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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 - Diabetes (2008)

Bottom Line: Whether adult disease is caused by intrauterine beta-cell-specific programming or by altered metabolism associated with catch-up growth is unknown.FASDEL beta-cells had altered proliferative and apoptotic responses to the common stress of a high-fat diet.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Division of Endocrinology, Metabolism and Lipid Research, Washington University, St. Louis, Missouri, USA.

ABSTRACT

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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Related in: MedlinePlus

Postnatal FASDEL mice do not catch up in weight despite high fat feeding. A and B: Body weight on standard chow and HFD at 3 (A) and 12 (B) months of age. D, FASDEL; W, wild type. C and D: Percent change in body weight over the 10-week HFD feeding period at 3 (C) and 12 (D) months. Results are means ± SE of 8–10 animals per group. *P < 0.05 vs. the corresponding wild-type mice. C and D: ▵, wild type/standard chow diet; ▴, FASDEL/standard chow diet; ○, wild type/HFD; •, FASDEL/HFD.
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f2: Postnatal FASDEL mice do not catch up in weight despite high fat feeding. A and B: Body weight on standard chow and HFD at 3 (A) and 12 (B) months of age. D, FASDEL; W, wild type. C and D: Percent change in body weight over the 10-week HFD feeding period at 3 (C) and 12 (D) months. Results are means ± SE of 8–10 animals per group. *P < 0.05 vs. the corresponding wild-type mice. C and D: ▵, wild type/standard chow diet; ▴, FASDEL/standard chow diet; ○, wild type/HFD; •, FASDEL/HFD.

Mentions: FASDEL mice maintained a lower weight on a high-fat diet (HFD) at 3 and 12 months of age (Fig. 2A–D). Metabolic parameters for both HFD groups were similar at 3 months of age, but feed efficiency was decreased and Vo2 increased in FASDEL compared with wild-type mice at 12 months of age (online appendix Table 2).


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 - Diabetes (2008)

Postnatal FASDEL mice do not catch up in weight despite high fat feeding. A and B: Body weight on standard chow and HFD at 3 (A) and 12 (B) months of age. D, FASDEL; W, wild type. C and D: Percent change in body weight over the 10-week HFD feeding period at 3 (C) and 12 (D) months. Results are means ± SE of 8–10 animals per group. *P < 0.05 vs. the corresponding wild-type mice. C and D: ▵, wild type/standard chow diet; ▴, FASDEL/standard chow diet; ○, wild type/HFD; •, FASDEL/HFD.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2551680&req=5

f2: Postnatal FASDEL mice do not catch up in weight despite high fat feeding. A and B: Body weight on standard chow and HFD at 3 (A) and 12 (B) months of age. D, FASDEL; W, wild type. C and D: Percent change in body weight over the 10-week HFD feeding period at 3 (C) and 12 (D) months. Results are means ± SE of 8–10 animals per group. *P < 0.05 vs. the corresponding wild-type mice. C and D: ▵, wild type/standard chow diet; ▴, FASDEL/standard chow diet; ○, wild type/HFD; •, FASDEL/HFD.
Mentions: FASDEL mice maintained a lower weight on a high-fat diet (HFD) at 3 and 12 months of age (Fig. 2A–D). Metabolic parameters for both HFD groups were similar at 3 months of age, but feed efficiency was decreased and Vo2 increased in FASDEL compared with wild-type mice at 12 months of age (online appendix Table 2).

Bottom Line: Whether adult disease is caused by intrauterine beta-cell-specific programming or by altered metabolism associated with catch-up growth is unknown.FASDEL beta-cells had altered proliferative and apoptotic responses to the common stress of a high-fat diet.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Division of Endocrinology, Metabolism and Lipid Research, Washington University, St. Louis, Missouri, USA.

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus