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Deficiency of SCAMP5 Triggers Pancreatic β-Cell Secretory Dysfunction and Apoptosis
Yingqi Zhang1,2, Donglan Tang1, Chenxi Yang1
1Shenzhen University Diabetes Institute, Shenzhen Key Laboratory of Metabolism and Cardiovascular Homeostasis, Shenzhen University Medical School, Shenzhen, 518060, China.
Abstract:
The late stage of type 2 diabetes is characterized by secretory dysfunction and increased β-cell apoptosis, but the underlying mechanisms are not fully understood. The expression and function of secretory carrier membrane protein 5 (SCAMP5) in β-cells are unclear. The aim is to explore the role of SCAMP5 in diabetic β-cell failure. SCAMP5 expression is reduced in β-cells under diabetic conditions. Notably, SCAMP5 deficiency diminishes insulin secretion, which is involved in reduced CaV1.2 expression. Additionally, decreased SCAMP5 triggers β-cell apoptosis, suggesting the anti-apoptotic role of SCAMP5 in β-cells. Mechanistically, SCAMP5 downregulates the protein expression of voltage-dependent anion channel (VDAC1) and interacts with it, thereby repressing VDAC1-recruited Bax to mitochondria, thus inhibiting the release of cytochrome c from mitochondria to the cytoplasm, culminating in preventing β-cell apoptosis. Furthermore, hyperglycemia-activated carbohydrate-responsive element-binding protein (ChREBP) epigenetically represses SCAMP5 expression by reducing trimethylation of histone H3 at lysine 4 (H3K4me3) within the Scamp5 promoter. These findings highlight the essential role of the ChREBP-controlled SCAMP5 in β-cell insulin secretion and apoptosis, revealing a previously unrecognized mechanism underlying the β-cell failure in diabetes.
Insights
Secretory carrier membrane protein 5 (SCAMP5) is crucial for pancreatic beta-cell function in type 2 diabetes. Reduced SCAMP5 impairs insulin secretion and promotes beta-cell apoptosis, revealing a new therapeutic target.
Area of Science:
- Endocrinology
- Molecular Biology
- Cell Biology
Background:
- Late-stage type 2 diabetes involves beta-cell dysfunction and apoptosis.
- Mechanisms driving beta-cell failure remain incompletely understood.
- The role of secretory carrier membrane protein 5 (SCAMP5) in beta-cells is unclear.
Purpose of the Study:
- To investigate the function of SCAMP5 in pancreatic beta-cells.
- To determine the role of SCAMP5 in diabetic beta-cell failure.
- To elucidate the molecular mechanisms underlying SCAMP5's function in beta-cells.
Main Methods:
- Assessed SCAMP5 expression in diabetic conditions.
- Investigated the impact of SCAMP5 deficiency on insulin secretion and apoptosis.
- Examined SCAMP5's interaction with voltage-dependent anion channel 1 (VDAC1).
- Analyzed the epigenetic regulation of SCAMP5 by carbohydrate-responsive element-binding protein (ChREBP).
Main Results:
- SCAMP5 expression is reduced in diabetic beta-cells.
- SCAMP5 deficiency impairs insulin secretion via reduced CaV1.2 expression.
- SCAMP5 prevents beta-cell apoptosis by inhibiting VDAC1-mediated cytochrome c release.
- Hyperglycemia-induced ChREBP epigenetically represses SCAMP5 expression.
Conclusions:
- SCAMP5 plays a vital role in maintaining beta-cell function and survival.
- The ChREBP-SCAMP5 axis is a key pathway in diabetic beta-cell failure.
- Targeting SCAMP5 may offer a novel therapeutic strategy for type 2 diabetes.
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