REVIEW ARTICLE MicroRNAs in islet hormone secretion Jonathan L. S. Esguerra MSc, PhD | Mototsugu Nagao MD, PhD | Jones K. Ofori MSc, PhD | Anna Wendt MSc, PhD | Lena Eliasson MSc, PhD Islet Cell Exocytosis, Lund University Diabetes Centre, Department of Clinical Sciences Malmö, Lund University, Clinical Research Centre, SUS, Malmö, Sweden Correspondence Professor Lena Eliasson, Department of Clinical Sciences Malmö, Clinical Research Centre 91-11, Box 50332, 202 13 Malmö, Sweden. Email: lena.eliasson@med.lu.se Funding information European Union's Horizon 2020 Research and Innovation Programme, Grant/Award Number: 667191; Syskonen Svenssons Fond; Byggmästare Olle Engqvist Foundation; Crafoordska Stiftelsen; Albert Påhlsson Foundation; the Diabetes Research and Wellness Network Sweden; Novo Nordisk Fonden; The Swedish Diabetes Foundation; Region Skåne-ALF; Swedish Research Council; Swedish Foundation for Strategic Research (IRC-LUDC) Pancreatic islet hormone secretion is central in the maintenance of blood glucose homeostasis. During development of hyperglycaemia, the β-cell is under pressure to release more insulin to compensate for increased insulin resistance. Failure of the β-cells to secrete enough insulin results in type 2 diabetes (T2D). MicroRNAs (miRNAs) are short non-coding RNA molecules suit- able for rapid regulation of the changes in target gene expression needed in β-cell adaptations. Moreover, miRNAs are involved in the maintenance of α-cell and β-cell phenotypic identities via cell-specific, or cell-enriched expression. Although many of the abundant miRNAs are highly expressed in both cell types, recent research has focused on the role of miRNAs in β-cells. It has been shown that highly abundant miRNAs, such as miR-375, are involved in several cellular functions indispensable in maintaining β-cell phenotypic identity, almost acting as “housekeeping genes” in the context of hormone secretion. Despite the abundance and impor- tance of miR-375, it has not been shown to be differentially expressed in T2D islets. On the contrary, the less abundant miRNAs such as miR-212/miR-132, miR-335, miR-130a/b and miR- 152 are deregulated in T2D islets, wherein the latter three miRNAs were shown to play key roles in regulating β-cell metabolism. In this review, we focus on β-cell function and describe miRNAs involved in insulin biosynthesis and processing, glucose uptake and metabolism, electri- cal activity and Ca 2+ -influx and exocytosis of the insulin granules. We present current status on miRNA regulation in α-cells, and finally we discuss the involvement of miRNAs in β-cell dysfunc- tion underlying T2D pathogenesis. KEYWORDS exocytosis, glucagon, insulin, metabolism, microRNA, α-cell, β-cell 1 | INTRODUCTION Type-2 diabetes (T2D) is an exponentially growing disease and it is projected to reach almost 700 million cases globally in 2045. 1 In search for better treatment strategies, Lund University Diabetes Cen- tre (LUDC) recently presented data in which all individuals with newly diagnosed diabetes in a large Swedish cohort (n = 8980; ANDIS cohort) cluster into 5 subgroups; 1 subgroup basically representing type-1 diabetes (severe autoimmune diabetes; SAID cluster) and 4 other distinct subgroups representing different types of T2D. 2 Within the T2D subgroups, the majority of patients had a HOMA-2B <100%. HOMA-2B is a homeostatic model to assess static β-cell func- tion in in vivo mesurements. A value of HOMA-2B <100% is indicative of reduced insulin secretion capacity. The clusters with reduced β-cell function were SIDD (severe insulin deficient diabetes; ~20% of all cases), MOD (mild obese diabetes; ~20%) and MARD (mild age- related diabetes; ~40%). Hence, these findings support the hypothesis that β-cell dysfunction and/or defective β-cell compensation is a major contributing factor in the disease progression. Insulin is produced and released from the β-cells within the pan- creatic islets of Langerhans and is the main peptide hormone lowering blood glucose levels after a meal through increased uptake of blood glucose in insulin-dependent target tissues. Upon increased insulin resistance, the demand on the β-cells increases and the cells adjust to the new condition. We and others have suggested that microRNAs (miRNAs) participate in β-cell compensation during pregnancy, obesity and T2D development. 3–6 miRNAs are short non-coding RNAs that mediate RNA silencing and posttranscriptional regulation of gene Received: 17 April 2018 Revised: 10 May 2018 Accepted: 23 May 2018 DOI: 10.1111/dom.13382 Diabetes Obes Metab. 2018;20(Suppl. 2):11–19. wileyonlinelibrary.com/journal/dom © 2018 John Wiley & Sons Ltd 11