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Postnatal expansion of the pancreatic beta-cell mass is dependent on survivin.

Jiang Y, Nishimura W, Devor-Henneman D, Kusewitt D, Wang H, Holloway MP, Dohi T, Sabo E, Robinson ML, Altieri DC, Sharma A, Altura RA - Diabetes (2008)

Bottom Line: Selective deletion of survivin in pancreatic endocrine cells in the mouse had no discernible effects during embryogenesis but was associated with striking decreases in beta-cell number after birth, leading to hyperglycemia and early-onset diabetes by 4 weeks of age.Serum insulin levels were significantly decreased in animals lacking endocrine cell survivin, with relative stability of other hormones.Exogenous expression of survivin in mature beta-cells lacking endogenous survivin completely rescued the hyperglycemic phenotype and the decrease in beta-cell mass, confirming the specificity of the survivin effect in these cells.

View Article: PubMed Central - PubMed

Affiliation: The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.

ABSTRACT

Objective: Diabetes results from a deficiency of functional beta-cells due to both an increase in beta-cell death and an inhibition of beta-cell replication. The molecular mechanisms responsible for these effects in susceptible individuals are mostly unknown. The objective of this study was to determine whether a gene critical for cell division and cell survival in cancer cells, survivin, might also be important for beta-cells.

Research design and methods: We generated mice harboring a conditional deletion of survivin in pancreatic endocrine cells using mice with a Pax-6-Cre transgene promoter construct driving tissue-specific expression of Cre-recombinase in these cells. We performed metabolic studies and immunohistochemical analyses to determine the effects of a mono- and biallelic deletion of survivin.

Results: Selective deletion of survivin in pancreatic endocrine cells in the mouse had no discernible effects during embryogenesis but was associated with striking decreases in beta-cell number after birth, leading to hyperglycemia and early-onset diabetes by 4 weeks of age. Serum insulin levels were significantly decreased in animals lacking endocrine cell survivin, with relative stability of other hormones. Exogenous expression of survivin in mature beta-cells lacking endogenous survivin completely rescued the hyperglycemic phenotype and the decrease in beta-cell mass, confirming the specificity of the survivin effect in these cells.

Conclusions: Our findings implicate survivin in the maintenance of beta-cell mass through both replication and antiapoptotic mechanisms. Given the widespread involvement of survivin in cancer, a novel role for survivin may well be exploited in beta-cell regulation in diseased states, such as diabetes.

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Related in: MedlinePlus

Loss of insulin-producing cells in survivin-deficient animals. A: Insulin, glucagon, and somatostatin expression in 3- and 12-week-old animals, shown by immunochemical staining of pancreatic sections isolated from control mice and Pax-6Cre;survivinlox/lox littermates. Bars = 40 μm. B: Mean (±SD) serum glucagon levels measured by immunoassay in age-matched animals at the indicated times. ▪, control mice (n = 21); □, Pax-6-Cre;survivinlox/lox mice (n = 25). (Please see http://dx.doi.org/10.2337/db08-0170 for a high-quality digital representation of this image.)
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f3: Loss of insulin-producing cells in survivin-deficient animals. A: Insulin, glucagon, and somatostatin expression in 3- and 12-week-old animals, shown by immunochemical staining of pancreatic sections isolated from control mice and Pax-6Cre;survivinlox/lox littermates. Bars = 40 μm. B: Mean (±SD) serum glucagon levels measured by immunoassay in age-matched animals at the indicated times. ▪, control mice (n = 21); □, Pax-6-Cre;survivinlox/lox mice (n = 25). (Please see http://dx.doi.org/10.2337/db08-0170 for a high-quality digital representation of this image.)

Mentions: To determine the cause of the metabolic abnormalities resulting from the low serum insulin levels, we examined pancreatic sections from the mice for pathological abnormalities over time. The onset of hyperglycemia in mice lacking survivin within endocrine cells was associated with a significant decrease in the number of insulin-producing cells after 4 weeks of age as measured by immunohistochemical staining for insulin (Fig. 3A) and by islet mass (Fig. 4A), suggesting that there was a lack of insulin production due to an inappropriate decrease in β-cell number. By contrast, a decrease in the number or function of α- and δ-cells, as determined by immunohistochemical staining for glucagon and somatostatin (Fig. 3A) and by measuring serum glucagon levels (Fig. 3B), was not observed during the early postnatal period. The findings of hyperglycemia, insulin deficiency, and a lack of insulin-producing β-cells in the face of a relative preservation of α- and δ-cells suggest that survivin plays an essential role in the regulation of β-cell number early after birth, preferentially affecting these cells over other endocrine subtypes. Given the known mechanisms of survivin function in cancer cells, both as an inhibitor of apoptosis and a regulator of cell division, survivin could have either one or both functions in pancreatic β-cells.


Postnatal expansion of the pancreatic beta-cell mass is dependent on survivin.

Jiang Y, Nishimura W, Devor-Henneman D, Kusewitt D, Wang H, Holloway MP, Dohi T, Sabo E, Robinson ML, Altieri DC, Sharma A, Altura RA - Diabetes (2008)

Loss of insulin-producing cells in survivin-deficient animals. A: Insulin, glucagon, and somatostatin expression in 3- and 12-week-old animals, shown by immunochemical staining of pancreatic sections isolated from control mice and Pax-6Cre;survivinlox/lox littermates. Bars = 40 μm. B: Mean (±SD) serum glucagon levels measured by immunoassay in age-matched animals at the indicated times. ▪, control mice (n = 21); □, Pax-6-Cre;survivinlox/lox mice (n = 25). (Please see http://dx.doi.org/10.2337/db08-0170 for a high-quality digital representation of this image.)
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2551682&req=5

f3: Loss of insulin-producing cells in survivin-deficient animals. A: Insulin, glucagon, and somatostatin expression in 3- and 12-week-old animals, shown by immunochemical staining of pancreatic sections isolated from control mice and Pax-6Cre;survivinlox/lox littermates. Bars = 40 μm. B: Mean (±SD) serum glucagon levels measured by immunoassay in age-matched animals at the indicated times. ▪, control mice (n = 21); □, Pax-6-Cre;survivinlox/lox mice (n = 25). (Please see http://dx.doi.org/10.2337/db08-0170 for a high-quality digital representation of this image.)
Mentions: To determine the cause of the metabolic abnormalities resulting from the low serum insulin levels, we examined pancreatic sections from the mice for pathological abnormalities over time. The onset of hyperglycemia in mice lacking survivin within endocrine cells was associated with a significant decrease in the number of insulin-producing cells after 4 weeks of age as measured by immunohistochemical staining for insulin (Fig. 3A) and by islet mass (Fig. 4A), suggesting that there was a lack of insulin production due to an inappropriate decrease in β-cell number. By contrast, a decrease in the number or function of α- and δ-cells, as determined by immunohistochemical staining for glucagon and somatostatin (Fig. 3A) and by measuring serum glucagon levels (Fig. 3B), was not observed during the early postnatal period. The findings of hyperglycemia, insulin deficiency, and a lack of insulin-producing β-cells in the face of a relative preservation of α- and δ-cells suggest that survivin plays an essential role in the regulation of β-cell number early after birth, preferentially affecting these cells over other endocrine subtypes. Given the known mechanisms of survivin function in cancer cells, both as an inhibitor of apoptosis and a regulator of cell division, survivin could have either one or both functions in pancreatic β-cells.

Bottom Line: Selective deletion of survivin in pancreatic endocrine cells in the mouse had no discernible effects during embryogenesis but was associated with striking decreases in beta-cell number after birth, leading to hyperglycemia and early-onset diabetes by 4 weeks of age.Serum insulin levels were significantly decreased in animals lacking endocrine cell survivin, with relative stability of other hormones.Exogenous expression of survivin in mature beta-cells lacking endogenous survivin completely rescued the hyperglycemic phenotype and the decrease in beta-cell mass, confirming the specificity of the survivin effect in these cells.

View Article: PubMed Central - PubMed

Affiliation: The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.

ABSTRACT

Objective: Diabetes results from a deficiency of functional beta-cells due to both an increase in beta-cell death and an inhibition of beta-cell replication. The molecular mechanisms responsible for these effects in susceptible individuals are mostly unknown. The objective of this study was to determine whether a gene critical for cell division and cell survival in cancer cells, survivin, might also be important for beta-cells.

Research design and methods: We generated mice harboring a conditional deletion of survivin in pancreatic endocrine cells using mice with a Pax-6-Cre transgene promoter construct driving tissue-specific expression of Cre-recombinase in these cells. We performed metabolic studies and immunohistochemical analyses to determine the effects of a mono- and biallelic deletion of survivin.

Results: Selective deletion of survivin in pancreatic endocrine cells in the mouse had no discernible effects during embryogenesis but was associated with striking decreases in beta-cell number after birth, leading to hyperglycemia and early-onset diabetes by 4 weeks of age. Serum insulin levels were significantly decreased in animals lacking endocrine cell survivin, with relative stability of other hormones. Exogenous expression of survivin in mature beta-cells lacking endogenous survivin completely rescued the hyperglycemic phenotype and the decrease in beta-cell mass, confirming the specificity of the survivin effect in these cells.

Conclusions: Our findings implicate survivin in the maintenance of beta-cell mass through both replication and antiapoptotic mechanisms. Given the widespread involvement of survivin in cancer, a novel role for survivin may well be exploited in beta-cell regulation in diseased states, such as diabetes.

Show MeSH
Related in: MedlinePlus