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

J Clin Invest. 2014 Oct;124(10):4395-410. doi: 10.1172/JCI74237. Epub 2014 Sep 2.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Weight
  • Calcium / metabolism
  • Diet, Protein-Restricted*
  • Female
  • Glucose Intolerance
  • Glucose Tolerance Test
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / cytology*
  • Insulin-Secreting Cells / pathology
  • Male
  • Maternal Nutritional Physiological Phenomena*
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / metabolism*
  • Pregnancy
  • Pregnancy, Animal
  • Prenatal Exposure Delayed Effects / physiopathology
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism*
  • Transgenes

Substances

  • Insulin
  • MicroRNAs
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Calcium