Abstract
Glucose-induced insulin secretion is an essential function of pancreatic β-cells that is partially lost in individuals affected by Type 2 diabetes. This unique property of β-cells is acquired through a poorly understood postnatal maturation process involving major modifications in gene expression programs. Here we show that β-cell maturation is associated with changes in microRNA expression induced by the nutritional transition that occurs at weaning. When mimicked in newborn islet cells, modifications in the level of specific microRNAs result in a switch in the expression of metabolic enzymes and cause the acquisition of glucose-induced insulin release. Our data suggest microRNAs have a central role in postnatal β-cell maturation and in the determination of adult functional β-cell mass. A better understanding of the events governing β-cell maturation may help understand why some individuals are predisposed to developing diabetes and could lead to new strategies for the treatment of this common metabolic disease.
Highlights
Glucose-induced insulin secretion is an essential function of pancreatic b-cells that is partially lost in individuals affected by Type 2 diabetes
Pancreatic b-cells are the key cell type governing blood glucose homeostasis thanks to their ability to sense changes in nutrient levels and their capacity to adapt the amount of insulin they secrete to match metabolic needs1,2. bcell glucose responsiveness is achieved through tight coupling of insulin exocytosis with glycolysis and mitochondrial metabolism[1]
We found that except for the overexpression of miR-106b-5p, which led to a partial loss of glucose-induced insulin secretion (Fig. 6k), restoration of newborn levels of the other miRNAs did not have an impact on glucose-stimulated insulin release (Fig. 6k,l)
Summary
Glucose-induced insulin secretion is an essential function of pancreatic b-cells that is partially lost in individuals affected by Type 2 diabetes This unique property of b-cells is acquired through a poorly understood postnatal maturation process involving major modifications in gene expression programs. The absence of Dicer[1] in Ngn3-expressing cells does not perturb endocrine cell specification during fetal development but leads to the loss of b-cells and severe metabolic disturbances during the postnatal period[31] Taken together, these observations point to a critical role for miRNAs in b-cell differentiation
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