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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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FASDEL mice are not insulin resistant. A and B: Insulin tolerance tests. Blood glucose concentration before and after intraperitoneal injection of insulin in standard chow–and HFD-fed mice (n = 6). ▵ and ○, wild type (WT); ▴ and •, FASDEL. C: Representative hematoxylin and eosin–stained histologic sections (× 20 magnification) of white adipose tissue from gonadal fat pads of 3- and 12-month-old male mice after 10 weeks of HFD feeding. WT, wild type. D: The distribution curve of diameter of 300 fat cells per mouse shows a preponderance of small-sized (20- to 40-μm) adipocytes (arrows) in the FASDEL mice compared with controls (n = 5). □, wild type (WT); ▪, FASDEL. E and F: Western blotting for phosphorylated and total Akt and total IRS-2 proteins in liver and skeletal muscles obtained from wild-type (W) and FASDEL (D) mice (top panel) in the fed state and the densitometric analysis of such blots from four mice per group (bottom panel). Data represent means ± SE. *P < 0.05 vs. the corresponding wild-type mice. **P < 0.05. (Please see http://dx.doi.org/10.2337/db08-0404 for a high-quality digital representation of this image.)
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f5: FASDEL mice are not insulin resistant. A and B: Insulin tolerance tests. Blood glucose concentration before and after intraperitoneal injection of insulin in standard chow–and HFD-fed mice (n = 6). ▵ and ○, wild type (WT); ▴ and •, FASDEL. C: Representative hematoxylin and eosin–stained histologic sections (× 20 magnification) of white adipose tissue from gonadal fat pads of 3- and 12-month-old male mice after 10 weeks of HFD feeding. WT, wild type. D: The distribution curve of diameter of 300 fat cells per mouse shows a preponderance of small-sized (20- to 40-μm) adipocytes (arrows) in the FASDEL mice compared with controls (n = 5). □, wild type (WT); ▪, FASDEL. E and F: Western blotting for phosphorylated and total Akt and total IRS-2 proteins in liver and skeletal muscles obtained from wild-type (W) and FASDEL (D) mice (top panel) in the fed state and the densitometric analysis of such blots from four mice per group (bottom panel). Data represent means ± SE. *P < 0.05 vs. the corresponding wild-type mice. **P < 0.05. (Please see http://dx.doi.org/10.2337/db08-0404 for a high-quality digital representation of this image.)

Mentions: FASDEL mice were more insulin sensitive than their control littermates at 2 weeks of age (not shown) and at 3 months on both standard chow and HFD (Fig. 5A). This effect was not detected at 12 months (Fig. 5B). Adipocyte size, reciprocally related to insulin sensitivity, was decreased in HFD-fed FASDEL mice (Fig. 5C and D) and on standard chow diet (not shown), suggesting that FASDEL mice are not insulin resistant. Phosphorylated Akt in liver and muscle (Fig. 5E) and IRS-2 protein (Fig. 5F) in liver were increased in young FASDEL compared with wild-type mice. These molecules were decreased in 12-month-old FASDEL mice (Fig. 5E and F), reflecting their hypoinsulinemia.


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)

FASDEL mice are not insulin resistant. A and B: Insulin tolerance tests. Blood glucose concentration before and after intraperitoneal injection of insulin in standard chow–and HFD-fed mice (n = 6). ▵ and ○, wild type (WT); ▴ and •, FASDEL. C: Representative hematoxylin and eosin–stained histologic sections (× 20 magnification) of white adipose tissue from gonadal fat pads of 3- and 12-month-old male mice after 10 weeks of HFD feeding. WT, wild type. D: The distribution curve of diameter of 300 fat cells per mouse shows a preponderance of small-sized (20- to 40-μm) adipocytes (arrows) in the FASDEL mice compared with controls (n = 5). □, wild type (WT); ▪, FASDEL. E and F: Western blotting for phosphorylated and total Akt and total IRS-2 proteins in liver and skeletal muscles obtained from wild-type (W) and FASDEL (D) mice (top panel) in the fed state and the densitometric analysis of such blots from four mice per group (bottom panel). Data represent means ± SE. *P < 0.05 vs. the corresponding wild-type mice. **P < 0.05. (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

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

f5: FASDEL mice are not insulin resistant. A and B: Insulin tolerance tests. Blood glucose concentration before and after intraperitoneal injection of insulin in standard chow–and HFD-fed mice (n = 6). ▵ and ○, wild type (WT); ▴ and •, FASDEL. C: Representative hematoxylin and eosin–stained histologic sections (× 20 magnification) of white adipose tissue from gonadal fat pads of 3- and 12-month-old male mice after 10 weeks of HFD feeding. WT, wild type. D: The distribution curve of diameter of 300 fat cells per mouse shows a preponderance of small-sized (20- to 40-μm) adipocytes (arrows) in the FASDEL mice compared with controls (n = 5). □, wild type (WT); ▪, FASDEL. E and F: Western blotting for phosphorylated and total Akt and total IRS-2 proteins in liver and skeletal muscles obtained from wild-type (W) and FASDEL (D) mice (top panel) in the fed state and the densitometric analysis of such blots from four mice per group (bottom panel). Data represent means ± SE. *P < 0.05 vs. the corresponding wild-type mice. **P < 0.05. (Please see http://dx.doi.org/10.2337/db08-0404 for a high-quality digital representation of this image.)
Mentions: FASDEL mice were more insulin sensitive than their control littermates at 2 weeks of age (not shown) and at 3 months on both standard chow and HFD (Fig. 5A). This effect was not detected at 12 months (Fig. 5B). Adipocyte size, reciprocally related to insulin sensitivity, was decreased in HFD-fed FASDEL mice (Fig. 5C and D) and on standard chow diet (not shown), suggesting that FASDEL mice are not insulin resistant. Phosphorylated Akt in liver and muscle (Fig. 5E) and IRS-2 protein (Fig. 5F) in liver were increased in young FASDEL compared with wild-type mice. These molecules were decreased in 12-month-old FASDEL mice (Fig. 5E and F), reflecting their hypoinsulinemia.

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