Role of Autophagy in the Pathogenesis of Diabetes and Therapeutic Potential of Autophagy Modulators in the Treatment of Diabetes and Metabolic Syndrome.
Soo-Jin OhMyung-Shik LeePublished in: Journal of Korean medical science (2022)
Autophagy is critically involved in the maintenance of intracellular nutrient homeostasis and organelle function. Dysregulated autophagy is likely to play a role in the development of metabolic disorders and diabetes because autophagy is critical in the rejuvenation of dysfunctional or stressed endoplasmic reticulum and mitochondria that play a crucial role in the development of diabetes. Indeed, systemic autophagy insufficiency led to the increased tissue lipid content, aggravated metabolic and finally more severe diabetes when metabolic stress was imposed, suggesting that autophagy insufficiency of dysfunction of lysosome, an effector organelle of autophagy, due to aging, genetic predisposition or environmental factors could be an underlying cause of diabetes. Conversely, autophagy enhancer could improve metabolic profile of obese mice by reducing tissue lipid content and ameliorating metabolic inflammation. Furthermore, clearance of human islet amyloid polypeptide (hIAPP) oligomer and amyloid that accumulate in pancreatic islets of > 90% of diabetes patients was also dependent on autophagy. Consistently, autophagy enhancer could improve glucose profile and β-cell function of transgenic mice expressing amyloidogenic hIAPP in pancreatic β-cells, which was accompanied by reduced accumulation of hIAPP oligomer or amyloid, ameliorated β-cell apoptosis and increased β-cell mass. These results suggest that autophagy enhancer could be a novel therapeutic modality against diabetes associated with lipid overload and human diabetes characterized by islet amyloid accumulation.
Keyphrases
- cell death
- endoplasmic reticulum stress
- oxidative stress
- type diabetes
- signaling pathway
- cardiovascular disease
- glycemic control
- induced apoptosis
- metabolic syndrome
- cell cycle arrest
- end stage renal disease
- endoplasmic reticulum
- chronic kidney disease
- stem cells
- small molecule
- dendritic cells
- bone marrow
- mesenchymal stem cells
- blood pressure
- pi k akt
- cell therapy
- dna methylation
- combination therapy
- genome wide
- single molecule