest 117: 246‐257, 2007.
 309.Thomou T, Mori MA, Dreyfuss JM, Konishi M, Sakaguchi M, Wolfrum C, Rao TN, Winnay JN, Garcia‐Martin R, Grinspoon SK, Gorden P, Kahn CR. Adipose‐derived circulating miRNAs regulate gene expression in other tissues. Nature 542: 450‐455, 2017.
 310.Towns WL, Begley TJ. Transfer RNA methytransferases and their corresponding modifications in budding yeast and humans: Activities, predications, and potential roles in human health. DNA Cell Biol 31: 434‐454, 2012.
 311.Tripathi V, Ellis JD, Shen Z, Song DY, Pan Q, Watt AT, Freier SM, Bennett CF, Sharma A, Bubulya PA, Blencowe BJ, Prasanth SG, Prasanth KV. The nuclear‐retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation. Mol Cell 39: 925‐938, 2010.
 312.Tugay K, Guay C, Marques AC, Allagnat F, Locke JM, Harries LW, Rutter GA, Regazzi R. Role of microRNAs in the age‐associated decline of pancreatic beta cell function in rat islets. Diabetologia 59: 161‐169, 2016.
 313.Turchinovich A, Weiz L, Langheinz A, Burwinkel B. Characterization of extracellular circulating microRNA. Nucleic Acids Res 39: 7223‐7233, 2011.
 314.Unger RH, Orci L. The essential role of glucagon in the pathogenesis of diabetes mellitus. Lancet 1: 14‐16, 1975.
 315.Upton JP, Wang L, Han D, Wang ES, Huskey NE, Lim L, Truitt M, McManus MT, Ruggero D, Goga A, Papa FR, Oakes SA. IRE1alpha cleaves select microRNAs during ER stress to derepress translation of proapoptotic Caspase‐2. Science 338: 818‐822, 2012.
 316.Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosome‐mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9: 654‐659, 2007.
 317.Vallabhajosyula P, Korutla L, Habertheuer A, Yu M, Rostami S, Yuan CX, Reddy S, Liu C, Korutla V, Koeberlein B, Trofe‐Clark J, Rickels MR, Naji A. Tissue‐specific exosome biomarkers for noninvasively monitoring immunologic rejection of transplanted tissue. J Clin Invest 127: 1375‐1391, 2017.
 318.van Niel G, D'Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol 19: 213‐228, 2018.
 319.van Rooij E, Kauppinen S. Development of microRNA therapeutics is coming of age. EMBO Mol Med 6: 851‐864, 2014.
 320.Vickers KC, Palmisano BT, Shoucri BM, Shamburek RD, Remaley AT. MicroRNAs are transported in plasma and delivered to recipient cells by high‐density lipoproteins. Nat Cell Biol 13: 423‐433, 2011.
 321.Vinod M, Patankar JV, Sachdev V, Frank S, Graier WF, Kratky D, Kostner GM. MiR‐206 is expressed in pancreatic islets and regulates glucokinase activity. Am J Physiol Endocrinol Metab 311: E175‐E185, 2016.
 322.Voight BF, Scott LJ, Steinthorsdottir V, Morris AP, Dina C, Welch RP, Zeggini E, Huth C, Aulchenko YS, Thorleifsson G, McCulloch LJ, Ferreira T, Grallert H, Amin N, Wu G, Willer CJ, Raychaudhuri S, McCarroll SA, Langenberg C, Hofmann OM, Dupuis J, Qi L, Segre AV, van Hoek M, Navarro P, Ardlie K, Balkau B, Benediktsson R, Bennett AJ, Blagieva R, Boerwinkle E, Bonnycastle LL, Bengtsson Bostrom K, Bravenboer B, Bumpstead S, Burtt NP, Charpentier G, Chines PS, Cornelis M, Couper DJ, Crawford G, Doney AS, Elliott KS, Elliott AL, Erdos MR, Fox CS, Franklin CS, Ganser M, Gieger C, Grarup N, Green T, Griffin S, Groves CJ, Guiducci C, Hadjadj S, Hassanali N, Herder C, Isomaa B, Jackson AU, Johnson PR, Jorgensen T, Kao WH, Klopp N, Kong A, Kraft P, Kuusisto J, Lauritzen T, Li M, Lieverse A, Lindgren CM, Lyssenko V, Marre M, Meitinger T, Midthjell K, Morken MA, Narisu N, Nilsson P, Owen KR, Payne F, Perry JR, Petersen AK, Platou C, Proenca C, Prokopenko I, Rathmann W, Rayner NW, Robertson NR, Rocheleau G, Roden M, Sampson MJ, Saxena R, Shields BM, Shrader P, Sigurdsson G, Sparso T, Strassburger K, Stringham HM, Sun Q, Swift AJ, Thorand B, Tichet J, Tuomi T, van Dam RM, van Haeften TW, van Herpt T, van Vliet‐Ostaptchouk JV, Walters GB, Weedon MN, Wijmenga C, Witteman J, Bergman RN, Cauchi S, Collins FS, Gloyn AL, Gyllensten U, Hansen T, Hide WA, Hitman GA, Hofman A, Hunter DJ, Hveem K, Laakso M, Mohlke KL, Morris AD, Palmer CN, Pramstaller PP, Rudan I, Sijbrands E, Stein LD, Tuomilehto J, Uitterlinden A, Walker M, Wareham NJ, Watanabe RM, Abecasis GR, Boehm BO, Campbell H, Daly MJ, Hattersley AT, Hu FB, Meigs JB, Pankow JS, Pedersen O, Wichmann HE, Barroso I, Florez JC, Frayling TM, Groop L, Sladek R, Thorsteinsdottir U, Wilson JF, Illig T, Froguel P, van Duijn CM, Stefansson K, Altshuler D, Boehnke M, McCarthy MI, MAGIC investigators, GIANT Consortium. Twelve type 2 diabetes susceptibility loci identified through large‐scale association analysis. Nat Genet 42: 579‐589, 2010.
 323.Wang K, Liang C, Liu J, Xiao H, Huang S, Xu J, Li F. Prediction of piRNAs using transposon interaction and a support vector machine. BMC Bioinformatics 15: 419, 2014.
 324.Wang K, Singh D, Zeng Z, Coleman SJ, Huang Y, Savich GL, He X, Mieczkowski P, Grimm SA, Perou CM, MacLeod JN, Chiang DY, Prins JF, Liu J. MapSplice: Accurate mapping of RNA‐seq reads for splice junction discovery. Nucleic Acids Res 38: e178, 2010.
 325.Wang K, Zhang S, Weber J, Baxter D, Galas DJ. Export of microRNAs and microRNA‐protective protein by mammalian cells. Nucleic Acids Res 38: 7248‐7259, 2010.
 326.Wang N, Zhu Y, Xie M, Wang L, Jin F, Li Y, Yuan Q, De W. Long noncoding RNA Meg3 regulates Mafa expression in mouse beta cells by inactivating Rad21, Smc3 or Sin3alpha. Cell Physiol Biochem 45: 2031‐2043, 2018.
 327.Wang P, Fiaschi‐Taesch NM, Vasavada RC, Scott DK, Garcia‐Ocana A, Stewart AF. Diabetes mellitus—advances and challenges in human beta‐cell proliferation. Nat Rev Endocrinol 11: 201‐212, 2015.
 328.Wenda JM, Homolka D, Yang Z, Spinelli P, Sachidanandam R, Pandey RR, Pillai RS. Distinct roles of RNA helicases MVH and TDRD9 in PIWI slicing‐triggered mammalian piRNA biogenesis and function. Dev Cell 41: 623‐637 e629, 2017.
 329.Wendt A, Esguerra JL, Eliasson L. Islet microRNAs in health and type‐2 diabetes. Curr Opin Pharmacol 43: 46‐52, 2018.
 330.Wessels HH, Lebedeva S, Hirsekorn A, Wurmus R, Akalin A, Mukherjee N, Ohler U. Global identification of functional microRNA‐mRNA interactions in Drosophila. Nat Commun 10: 1626, 2019.
 331.Westholm JO, Miura P, Olson S, Shenker S, Joseph B, Sanfilippo P, Celniker SE, Graveley BR, Lai EC. Genome‐wide analysis of drosophila circular RNAs reveals their structural and sequence properties and age‐dependent neural accumulation. Cell Rep 9: 1966‐1980, 2014.
 332.Wightman B, Ha I, Ruvkun G. Posttranscriptional regulation of the heterochronic gene lin‐14 by lin‐4 mediates temporal pattern formation in C. elegans. Cell 75: 855‐862, 1993.
 333.Wong WKM, Sorensen AE, Joglekar MV, Hardikar AA, Dalgaard LT. Non‐coding RNA in pancreas and beta‐cell development. Noncoding RNA 4. pii: E41, 2018.
 334.Wu H, Wu S, Zhu Y, Ye M, Shen J, Liu Y, Zhang Y, Bu S. Hsa_circRNA_0054633 is highly expressed in gestational diabetes mellitus and closely related to glycosylation index. Clin Epigenetics 11: 22, 2019.
 335.Wu M, Shen J. From super‐enhancer non‐coding RNA to immune checkpoint: Frameworks to functions. Front Oncol 9: 1307, 2019.
 336.Wu WS, Brown JS, Chen TT, Chu YH, Huang WC, Tu S, Lee HC. piRTarBase: A database of piRNA targeting sites and their roles in gene regulation. Nucleic Acids Res 47: D181‐D187, 2019.
 337.Wu WS, Huang WC, Brown JS, Zhang D, Song X, Chen H, Tu S, Weng Z, Lee HC. pirScan: A webserver to predict piRNA targeting sites and to avoid transgene silencing in C. elegans. Nucleic Acids Res 46: W43‐W48, 2018.
 338.Xu G, Chen J, Jing G, Grayson TB, Shalev A. miR‐204 Targets PERK and Regulates UPR Signaling and beta‐Cell Apoptosis. Mol Endocrinol 30: 917‐924, 2016.
 339.Xu G, Chen J, Jing G, Shalev A. Thioredoxin‐interacting protein regulates insulin transcription through microRNA‐204. Nat Med 19: 1141‐1146, 2013.
 340.Xu H, Guo S, Li W, Yu P. The circular RNA Cdr1as, via miR‐7 and its targets, regulates insulin transcription and secretion in islet cells. Sci Rep 5: 12453, 2015.
 341.Xu X, Chen J, Hu L, Liang M, Wang X, Feng S, Shen J, Luan X. Liraglutide regulates the viability of pancreatic alpha‐cells and pancreatic beta‐cells through cAMP‐PKA signal pathway. Life Sci 195: 87‐94, 2018.
 342.Ying W, Riopel M, Bandyopadhyay G, Dong Y, Birmingham A, Seo JB, Ofrecio JM, Wollam J, Hernandez‐Carretero A, Fu W, Li P, Olefsky JM. Adipose tissue macrophage‐derived exosomal miRNAs can modulate in vivo and in vitro insulin sensitivity. Cell 171: 372‐384 e312, 2017.
 343.You L, Wang N, Yin D, Wang L, Jin F, Zhu Y, Yuan Q, De W. Downregulation of long noncoding RNA Meg3 affects insulin synthesis and secretion in mouse pancreatic beta cells. J Cell Physiol 231: 852‐862, 2016.
 344.You X, Vlatkovic I, Babic A, Will T, Epstein I, Tushev G, Akbalik G, Wang M, Glock C, Quedenau C, Wang X, Hou J, Liu H, Sun W, Sambandan S, Chen T, Schuman EM, Chen W. Neural circular RNAs are derived from synaptic genes and regulated by development and plasticity. Nat Neurosci 18: 603‐610, 2015.
 345.Yousef M, Nebozhyn M, Shatkay H, Kanterakis S, Showe LC, Showe MK. Combining multi‐species genomic data for microRNA identification using a Naive Bayes classifier. Bioinformatics 22: 1325‐1334, 2006.
 346.Zemel S, Bartolomei MS, Tilghman SM. Physical linkage of two mammalian imprinted genes, H19 and insulin‐like growth factor 2. Nat Genet 2: 61‐65, 1992.
 347.Zhang D, Tu S, Stubna M, Wu WS, Huang WC, Weng Z, Lee HC. The piRNA targeting rules and the resistance to piRNA silencing in endogenous genes. Science 359: 587‐592, 2018.
 348.Zhang H, Liu R, Deng T, Wang X, Lang H, Qu Y, Duan J, Huang D, Ying G, Ba Y. The microRNA‐124‐iGluR2/3 pathway regulates glucagon release from alpha cells. Oncotarget 7: 24734‐24743, 2016.
 349.Zhang XO, Dong R, Zhang Y, Zhang JL, Luo Z, Zhang J, Chen LL, Yang L. Diverse alternative back‐splicing and alternative splicing landscape of circular RNAs. Genome Res 26: 1277‐1287, 2016.
 350.Zhang Y, Wang X, Kang L. A k‐mer scheme to predict piRNAs and characterize locust piRNAs. Bioinformatics 27: 771‐776, 2011.
 351.Zhao E, Keller MP, Rabaglia ME, Oler AT, Stapleton DS, Schueler KL, Neto EC, Moon JY, Wang P, Wang IM, Lum PY, Ivanovska I, Cleary M, Greenawalt D, Tsang J, Choi YJ, Kleinhanz R, Shang J, Zhou YP, Howard AD, Zhang BB, Kendziorski C, Thornberry NA, Yandell BS, Schadt EE, Attie AD. Obesity and genetics regulate microRNAs in islets, liver, and adipose of diabetic mice. Mamm Genome 20: 476‐485, 2009.
 352.Zhao Z, Li X, Jian D, Hao P, Rao L, Li M. Hsa_circ_0054633 in peripheral blood can be used as a diagnostic biomarker of pre‐diabetes and type 2 diabetes mellitus. Acta Diabetol 54: 237‐245, 2017.
 353.Zheng G, Qin Y, Clark WC, Dai Q, Yi C, He C, Lambowitz AM, Pan T. Efficient and quantitative high‐throughput tRNA sequencing. Nat Methods 12: 835‐837, 2015.
 354.Zheng LL, Xu WL, Liu S, Sun WJ, Li JH, Wu J, Yang JH, Qu LH. tRF2Cancer: A web server to detect tRNA‐derived small RNA fragments (tRFs) and their expression in multiple cancers. Nucleic Acids Res 44: W185‐W193, 2016.
 355.Zhou Y, Zhang X, Klibanski A. MEG3 noncoding RNA: A tumor suppressor. J Mol Endocrinol 48: R45‐R53, 2012.
 356.Zhu H, Shah S, Shyh‐Chang N, Shinoda G, Einhorn WS, Viswanathan SR, Takeuchi A, Grasemann C, Rinn JL, Lopez MF, Hirschhorn JN, Palmert MR, Daley GQ. Lin28a transgenic mice manifest size and puberty phenotypes identified in human genetic association studies. Nat Genet 42: 626‐630, 2010.
 357.Zhu H, Shyh‐Chang N, Segre AV, Shinoda G, Shah SP, Einhorn WS, Takeuchi A, Engreitz JM, Hagan JP, Kharas MG, Urbach A, Thornton JE, Triboulet R, Gregory RI, Altshuler D, Daley GQ. The Lin28/let‐7 axis regulates glucose metabolism. Cell 147: 81‐94, 2011.
 358.Zhu M, Wei Y, Geissler C, Abschlag K, Corbalan Campos J, Hristov M, Mollmann J, Lehrke M, Karshovska E, Schober A. Hyperlipidemia‐induced microRNA‐155‐5p improves beta‐cell function by targeting Mafb. Diabetes 66: 3072‐3084, 2017.
 359.Zhu Y, You W, Wang H, Li Y, Qiao N, Shi Y, Zhang C, Bleich D, Han X. MicroRNA‐24/MODY gene regulatory pathway mediates pancreatic beta‐cell dysfunction. Diabetes 62: 3194‐3206, 2013.

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

Claudiane Guay, Cécile Jacovetti, Mustafa Bilal Bayazit, Flora Brozzi, Adriana Rodriguez‐Trejo, Kejing Wu, Romano Regazzi. Roles of Noncoding RNAs in Islet Biology. Compr Physiol null, 10: 893-932. doi: 10.1002/cphy.c190032