Decreased fetal size is associated with beta-cell hyperfunction in early life and failure with age.

Chakravarthy MV; Zhu Y; Wice MB; Coleman T; Pappan KL; Marshall CA; McDaniel ML; Semenkovich CF; Chakravarthy, Manu V; Zhu, Yimin; Wice, Mitchell B; Coleman, Trey; Pappan, Kirk L; Marshall, Connie A; McDaniel, Michael L; Semenkovich, Clay F

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 (FAS deletion [FASDEL]). Developmental programming of diabetes in these mice was assessed from in utero to 1 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 because beta-cell mass was increased in utero in FASDEL 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.

Diabetes, 2008, Vol 57, Issue 10, p2698

0012-1797

Academic Journal

10.2337/db08-0404