289-OR: Autophagy Promotes Islet α-Cell Function by Maintaining ER Proteostasis and Glucagon Production

Introduction & Objective: Islet α cells have traditionally been maligned for contributing to hyperglycemia in diabetes but are increasingly recognized for their potential to promote β cell mass and function. The cellular mechanisms regulating proglucagon production and its subsequent processing into glucagon and/or glucagon-like peptide 1 (GLP-1) in α cells are incompletely understood. Autophagy, the process of recycling cellular components by lysosomal degradation, is essential for insulin production and β cell survival.

Methods: To investigate the role of autophagy in α cells, we deleted the key autophagosome protein Atg7 using the Cre-lox system in mice or CRISPR in αTC cells.

Results: Atg7 ^ΔGcg mice showed normal growth and oral glucose tolerance into adulthood but had impaired glucagon secretion following hypoglycemia by two months of age. Islet α cells in Atg7 ^ΔGcg mice became hypertrophic and vacuolated with age, but survived without a substantial decline in mass. Instead, pancreatic glucagon content was reduced in Atg7 ^ΔGcg mice (42.2 +/- 7.3 vs. 75.3 +/- 9.1 ng/g). Electron microscopy revealed α cells with fewer glucagon granules and dilated endoplasmic reticulum (ER), and increased expression of the ER chaperone BiP was confirmed in αTC^ΔAtg7 cells. This was associated with a decrease in the proglucagon processing hormone PC2, possibly limiting production of mature glucagon. Interestingly, total pancreatic GLP-1 content was increased in Atg7 ^ΔGcg mice (1351 +/- 114 vs. 891 +/- 75 pg/g) without changes in serum GLP-1 levels. Using the GLP-1 receptor antagonist exendin(9-39), we observed a similar impairment in oral glucose tolerance in Atg7 ^ΔGcg mice and littermate controls.

Conclusion: These data show that autophagy promotes classic α cell function by maintaining ER proteostasis and glucagon production. However, defective α cell autophagy does not entirely disrupt proglucagon-mediated signaling in vivo and may promote α cell GLP-1 production.