Review: Placental programming of postnatal diabetes and impaired insulin action after IUGR

Abstract

Being born small due to poor growth before birth increases the risk of developing metabolic disease, including type 2 diabetes, in later life. Inadequate insulin secretion and decreasing insulin sensitivity contribute to this increased diabetes risk. Impaired placental growth, development and function are major causes of impaired fetal growth and development and therefore of IUGR. Restricted placental growth (PR) and function in non-human animals induces similar changes in insulin secretion and sensitivity as in human IUGR, making these valuable tools to investigate the underlying mechanisms and to test interventions to prevent or ameliorate the risk of disease after IUGR. Epigenetic changes induced by an adverse fetal environment are strongly implicated as causes of later impaired insulin action. These have been well-characterised in the PR rat, where impaired insulin secretion is linked to epigenetic changes at the Pdx-1 promotor and reduced expression of this transcription factor. Present research is particularly focussed on developing intervention strategies to prevent or reverse epigenetic changes, and normalise gene expression and insulin action after PR, in order to translate this to treatments to improve outcomes in human IUGR.

Fig. 1

IUGR and insulin action in humans. Restriction of growth before birth enhances insulin sensitivity in neonates with reversal to impaired insulin sensitivity by adulthood. Insulin secretion is impaired from early postnatal life, and together these contribute to increased risks of T2D in the adult who was small at birth. Effects of IUGR/SGA are relative to AGA individuals, who are indicated by the thick dashed line. The dotted vertical line indicates birth.

Fig. 2

PR and insulin action in sheep and rats. PR rats and sheep exhibit similar changes in insulin secretion and sensitivity with ageing as IUGR humans, including decreasing insulin sensitivity and impaired insulin secretion. Effects of PR are relative to control individuals, who are indicated by the thick dashed line. The dotted vertical line indicates birth.