Decreased Fetal Size Is Associated With β-Cell Hyperfunction in Early Life and Failure With Age
| Autor: | Michael L. McDaniel, Connie A. Marshall, Clay F. Semenkovich, Manu V. Chakravarthy, Trey Coleman, Kirk L. Pappan, Yimin Zhu, Mitchell B. Wice |
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| Rok vydání: | 2008 |
| Předmět: |
Male
medicine.medical_specialty Endocrinology Diabetes and Metabolism medicine.medical_treatment Immunoblotting Intrauterine growth restriction Mice Transgenic 030209 endocrinology & metabolism Biology Mice 03 medical and health sciences 0302 clinical medicine Insulin resistance Insulin-Secreting Cells Commentaries Diabetes mellitus Internal medicine Internal Medicine medicine Animals Body Size Insulin 030304 developmental biology 0303 health sciences Fetus Fetal Growth Retardation Reverse Transcriptase Polymerase Chain Reaction Glucose clamp technique medicine.disease Immunohistochemistry Blotting Southern Low birth weight Endocrinology Fetal Weight In utero Glucose Clamp Technique Female Fatty Acid Synthases Insulin Resistance medicine.symptom |
| Zdroj: | Diabetes |
| ISSN: | 1939-327X 0012-1797 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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