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Palmitoylation couples insulin hypersecretion with β cell failure in diabetes
Guifang Dong1, Sangeeta Adak2, George Spyropoulos3
1Division of Endocrinology, Metabolism & Lipid Research, Washington University, St. Louis, MO 63110, USA; Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan 430023, China.
Cell Metabolism
|January 12, 2023
Summary
Acyl-protein thioesterase 1 (APT1) deficiency causes insulin hypersecretion and beta cell failure, modeling type 2 diabetes progression. Restoring APT1 function prevents these detrimental effects.
Area of Science:
- Endocrinology
- Molecular Biology
- Metabolic Diseases
Background:
- Hyperinsulinemia is an early sign of type 2 diabetes.
- Acyl-protein thioesterase 1 (APT1) regulates protein palmitoylation, a key process in cellular functions like exocytosis.
Purpose of the Study:
- To investigate the role of APT1 in insulin secretion and pancreatic beta cell function.
- To explore the link between APT1, palmitoylation, and the pathogenesis of type 2 diabetes.
Main Methods:
- Analysis of APT1 in human diabetic pancreatic islets.
- APT1 knockdown and knockout mouse models.
- Palmitoylation proteomics to identify APT1 substrates.
- Genetic manipulation of Scamp1 (an APT1 substrate).
Main Results:
- APT1 alterations were observed in human diabetic islets.
- APT1 deficiency in mice led to hyperinsulinemia, prolonged insulin granule fusion, and beta cell failure.
- Scamp1 was identified as an APT1 substrate involved in insulin secretion.
- Impaired Scamp1 palmitoylation mimicked APT1 deficiency effects.
Conclusions:
- APT1 plays a critical role in regulating insulin secretion and beta cell survival.
- APT1 deficiency contributes to hyperinsulinemia and beta cell failure, potentially modeling aspects of type 2 diabetes.
- Targeting APT1 or its substrates like Scamp1 may offer therapeutic avenues for type 2 diabetes.
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