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Forkhead Box Protein 1 (FoxO1) Inhibits Accelerated β Cell Aging in Pancreas-specific SMAD7 Mutant Mice
Xiangwei Xiao1, Congde Chen2, Ping Guo3
1Divisions of Pediatric Surgery.
Abstract:
The mechanisms underlying the effects of exocrine dysfunction on the development of diabetes remain largely unknown. Here we show that pancreatic depletion of SMAD7 resulted in age-dependent increases in β cell dysfunction with accelerated glucose intolerance, followed by overt diabetes. The accelerated β cell dysfunction and loss of proliferation capacity, two features of β cell aging, appeared to be non-cell-autonomous, secondary to the adjacent exocrine failure as a "bystander effect." Increased Forkhead box protein 1 (FoxO1) acetylation and nuclear retention was followed by progressive FoxO1 loss in β cells that marked the onset of diabetes. Moreover, forced FoxO1 expression in β cells prevented β cell dysfunction and loss in this model. Thus, we present a model of accelerated β cell aging that may be useful for studying the mechanisms underlying β cell failure in diabetes. Moreover, we provide evidence highlighting a critical role of FoxO1 in maintaining β cell identity in the context of SMAD7 failure.
Insights
Pancreatic SMAD7 depletion causes exocrine failure, leading to bystander beta cell aging and diabetes. Restoring Forkhead box protein 1 (FoxO1) prevents this dysfunction, highlighting its role in maintaining beta cell identity.
Area of Science:
- Endocrinology
- Cell Biology
- Metabolic Diseases
Background:
- The link between exocrine dysfunction and diabetes development is poorly understood.
- Beta cell aging contributes to glucose intolerance and diabetes.
Purpose of the Study:
- To investigate the impact of SMAD7 depletion on pancreatic beta cells and diabetes development.
- To elucidate the role of Forkhead box protein 1 (FoxO1) in beta cell dysfunction secondary to exocrine failure.
Main Methods:
- Induction of pancreatic SMAD7 depletion in a mouse model.
- Assessment of beta cell function, proliferation, and aging markers.
- Analysis of FoxO1 acetylation, nuclear retention, and expression levels in beta cells.
Main Results:
- SMAD7 depletion led to age-dependent beta cell dysfunction, impaired glucose tolerance, and overt diabetes.
- Beta cell aging and loss of proliferation were non-cell-autonomous, resulting from adjacent exocrine failure (bystander effect).
- Increased FoxO1 acetylation and subsequent loss in beta cells preceded diabetes onset; forced FoxO1 expression protected beta cells.
Conclusions:
- Pancreatic exocrine failure can accelerate beta cell aging and lead to diabetes through a bystander effect.
- FoxO1 plays a critical role in maintaining beta cell identity and function, particularly under conditions of SMAD7 deficiency.
- This study presents a novel model for investigating accelerated beta cell aging and diabetes mechanisms.
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