Dissecting the role of micro-RNAs in diabetes

Abstract: The role of miRNAs in pancreatic islets and β-cell function and in the development of diabetes in human and rodents have been investigated in this thesis. Dicer1 was specifically deleted in vivo in pancreatic β-cells under the RIP-promoter in mice. The results show that disruption of miRNAprocessing in mouse pancreatic β-cells, while compatible with β-cell development, leads to defective insulin-secreting function and progressive overt diabetes mellitus. The miRNA profiles were investigated in the non-obese type 2 diabetes rat model, Goto-Kakizaki (GK), and in healthy Wistar controls, revealing that specific miRNAs in GK rat pancreatic islets display aberrant expression when islets were challenged with glucose. One of these miRNAs, miR-335, was experimentally shown to target Syntaxin-binding protein-1 (Stxbp1), a protein important for insulin exocytosis. In the non-obese diabetic mouse (NOD), a well-established mouse model for type 1 diabetes, the possibility of miRNA-involvment in the apoptosis-resistance in thymocytes in these mice were investigated. Apoptosis-resistant auto-reactive thymocytes may give rise to the autoimmune diabetes observed in the NOD mouse. The results showed that miR-34a/b/c is defectively upregulated in NOD thymocytes compared to B6 mouse control thymocytes. Additionally, the genes of this miRNA-family resides in diabetes susceptibility loci. Sequencing mir-34a revealed a deletion in the pregene segment within a basepair from a putative p53-binding site. Finally, it has been observed in other studies (1, 2) that the well-known islet miRNA, miR-375, is abundantly expressed in islets. This was confirmed and it was also demonstrated that miR-375 is positively correlated to insulin biosynthesis in healthy human islets (HbA1c < 6.1). The same interesting pattern of expression was observed for miR-122, 127-3p and miR-184. Additionally, miR-127-3p and miR-184 were negatively correlated to glucose-stimulated insulin secretion (GSIS). All correlation between these miRNAs and the insulin mRNA and insulin secretion was lost in human islets from glucose intolerant donors with (HbA1c ≥ 6.1). To conclude, miRNAs have been demonstrated to be essential for β-cells and islet function in mouse, rat and human. From the results of this thesis it can be suggested that a disturbed miRNA network in the ieither a cause or a consequence of events giving rise to pathogenicity in the form of diabetes.