Decreased Fetal Size is Associated with Beta Cell Hyperfunction in Early Life and Failure with Age

Abstract

Objective: Low birth weight is associated with diabetes in adult life. Accelerated or “catch-up” postnatal growth in response to small birth size is thought to presage disease years later. Whether adult disease is caused by intrauterine beta cell-specific programming or by altered metabolism associated with catch-up growth is unknown.

Research Design and Methods: We generated a new model of intrauterine growth restriction due to fatty acid synthase (FAS) haploinsufficiency (FASDEL). Developmental programming of diabetes in these mice was assessed from in utero to one year of age.

Results: FASDEL mice did not manifest catch-up growth or insulin resistance. Beta cell mass and insulin secretion were strikingly increased in young FASDEL mice but beta cell failure and diabetes occurred with age. FASDEL beta cells had altered proliferative and apoptotic responses to the common stress of a high-fat diet. This sequence appeared to be developmentally entrained since beta cell mass was increased in utero in FAS haploinsufficient mice and in another model of intrauterine growth restriction caused by ectopic expression of uncoupling protein-1. Increasing intrauterine growth in FASDEL mice by supplementing caloric intake of pregnant dams normalized beta cell mass in utero.

Conclusions: Decreased intrauterine body size, independent of postnatal growth and insulin resistance, appears to regulate beta cell mass, suggesting that developing body size might represent a physiological signal that is integrated through the pancreatic beta cell to establish a template for hyperfunction in early life and beta cell failure with age.