The intrauterine environment of the fetus is a preeminent actor in long-term health. Indeed, mounting evidence shows that maternal malnutrition increases the risk of type 2 diabetes (T2D) in progeny. Although the consequences of disturbed prenatal environment on pancreas development are known, the underlying mechanisms are poorly defined. In rats, gestational protein restriction alters the endocrine pancreas development and favors T2D appearance later in life. Here we evaluate the potential role of perturbed microRNA (miRNA) expression in the decreased β-cell mass and insulin secretion characterizing progeny of pregnant dams fed a low protein (LP) diet. miRNA profiling shows increased expression of several miRNAs in pancreas of LP fetuses including miR-375. Its expression remains augmented in neoformed islets derived from LP fetuses and in islets from adult 3 month-old LP progeny. miR-375 regulates the proliferation and insulin secretion of dissociated islet cells, contributing to the reduced β-cell mass and function of LP progeny. Remarkably, miR-375 normalization in LP derived islet cells restores β-cell proliferation and insulin secretion. Our findings suggest the existence of a developmental memory in islets that registers intrauterine protein restriction. Hence, pancreatic failure after in utero malnutrition could result from transgenerational transmission of microRNA misexpression in β-cells.
- Received September 17, 2013.
- Accepted May 7, 2014.
- © 2014 by the American Diabetes Association.
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