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Published online June 30, 2008
Diabetes 57:2698-2707, 2008
DOI: 10.2337/db08-0404
© 2008 by the American Diabetes Association
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Decreased Fetal Size Is Associated With β-Cell Hyperfunction in Early Life and Failure With Age

Manu V. Chakravarthy1, Yimin Zhu1, Mitchell B. Wice1, Trey Coleman1, Kirk L. Pappan2, Connie A. Marshall2, Michael L. McDaniel2, and Clay F. Semenkovich1,3

1 Department of Medicine, Division of Endocrinology, Metabolism and Lipid Research, Washington University, St. Louis, Missouri
2 Department of Pathology and Immunology, Washington University, St. Louis, Missouri
3 Department of Cell Biology and Physiology, Washington University, St. Louis, Missouri

Corresponding author: Clay F. Semenkovich, csemenko{at}wustl.edu

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 β-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. β-Cell mass and insulin secretion were strikingly increased in young FASDEL mice, but β-cell failure and diabetes occurred with age. FASDEL β-cells had altered proliferative and apoptotic responses to the common stress of a high-fat diet. This sequence appeared to be developmentally entrained because β-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 β-cell mass in utero.

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


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Copyright © 2008 by the American Diabetes Association.