Postnatal expansion of the pancreatic beta-cell mass is dependent on survivin
Yuying Jiang1, Wataru Nishimura, Deborah Devor-Henneman
1The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
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.
Insights
Survivin is crucial for maintaining beta-cell mass and function. Its deletion in mice causes diabetes, highlighting its potential role in diabetes treatment.
Area of Science:
- Endocrinology
- Molecular Biology
- Genetics
Background:
- Diabetes mellitus stems from insufficient functional beta-cells, caused by increased cell death and reduced replication.
- The precise molecular triggers for these beta-cell defects in susceptible individuals remain largely unidentified.
Purpose of the Study:
- To investigate the role of survivin, a gene vital for cell division and survival in cancer, in the regulation of beta-cell mass and function.
Main Methods:
- Generation of mice with a conditional deletion of survivin in pancreatic endocrine cells using a Pax-6-Cre transgene.
- Metabolic studies and immunohistochemical analyses to assess the impact of survivin deletion.
Main Results:
- Deletion of survivin in pancreatic endocrine cells led to decreased beta-cell numbers, hyperglycemia, and early-onset diabetes in mice.
- Reduced serum insulin levels were observed, while other hormone levels remained stable.
- Restoring survivin expression in beta-cells reversed the diabetic phenotype and restored beta-cell mass.
Conclusions:
- Survivin plays a critical role in maintaining beta-cell mass through promoting cell replication and preventing apoptosis.
- Survivin's function in beta-cells suggests a potential therapeutic target for diabetes and other related diseases.
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