Abstract
Pancreatic β-cells regulate glucose metabolism by secreting insulin, which in turn stimulates the utilization or storage of the sugar by peripheral tissues. Insulin insufficiency and a prolonged period of insulin resistance are usually the core components of type 2 diabetes (T2D). Although, decreased insulin levels in T2D have long been attributed to a decrease in β-cell function and/or mass, this model has recently been refined with the recognition that a loss of β-cell “identity” and dedifferentiation also contribute to the decline in insulin production. MicroRNAs (miRNAs) are key regulatory molecules that display tissue-specific expression patterns and maintain the differentiated state of somatic cells. During the past few years, great strides have been made in understanding how miRNA circuits impact β-cell identity. Here, we review current knowledge on the role of miRNAs in regulating the acquisition of the β-cell fate during development and in maintaining mature β-cell identity and function during stress situations such as obesity, pregnancy, aging, or diabetes. We also discuss how miRNA function could be harnessed to improve our ability to generate β-cells for replacement therapy for T2D.
Highlights
Pancreatic β-cells are responsible for insulin release and are essential for normal blood glucose homeostasis
Our studies demonstrated that the β-cell capacity to secrete insulin in response to a glucose challenge in miRNA-null islets was significantly impaired, a defect that preceded any loss in β-cell mass or insulin content
Quantification of miR-7 gene expression in islets from mildly diabetic patients (HbAlc 6.6 mmol/mol) surprisingly revealed lower miR-7 levels compared to controls, suggesting that the human response to metabolic stress in islets may differ from mice or alternatively that treatment of those patients may have allowed compensatory n-cell function to obesity and insulin resistance
Summary
Pancreatic β-cells are responsible for insulin release and are essential for normal blood glucose homeostasis. Quantification of miR-7 gene expression in islets from mildly diabetic patients (HbAlc 6.6 mmol/mol) surprisingly revealed lower miR-7 levels compared to controls, suggesting that the human response to metabolic stress in islets may differ from mice or alternatively that treatment of those patients may have allowed compensatory n-cell function to obesity and insulin resistance. Together, this reveals a dynamic remodeling of miR-7 expression during the natural progression of T2D, which contributes to the functional adaptation of β-cells to metabolic stress (Figure 2B). We will focus on (1) the impact of miRNAs in β-cell identity and function through regulation of “disallowed” genes and (2) the role that miRNAs may play in loss of β-cell identity in situations of cellular stress, including diabetes, obesity, pregnancy, or aging
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