Aims/hypothesisAgeing can lead to reduced insulin sensitivity and loss of pancreatic beta cell function, predisposing individuals to the development of diabetes. The aim of this study was to assess the contribution of microRNAs (miRNAs) to age-associated beta cell dysfunction.MethodsThe global mRNA and miRNA profiles of 3- and 12-month-old rat islets were collected by microarray. The functional impact of age-associated differences in miRNA expression was investigated by mimicking the observed changes in primary beta cells from young animals.ResultsBeta cells from 12-month-old rats retained normal insulin content and secretion, but failed to proliferate in response to mitotic stimuli. The islets of these animals displayed modifications at the level of several miRNAs, including upregulation of miR-34a, miR-124a and miR-383, and downregulation of miR-130b and miR-181a. Computational analysis of the transcriptomic modifications observed in the islets of 12-month-old rats revealed that the differentially expressed genes were enriched for miR-34a and miR-181a targets. Indeed, the induction of miR-34a and reduction of miR-181a in the islets of young animals mimicked the impaired beta cell proliferation observed in old animals. mRNA coding for alpha-type platelet-derived growth factor receptor, which is critical for compensatory beta cell mass expansion, is directly inhibited by miR34a and is likely to be at least partly responsible for the effects of this miRNA.Conclusions/interpretationChanges in the level of specific miRNAs that occur during ageing affect the proliferative capacity of beta cells. This might reduce their ability to expand under conditions of increased insulin demand, favouring the development of type 2 diabetes.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-015-3783-5) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

SummaryMicroRNAs are major regulators of gene expression that are emerging as central players in the development of many human diseases, including diabetes mellitus. In fact, diabetes manifestation is associated with alterations in the microRNA profile in insulin-secreting cells, insulin target tissues and, in case of long-term diabetes complications, in many additional organs. Diabetes results also in changes in the profile of microRNAs detectable in blood and other body fluids. This has boosted an ever increasing interest in the use of circulating microRNAs as potential biomarkers to predict the development of diabetes and its devastating complications. Moreover, promising approaches to correct the level of selected microRNAs are emerging, permitting to envisage new therapeutic strategies to treat diabetes and its complications.Key words: Diabetes mellitus; Insulin; pancreatic islet; microRNA; Gene expression; biomarker; diabetic complication; Adeno-associated virus 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 of target mRNAs that are initially recognized through base pairing to a conserved "seed" sequence corresponding to nucleotides 2-8 of the miRNAs, leading to inhibition of mRNA translational and/or to a decrease in messenger stability [2, 3]. A single miRNA typically controls hundreds of targets and each mRNA can be targeted by different miRNAs, conferring to this class of non-coding RNA molecules a huge regulatory potential [4]. In the past decade, a large body of evidence has been accumulated pointing to a role for miRNAs in the etiology and pathogenesis of diabetes and its complications. Indeed, alterations in the level of these non-coding RNAs has been observed both in insulin-secreting cells and in insulin-target tissues isolated from diabetes animal models or diabetic patients [5]. Moreover, changes in miRNA expression have been associated with long-term diabetes complications including neuropathy, retinopathy, renal failure and macrovascular diseases. Page 1 of 36 Expert Review of Endocrinology & MetabolismThe first demonstration of the involvement of miRNAs in the control of specialized β-cell functions has been provided ten years ago by Poy et al. who showed that inappropriate levels of miR-375, one of the most abundant miRNAs present in β-cells, can affect insulin secretion [6]. Later on, this and several other miRNAs including miR-15a/b, miR-16, miR-195, miR-503, miR-451, miR-214, miR-9, miR-124a, miR-7 and miR-376 were demonstrated to play important roles in the differentiation of pancreatic islet cells [7][8][9][10][11][12]. Moreover, changes in the levels of many miRNAs, including miR-9, miR...