PUBLICATION
Ppid is Necessary for Overnutrition-Induced β-cell Loss
- Authors
- Covington, B.A., Tang, Z., Maddison, L.A., Yang, B., Chen, W.
- ID
- ZDB-PUB-251216-2
- Date
- 2025
- Source
- American journal of physiology. Endocrinology and metabolism 330: E152-E160 (Journal)
- Registered Authors
- Chen, Wenbiao
- Keywords
- PPID, Zebrafish, beta cell death, diabetes, inflammation
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Cell Death/drug effects
- Cell Death/genetics
- Cyclophilins*/antagonists & inhibitors
- Cyclophilins*/genetics
- Cyclophilins*/metabolism
- Cyclosporine/pharmacology
- Insulin Resistance
- Insulin-Secreting Cells*/drug effects
- Insulin-Secreting Cells*/metabolism
- Insulin-Secreting Cells*/pathology
- Mitochondria/metabolism
- Mitochondrial Membrane Transport Proteins/metabolism
- Mitochondrial Permeability Transition Pore
- Overnutrition*/complications
- Overnutrition*/metabolism
- Overnutrition*/pathology
- Peptidyl-Prolyl Isomerase F*/genetics
- Peptidyl-Prolyl Isomerase F*/metabolism
- Reactive Oxygen Species/metabolism
- Zebrafish
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- PubMed
- 41397247 Full text @ Am. J. Physiol. Endocrinol. Metab.
Citation
Covington, B.A., Tang, Z., Maddison, L.A., Yang, B., Chen, W. (2025) Ppid is Necessary for Overnutrition-Induced β-cell Loss. American journal of physiology. Endocrinology and metabolism. 330:E152-E160.
Abstract
Type 2 diabetes (T2D) involves progressive loss of functional β-cell mass. In a zebrafish insulin-resistant model (zMIR), overnutrition triggers islet inflammation and nocturnal β-cell death. The cell death is prevented by the cyclophilin D (Ppid) inhibitor, cyclosporin A (CsA). Reducing mitochondrial ROS with mito-TEMPO or mitochondrial calcium with Ru360 protects β cells, further implicating the mitochondrial permeability transition pore (mPTP) in β-cell loss. The timing of β-cell death coincides with lower mitochondrial antioxidant gene expression, indicating diurnal mitochondrial vulnerability. Global ppid-/- preserves β-cell mass without altering islet inflammation or macrophage recruitment. Conversely, β-cell-specific PPID re-expression restores-and exacerbates-β-cell loss, which remains CsA-sensitive. These findings identify Ppid as a β-cell-intrinsic mediator of overnutrition-induced β-cell loss.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping