Maternal diet-induced microRNAs and mTOR underlie β cell dysfunction in offspring

Emilyn U. Alejandro, Brigid Gregg, Taylor Wallen, Doga Kumusoglu, Daniel Meister, Angela Chen, Matthew J. Merrins, Leslie S. Satin, Ming Liu, Peter Arvan, Ernesto Bernal-Mizrachi

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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.

Original languageEnglish (US)
Pages (from-to)4395-4410
Number of pages16
JournalJournal of Clinical Investigation
Volume124
Issue number10
DOIs
StatePublished - Oct 1 2014

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Alejandro, E. U., Gregg, B., Wallen, T., Kumusoglu, D., Meister, D., Chen, A., Merrins, M. J., Satin, L. S., Liu, M., Arvan, P., & Bernal-Mizrachi, E. (2014). Maternal diet-induced microRNAs and mTOR underlie β cell dysfunction in offspring. Journal of Clinical Investigation, 124(10), 4395-4410. https://doi.org/10.1172/JCI74237