Abstract
MicroRNAs play a crucial role in the regulation of cell growth and differentiation. Mice with genetic deletion of miR-375 exhibit impaired glycemic control due to decreased β-cell and increased α-cell mass and function. The relative importance of these processes for the overall phenotype of miR-375KO mice is unknown. Here, we show that mice overexpressing miR-375 exhibit normal β-cell mass and function. Selective re-expression of miR-375 in β-cells of miR-375KO mice normalizes both, α- and β-cell phenotypes as well as glucose metabolism. Using this model, we also analyzed the contribution of β-cells to the total plasma miR-375 levels. Only a small proportion (≈1 %) of circulating miR-375 originates from β-cells. Furthermore, acute and profound β-cell destruction is sufficient to detect elevations of miR-375 levels in the blood. These findings are supported by higher miR-375 levels in the circulation of type 1 diabetes (T1D) subjects but not mature onset diabetes of the young (MODY) and type 2 diabetes (T2D) patients. Together, our data support an essential role for miR-375 in the maintenance of β-cell mass and provide in vivo evidence for release of miRNAs from pancreatic β-cells. The small contribution of β-cells to total plasma miR-375 levels make this miRNA an unlikely biomarker for β-cell function but suggests a utility for the detection of acute β-cell death for autoimmune diabetes.Key messagesOverexpression of miR-375 in β-cells does not influence β-cell mass and function.Increased α-cell mass in miR-375KO arises secondarily to loss of miR-375 in β-cells.Only a small proportion of circulating miR-375 levels originates from β-cells.Acute β-cell destruction results in measurable increases of miR-375 in the blood.Circulating miR-375 levels are not a biomarker for pancreatic β-cell function.Electronic supplementary materialThe online version of this article (doi:10.1007/s00109-015-1296-9) contains supplementary material, which is available to authorized users.
Highlights
Pancreatic α- and β-cells are the main cell types regulating glucose metabolism through the secretion of glucagon and insulin, respectively
Autoimmune destruction of insulin-producing cells underlies the pathophysiology of type 1 diabetes (T1D) [1], whereas chronic metabolic stress linked to obesity and insulin resistance results in a gradual impairment of pancreatic function, demise of β-cells, and causes type 2 diabetes (T2D) [2, 3]
Metabolic characterization of Tg375 did not reveal significant changes in weight, blood glucose, glucose tolerance, or pancreatic endocrine function as compared to control littermate mice (Figs. 1c–f, 3, and 4). These results indicate that increased miR-375 gene dosage in pancreatic β-cells of mice does not alter pancreatic endocrine cell composition and glucose tolerance
Summary
Pancreatic α- and β-cells are the main cell types regulating glucose metabolism through the secretion of glucagon and insulin, respectively. Global miR-375 gene inactivation in mice leads to overt diabetes due in part to decreased β-cell mass [10]. Several negative regulators of cell growth are induced in miR-375KO islets and underlie the anti-proliferative effects in pancreatic β-cells. Noteworthy is the increased α-cell mass and circulating glucagon levels found in miR-375KO mice, which induce augmented hepatic glucose production and, together with the decreased β-cell function, further exacerbates glycemic control [10]. The relative importance of αand β-cell defects in the diabetic phenotype of global miR375KO mice still remains to be determined
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