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

被引:20
作者
Chakravarthy, Mann V. [1 ]
Zhu, Yimin [1 ]
Wice, Mitchell B. [1 ]
Coleman, Trey [1 ]
Pappan, Kirk L. [2 ]
Marshall, Connie A. [2 ]
McDaniel, Michael L. [2 ]
Semenkovich, Clay F. [1 ,3 ]
机构
[1] Washington Univ, Dept Med, Div Endocrinol Metab & Lipid Res, St Louis, MO 63130 USA
[2] Washington Univ, Dept Pathol & Immunol, St Louis, MO USA
[3] Washington Univ, Dept Cell Biol & Physiol, St Louis, MO 63110 USA
关键词
D O I
10.2337/db08-0404
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
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收藏
页码:2698 / 2707
页数:10
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