| First Author | Alejandro EU | Year | 2014 |
| Journal | J Clin Invest | Volume | 124 |
| Issue | 10 | Pages | 4395-410 |
| PubMed ID | 25180600 | Mgi Jnum | J:217642 |
| Mgi Id | MGI:5615079 | Doi | 10.1172/JCI74237 |
| Citation | Alejandro EU, et al. (2014) Maternal diet-induced microRNAs and mTOR underlie beta cell dysfunction in offspring. J Clin Invest 124(10):4395-410 |
| abstractText | A maternal diet that is low in protein increases the susceptibility of offspring to type 2 diabetes by inducing long-term alterations in beta cell mass and function. Nutrients and growth factor signaling converge through mTOR, suggesting that this pathway participates in beta 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 beta 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 beta cell mass reduction. The beta 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 beta 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 beta 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. |
