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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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β-Cells respond to intrauterine body size. A and B: Representative whole-mount sections of E18.5 fetuses from standard chow–fed dams stained with hematoxylin and eosin (A) and fetal body weights (B) (n = 12). WT, wild type. C: Representative pancreatic sections immunostained with anti-insulin antibody. The arrows depict insulin-positive areas within each islet surrounded by normal pancreatic acinar cells (×10 magnification). WT, wild type. D: β-Cell mass in E18.5 fetuses (n = 12). WT, wild type. E: Representative pancreatic sections double immunostained with antiphosphorylated Akt (red, panel 1) and anti-insulin (green, panel 2) and visualized using a dual red-green filter (merged, panel 3) at ×20 magnification. Arrows in panel 3 identify β-cells expressing phosphorylated Akt (yellow). Representative sections of cerebral hemispheres from E18.5 fetuses (panel 4) and whole-mount sections (panel 5) stained with phosphorylated Akt (brown staining). Arrow in panel 4 indicates phosphorylated Akt–positive areas. WT, wild type. F: Representative whole-mount sections of E18.5 fetuses from HFD-fed dams (HFD fed from day 0.5 to day 18.5) stained with hematoxylin and eosin. WT, wild type. G: Weights of fetuses from HFD-fed dams (top panel) and the percentage change in body weight compared with fetuses from standard chow–fed dams (bottom panel) (n = 10). WT, wild type. H: Representative pancreatic sections (×10 magnification) immunostained with anti-insulin antibody as in C. WT, wild type. I: β-Cell mass in E18.5 fetuses from HFD-fed dams (top panel) and the percentage change in β-cell mass compared with fetuses from standard chow–fed dams (bottom panel) (n = 10). WT, wild type. Results are means ± SE. *P < 0.05 vs. the corresponding wild type mice. (Please see http://dx.doi.org/10.2337/db08-0404 for a high-quality digital representation of this image.)
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f6: β-Cells respond to intrauterine body size. A and B: Representative whole-mount sections of E18.5 fetuses from standard chow–fed dams stained with hematoxylin and eosin (A) and fetal body weights (B) (n = 12). WT, wild type. C: Representative pancreatic sections immunostained with anti-insulin antibody. The arrows depict insulin-positive areas within each islet surrounded by normal pancreatic acinar cells (×10 magnification). WT, wild type. D: β-Cell mass in E18.5 fetuses (n = 12). WT, wild type. E: Representative pancreatic sections double immunostained with antiphosphorylated Akt (red, panel 1) and anti-insulin (green, panel 2) and visualized using a dual red-green filter (merged, panel 3) at ×20 magnification. Arrows in panel 3 identify β-cells expressing phosphorylated Akt (yellow). Representative sections of cerebral hemispheres from E18.5 fetuses (panel 4) and whole-mount sections (panel 5) stained with phosphorylated Akt (brown staining). Arrow in panel 4 indicates phosphorylated Akt–positive areas. WT, wild type. F: Representative whole-mount sections of E18.5 fetuses from HFD-fed dams (HFD fed from day 0.5 to day 18.5) stained with hematoxylin and eosin. WT, wild type. G: Weights of fetuses from HFD-fed dams (top panel) and the percentage change in body weight compared with fetuses from standard chow–fed dams (bottom panel) (n = 10). WT, wild type. H: Representative pancreatic sections (×10 magnification) immunostained with anti-insulin antibody as in C. WT, wild type. I: β-Cell mass in E18.5 fetuses from HFD-fed dams (top panel) and the percentage change in β-cell mass compared with fetuses from standard chow–fed dams (bottom panel) (n = 10). WT, wild type. Results are means ± SE. *P < 0.05 vs. the corresponding wild type mice. (Please see http://dx.doi.org/10.2337/db08-0404 for a high-quality digital representation of this image.)

Mentions: In >15 litters at E18.5 (when distinct islets appear) (31), FAS haploinsufficiency decreased fetal body weight by 21% (Fig. 6A and B) and body length by 23% compared with wild-type littermates, changes associated with a doubling of β-cell mass (Fig. 6C and D) (online appendix Fig. 1A). Islet area was increased approximately twofold, which is associated with increased proliferation and decreased apoptosis (Table 1) without effect on β-cell size or density (not shown). Since pancreatic weight, acinar architecture, and α-cells were unaffected (not shown), increased E18.5 FASDEL insulin content (Table 1) appears to be due to increased β-cell mass. Increased phosphorylated Akt was present in E18.5 islets and whole fetus (especially brain) (Fig. 6E), suggesting that expanded β-cell mass in FASDEL fetuses is not due to insulin resistance. In support of this notion, glucose and free fatty acid levels were decreased, whereas insulin levels were increased in E18.5 fetuses (online appendix Table 3).


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)

β-Cells respond to intrauterine body size. A and B: Representative whole-mount sections of E18.5 fetuses from standard chow–fed dams stained with hematoxylin and eosin (A) and fetal body weights (B) (n = 12). WT, wild type. C: Representative pancreatic sections immunostained with anti-insulin antibody. The arrows depict insulin-positive areas within each islet surrounded by normal pancreatic acinar cells (×10 magnification). WT, wild type. D: β-Cell mass in E18.5 fetuses (n = 12). WT, wild type. E: Representative pancreatic sections double immunostained with antiphosphorylated Akt (red, panel 1) and anti-insulin (green, panel 2) and visualized using a dual red-green filter (merged, panel 3) at ×20 magnification. Arrows in panel 3 identify β-cells expressing phosphorylated Akt (yellow). Representative sections of cerebral hemispheres from E18.5 fetuses (panel 4) and whole-mount sections (panel 5) stained with phosphorylated Akt (brown staining). Arrow in panel 4 indicates phosphorylated Akt–positive areas. WT, wild type. F: Representative whole-mount sections of E18.5 fetuses from HFD-fed dams (HFD fed from day 0.5 to day 18.5) stained with hematoxylin and eosin. WT, wild type. G: Weights of fetuses from HFD-fed dams (top panel) and the percentage change in body weight compared with fetuses from standard chow–fed dams (bottom panel) (n = 10). WT, wild type. H: Representative pancreatic sections (×10 magnification) immunostained with anti-insulin antibody as in C. WT, wild type. I: β-Cell mass in E18.5 fetuses from HFD-fed dams (top panel) and the percentage change in β-cell mass compared with fetuses from standard chow–fed dams (bottom panel) (n = 10). WT, wild type. Results are means ± SE. *P < 0.05 vs. the corresponding wild type mice. (Please see http://dx.doi.org/10.2337/db08-0404 for a high-quality digital representation of this image.)
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f6: β-Cells respond to intrauterine body size. A and B: Representative whole-mount sections of E18.5 fetuses from standard chow–fed dams stained with hematoxylin and eosin (A) and fetal body weights (B) (n = 12). WT, wild type. C: Representative pancreatic sections immunostained with anti-insulin antibody. The arrows depict insulin-positive areas within each islet surrounded by normal pancreatic acinar cells (×10 magnification). WT, wild type. D: β-Cell mass in E18.5 fetuses (n = 12). WT, wild type. E: Representative pancreatic sections double immunostained with antiphosphorylated Akt (red, panel 1) and anti-insulin (green, panel 2) and visualized using a dual red-green filter (merged, panel 3) at ×20 magnification. Arrows in panel 3 identify β-cells expressing phosphorylated Akt (yellow). Representative sections of cerebral hemispheres from E18.5 fetuses (panel 4) and whole-mount sections (panel 5) stained with phosphorylated Akt (brown staining). Arrow in panel 4 indicates phosphorylated Akt–positive areas. WT, wild type. F: Representative whole-mount sections of E18.5 fetuses from HFD-fed dams (HFD fed from day 0.5 to day 18.5) stained with hematoxylin and eosin. WT, wild type. G: Weights of fetuses from HFD-fed dams (top panel) and the percentage change in body weight compared with fetuses from standard chow–fed dams (bottom panel) (n = 10). WT, wild type. H: Representative pancreatic sections (×10 magnification) immunostained with anti-insulin antibody as in C. WT, wild type. I: β-Cell mass in E18.5 fetuses from HFD-fed dams (top panel) and the percentage change in β-cell mass compared with fetuses from standard chow–fed dams (bottom panel) (n = 10). WT, wild type. Results are means ± SE. *P < 0.05 vs. the corresponding wild type mice. (Please see http://dx.doi.org/10.2337/db08-0404 for a high-quality digital representation of this image.)
Mentions: In >15 litters at E18.5 (when distinct islets appear) (31), FAS haploinsufficiency decreased fetal body weight by 21% (Fig. 6A and B) and body length by 23% compared with wild-type littermates, changes associated with a doubling of β-cell mass (Fig. 6C and D) (online appendix Fig. 1A). Islet area was increased approximately twofold, which is associated with increased proliferation and decreased apoptosis (Table 1) without effect on β-cell size or density (not shown). Since pancreatic weight, acinar architecture, and α-cells were unaffected (not shown), increased E18.5 FASDEL insulin content (Table 1) appears to be due to increased β-cell mass. Increased phosphorylated Akt was present in E18.5 islets and whole fetus (especially brain) (Fig. 6E), suggesting that expanded β-cell mass in FASDEL fetuses is not due to insulin resistance. In support of this notion, glucose and free fatty acid levels were decreased, whereas insulin levels were increased in E18.5 fetuses (online appendix Table 3).

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