Role of islet microRNAs in diabetes: which model for which question?

Abstract

MicroRNAs are important regulators of gene expression. The vast majority of the cells in our body rely on hundreds of these tiny non-coding RNA molecules to precisely adjust their protein repertoire and faithfully accomplish their tasks. Indeed, alterations in the microRNA profile can lead to cellular dysfunction that favours the appearance of several diseases. A specific set of microRNAs plays a crucial role in pancreatic beta cell differentiation and is essential for the fine-tuning of insulin secretion and for compensatory beta cell mass expansion in response to insulin resistance. Recently, several independent studies reported alterations in microRNA levels in the islets of animal models of diabetes and in islets isolated from diabetic patients. Surprisingly, many of the changes in microRNA expression observed in animal models of diabetes were not detected in the islets of diabetic patients and vice versa. These findings are unlikely to merely reflect species differences because microRNAs are highly conserved in mammals. These puzzling results are most probably explained by fundamental differences in the experimental approaches which selectively highlight the microRNAs directly contributing to diabetes development, the microRNAs predisposing individuals to the disease or the microRNAs displaying expression changes subsequent to the development of diabetes. In this review we will highlight the suitability of the different models for addressing each of these questions and propose future strategies that should allow us to obtain a better understanding of the contribution of microRNAs to the development of diabetes mellitus in humans.Keywords Animal models of Diabetes . Diabetes . Human islet donors . Insulin . Islets of Langerhans . MicroRNAs . Pancreatic beta cells . Review MicroRNAs as regulators of beta cell differentiation and functionType 2 diabetes is a chronic metabolic disorder characterised by major alterations in gene expression, which affects several organs, including the islets of Langerhans. A growing number of studies demonstrate that these changes are not only caused by deregulation of key transcription factors such as v-maf musculoaponeurotic fibrosarcoma oncogene family, protein A (avian) (MafA) or pancreatic and duodenal homeobox 1 (PDX1) but are also driven by modifications in the level of another group of molecules regulating gene expression, the microRNAs [1][2][3][4]. MicroRNAs are small non-coding RNAs (typically 21-23 nucleotides long) that pair to the 3′ untranslated region of target mRNAs leading to translational repression and/or a decrease in messenger stability [5].The importance of the microRNA regulatory network for proper differentiation and function of beta cells is highlighted by the phenotypic traits of mice lacking Dicer1, an enzyme essential for the generation of most microRNAs [5]. Deletion of Dicer1 at different stages of pancreas development or of the pancreatic endocrine lineage results in a dramatic loss of microRNAs, accompanied by severe defects in pancreas m...

Biological roles of microRNAs in the control of insulin secretion and action

“…Second, knowledge of the role of miRNAs in the regulation of insulin secretion and action is emerging mostly from experiments in animal models and will undoubtedly keep improving with paralleled genome-wide expression profiling data sets of miRNAs and mRNAs (36). However, a critical issue with miRNA studies in model systems lies in the potential conservation of DNA sequences of both miRNAs and their binding sites across species (23). Translation of regulatory mechanisms involving miRNAs between species relies on conservation of both miRNA catalogs and DNA sequences at the levels of miRNA seeds and target sites in mRNAs mainly localized in noncoding regions of genes, which may be more divergent between species than coding sequences.…”

Circulating microRNAs and diabetes: potential applications in medical practice

“…Among the miRNAs expressed in the endocrine pancreas, miR-375 has one of the highest levels of expression both in humans and rodents. In animal studies, miR-375 seems to play a complex role in beta cell function and physiology [5,7]. Under physiological conditions its overexpression leads to reduced beta cell growth [50], while in stressed beta cells its decreased expression appears to counteract the beta cell hyperplasia [51].…”

“…Under physiological conditions its overexpression leads to reduced beta cell growth [50], while in stressed beta cells its decreased expression appears to counteract the beta cell hyperplasia [51]. Its altered expression in islets and/or pancreas has been observed in animal models with a predisposition to type 2 diabetes [52] and overt diabetes [7]. While miR-375 expression is not significantly augmented in human islets from glucose intolerant donors [53], increased levels have been observed in the pancreas [54] and blood of type 2 diabetic patients [22,33].…”

“…Hence, miRNAs impact on physiological processes, including cell proliferation, differentiation, apoptosis and metabolism [4][5][6]. Consequently, their dysregulation appears to be involved in various disorders, including metabolic diseases such as diabetes (for reviews, see [5,7]). …”

Impaired Immune Phenotype of Circulating Endothelial-Derived Microparticles in None-Diabetic Patients with Chronic Heart Failure: Impact on Insulin Resistance

“…Apoptotic-derived or activated endothelial cell-derived EMPs are capable of transferring biological information, regulating peptides, hormones, proteins, lipid components without direct cell-to-cell contact to maintain cell homeostasis [22,23]. Interestingly, circulating EMPs derived from activated endothelial cells did not contain nuclear components and they have also been shown to have pro-angiogenic and cardio-protective properties [24,25].…”