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


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.
Chakravarthy
Manu V
MV
Department of Medicine, Division of Endocrinology, Metabolism and Lipid Research, Washington University, St. Louis, Missouri, USA.
Zhu
Yimin
Y
Wice
Mitchell B
MB
Coleman
Trey
T
Pappan
Kirk L
KL
Marshall
Connie A
CA
McDaniel
Michael L
ML
Semenkovich
Clay F
CF
D000818:Animals; D015139:Blotting, Southern; D049628:Body Size / Q000235:genetics / Q000502:physiology; D064429:Fatty Acid Synthases / Q000235:genetics / Q000378:metabolism; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics / Q000503:physiopathology*; D020567:Fetal Weight / Q000235:genetics / Q000502:physiology*; D015309:Glucose Clamp Technique; D015151:Immunoblotting; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction
D007328:Insulin; D064429:Fatty Acid Synthases