1. Maternal diet-induced microRNAs and mTOR underlie β cell dysfunction in offspring.
- Author
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Alejandro, Emilyn U., Gregg, Brigid, Wallen, Taylor, Kumusoglu, Doga, Meister, Daniel, Chen, Angela, Merrins, Matthew J., Satin, Leslie S., Liu, Ming, Arvan, Peter, and Bernal-Mizrachi, Ernesto
- Subjects
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MICRORNA , *TYPE 2 diabetes risk factors , *MATERNAL nutrition , *LOW-protein diet , *MTOR protein - Abstract
A maternal diet that is low in protein increases the susceptibility of offspring to type 2 diabetes by inducing long-term alterations in β cell mass and function. Nutrients and growth factor signaling converge through mTOR, suggesting that this pathway participates in β cell programming during fetal development. Here, we revealed that newborns of dams exposed to low-protein diet (LP0.5) throughout pregnancy exhibited decreased insulin levels, a lower β cell fraction, and reduced mTOR signaling. Adult offspring of LP0.5-exposed mothers exhibited glucose intolerance as a result of an insulin secretory defect and not β cell mass reduction. The β cell insulin secretory defect was distal to glucose-dependent Ca2+ influx and resulted from reduced proinsulin biosynthesis and insulin content. Islets from offspring of LP0.5-fed dams exhibited reduced mTOR and increased expression of a subset of microRNAs, and blockade of microRNA-199a-3p and -342 in these islets restored mTOR and insulin secretion to normal. Finally, transient β cell activation of mTORC1 signaling in offspring during the last week of pregnancy of mothers fed a LP0.5 rescued the defect in the neonatal β cell fraction and metabolic abnormalities in the adult. Together, these findings indicate that a maternal low-protein diet alters microRNA and mTOR expression in the offspring, influencing insulin secretion and glucose homeostasis. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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