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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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Loss of survivin results in insulin-deficient diabetes. A: Mean (±SD) random glucose levels in littermate control (survivinlox/+ or survivinlox/lox) mice (○, n = 8 at each time point) and homozygous survivin-deficient (Pax6-Cre;survivinlox/lox) mice (▪, n = 8 at each time point) at various ages after birth. *Significance at P < 0.01. B: Glucose tolerance test (mean ± SD) in 6-week-old male littermates. Control (○, n = 7) and homozygous survivin-deficient (▪, n = 7) mice were fasted for 5 h then injected with dextrose (2 g/kg body wt) intraperitoneally. *Significance at P < 0.05. C: Insulin challenge test in 4-week-old littermates. Four-week-old control (○, n = 3) and homozygous survivin-deficient (▪, n = 4) mice were injected with 0.75 unit/kg insulin (fed state). No statistically significant differences were found at any time point. D: Random serum insulin levels measured by enzyme-linked immunosorbent assay in age-matched animals at the indicated times. ○, insulin levels in individual control animals (n = 16); ▴, levels in individual Pax-6Cre;survivinlox/lox animals (n = 12). See supplementary Table 1 for individual values.
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f2: Loss of survivin results in insulin-deficient diabetes. A: Mean (±SD) random glucose levels in littermate control (survivinlox/+ or survivinlox/lox) mice (○, n = 8 at each time point) and homozygous survivin-deficient (Pax6-Cre;survivinlox/lox) mice (▪, n = 8 at each time point) at various ages after birth. *Significance at P < 0.01. B: Glucose tolerance test (mean ± SD) in 6-week-old male littermates. Control (○, n = 7) and homozygous survivin-deficient (▪, n = 7) mice were fasted for 5 h then injected with dextrose (2 g/kg body wt) intraperitoneally. *Significance at P < 0.05. C: Insulin challenge test in 4-week-old littermates. Four-week-old control (○, n = 3) and homozygous survivin-deficient (▪, n = 4) mice were injected with 0.75 unit/kg insulin (fed state). No statistically significant differences were found at any time point. D: Random serum insulin levels measured by enzyme-linked immunosorbent assay in age-matched animals at the indicated times. ○, insulin levels in individual control animals (n = 16); ▴, levels in individual Pax-6Cre;survivinlox/lox animals (n = 12). See supplementary Table 1 for individual values.

Mentions: To determine the potential physiological effects of survivin loss within the endocrine cells after birth, we performed serial metabolic studies on mice lacking endocrine-survivin (Pax6-Cre;survivinlox/lox mice). During the first 3 weeks after birth, survivin-deficient animals had random glucose levels that were similar to their littermate controls with intact survivin genes (Fig. 2A). At 4 weeks of life, however, the Pax6-Cre;survivinlox/lox mice developed hyperglycemia (Fig. 2A) and a reduced glucose tolerance, as determined by injection with 2 g/kg dextrose after a 5-h fast (Fig. 2B), findings consistent with early-onset diabetes. The glucose abnormalities in these mice became more striking as the animals aged (Fig. 2A). At 4 weeks of age, Pax6-Cre;survivinlox/lox mice responded similarly to littermate control animals when treated with the same doses (0.75 unit/kg) of exogenous insulin (Fig. 2C), consistent with a primary lack of insulin availability as the cause of the hyperglycemia due to a loss of survivin. To further understand this process, we quantified the serum insulin of the mice over time. Survivin-deficient mice had very low to undetectable (below assay threshold) insulin levels from 3 to 13 weeks of life (Fig. 2D; supplementary Table 1), suggesting either a failure of insulin production or secretion. Mice with a one-allele loss of endocrine-survivin (Pax6-Cre;survivinlox/+ mice) had 12-h fasting glucose levels that were comparable with control animals at 4 and 5 weeks of age (supplementary Fig. 2A). At 17 weeks of age, however, these heterozygotes began to develop some signs of glucose intolerance, as shown by their higher serum glucose levels after dextrose administration (supplementary Fig. 2B).


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 survivin results in insulin-deficient diabetes. A: Mean (±SD) random glucose levels in littermate control (survivinlox/+ or survivinlox/lox) mice (○, n = 8 at each time point) and homozygous survivin-deficient (Pax6-Cre;survivinlox/lox) mice (▪, n = 8 at each time point) at various ages after birth. *Significance at P < 0.01. B: Glucose tolerance test (mean ± SD) in 6-week-old male littermates. Control (○, n = 7) and homozygous survivin-deficient (▪, n = 7) mice were fasted for 5 h then injected with dextrose (2 g/kg body wt) intraperitoneally. *Significance at P < 0.05. C: Insulin challenge test in 4-week-old littermates. Four-week-old control (○, n = 3) and homozygous survivin-deficient (▪, n = 4) mice were injected with 0.75 unit/kg insulin (fed state). No statistically significant differences were found at any time point. D: Random serum insulin levels measured by enzyme-linked immunosorbent assay in age-matched animals at the indicated times. ○, insulin levels in individual control animals (n = 16); ▴, levels in individual Pax-6Cre;survivinlox/lox animals (n = 12). See supplementary Table 1 for individual values.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2551682&req=5

f2: Loss of survivin results in insulin-deficient diabetes. A: Mean (±SD) random glucose levels in littermate control (survivinlox/+ or survivinlox/lox) mice (○, n = 8 at each time point) and homozygous survivin-deficient (Pax6-Cre;survivinlox/lox) mice (▪, n = 8 at each time point) at various ages after birth. *Significance at P < 0.01. B: Glucose tolerance test (mean ± SD) in 6-week-old male littermates. Control (○, n = 7) and homozygous survivin-deficient (▪, n = 7) mice were fasted for 5 h then injected with dextrose (2 g/kg body wt) intraperitoneally. *Significance at P < 0.05. C: Insulin challenge test in 4-week-old littermates. Four-week-old control (○, n = 3) and homozygous survivin-deficient (▪, n = 4) mice were injected with 0.75 unit/kg insulin (fed state). No statistically significant differences were found at any time point. D: Random serum insulin levels measured by enzyme-linked immunosorbent assay in age-matched animals at the indicated times. ○, insulin levels in individual control animals (n = 16); ▴, levels in individual Pax-6Cre;survivinlox/lox animals (n = 12). See supplementary Table 1 for individual values.
Mentions: To determine the potential physiological effects of survivin loss within the endocrine cells after birth, we performed serial metabolic studies on mice lacking endocrine-survivin (Pax6-Cre;survivinlox/lox mice). During the first 3 weeks after birth, survivin-deficient animals had random glucose levels that were similar to their littermate controls with intact survivin genes (Fig. 2A). At 4 weeks of life, however, the Pax6-Cre;survivinlox/lox mice developed hyperglycemia (Fig. 2A) and a reduced glucose tolerance, as determined by injection with 2 g/kg dextrose after a 5-h fast (Fig. 2B), findings consistent with early-onset diabetes. The glucose abnormalities in these mice became more striking as the animals aged (Fig. 2A). At 4 weeks of age, Pax6-Cre;survivinlox/lox mice responded similarly to littermate control animals when treated with the same doses (0.75 unit/kg) of exogenous insulin (Fig. 2C), consistent with a primary lack of insulin availability as the cause of the hyperglycemia due to a loss of survivin. To further understand this process, we quantified the serum insulin of the mice over time. Survivin-deficient mice had very low to undetectable (below assay threshold) insulin levels from 3 to 13 weeks of life (Fig. 2D; supplementary Table 1), suggesting either a failure of insulin production or secretion. Mice with a one-allele loss of endocrine-survivin (Pax6-Cre;survivinlox/+ mice) had 12-h fasting glucose levels that were comparable with control animals at 4 and 5 weeks of age (supplementary Fig. 2A). At 17 weeks of age, however, these heterozygotes began to develop some signs of glucose intolerance, as shown by their higher serum glucose levels after dextrose administration (supplementary Fig. 2B).

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