Beta-Cell Specific Deletion of Dicer1 Leads to Defective Insulin Secretion and Diabetes Mellitus

Abstract

Mature microRNAs (miRNAs), derived through cleavage of pre-miRNAs by the Dicer1 enzyme, regulate protein expression in many cell-types including cells in the pancreatic islets of Langerhans. To investigate the importance of miRNAs in mouse insulin secreting β-cells, we have generated mice with a β-cells specific disruption of the Dicer1 gene using the Cre-lox system controlled by the rat insulin promoter (RIP). In contrast to their normoglycaemic control littermates (RIP-Cre+/− Dicer1 Δ/wt), RIP-Cre+/− Dicer1flox/flox mice (RIP-Cre Dicer1 Δ/Δ) developed progressive hyperglycaemia and full-blown diabetes mellitus in adulthood that recapitulated the natural history of the spontaneous disease in mice. Reduced insulin gene expression and concomitant reduced insulin secretion preceded the hyperglycaemic state and diabetes development. Immunohistochemical, flow cytometric and ultrastructural analyses revealed altered islet morphology, marked decreased β-cell mass, reduced numbers of granules within the β-cells and reduced granule docking in adult RIP-Cre Dicer1 Δ/Δ mice. β-cell specific Dicer1 deletion did not appear to disrupt fetal and neonatal β-cell development as 2-week old RIP-Cre Dicer1 Δ/Δ mice showed ultrastructurally normal β-cells and intact insulin secretion. In conclusion, we have demonstrated that a β-cell specific disruption of the miRNAs network, although allowing for apparently normal β-cell development, leads to progressive impairment of insulin secretion, glucose homeostasis and diabetes development.

Beyond the Protein-Coding Sequence: Noncoding RNAs in the Pathogenesis of Type 2 Diabetes

“…Dicer1-depleted mice exhibited reduced insulin gene expression and impaired insulin secretion, both of which preceded the development of progressive hyperglycemia and diabetes. These animals also showed altered islet cell morphology, reduced β-cell mass, and differential pancreatic islet morphology, although fetal and neonatal β-cell development and insulin secretory function were normal [24,26]. Thus, despite normal β-cell development, disruption of the miRNA network effectively resulted in defective insulin secretion, hyperglycemia, and diabetes, implying a significant function for miRNAs in this cell type.…”

“…Aberrant regulation of miRNAs has been associated with the development of many diseases including neurologic disorders, cardiovascular diseases, and certain cancers [22,23]. miRNAs have also been found to be critical for pancreatic development [24][25][26], maintenance of β-cell identity [27], and regulation of biological processes related to T2D pathogenesis, including glucose-stimulated insulin secretion, glucose uptake in muscle and liver, adipogenesis, and adipocyte function [28][29][30].…”

“…To investigate the overall importance of miRNAs in β-cells, Kalis et al generated mice with a β-cell-specific disruption of Dicer1 [24], an endoribonuclease that plays a critical role in the processing and generation of miRNAs [45]. Dicer1-depleted mice exhibited reduced insulin gene expression and impaired insulin secretion, both of which preceded the development of progressive hyperglycemia and diabetes.…”

miRNAs: novel regulators of autoimmunity-mediated pancreatic β-cell destruction in type 1 diabetes

“…86 miRNAs control insulin synthesis and secretion β-cell-specific ablation of Dicer1 can result in the onset of diabetes as a consequence of impaired insulin biosynthesis and glucose-stimulated insulin secretion (GSIS). [87][88][89] Recent studies have indicated that Ago2 is also critical for the insulin-secreting capacity and compensatory expansion of β-cells. 90 Deletion of Ago2 in insulin-producing β-cells (the MIN6 cell line) enhances insulin production.…”

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

“…RIP-Cre-Dicer1 flox/flox mice exhibit normal beta cell formation during fetal and neonatal life, but become progressively hyperglycaemic and finally develop overt diabetes in adulthood. These mice display defects in islet number, size and architecture, in beta-cell mass, and in insulin biosynthesis and secretion [9,10]. Loss of Dicer1 in the adult does not affect total beta cell mass, but results in insufficient insulin biosynthesis and release in response to glucose, causing hyperglycaemia in both fed and fasted states [11].…”