Misrouting of Glucagon and Stathmin-2 Towards Lysosomal System of α-Cells in Glucagon Hypersecretion of Diabetes
| Autor: | Asadi F, Dhanvantari S |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
endocrine system
0303 health sciences medicine.medical_specialty Chemistry Glucagon secretion 030209 endocrinology & metabolism Streptozotocin medicine.disease Glucagon 03 medical and health sciences 0302 clinical medicine medicine.anatomical_structure Endocrinology Lysosome Internal medicine Diabetes mellitus medicine Secretion hormones hormone substitutes and hormone antagonists Late endosome 030304 developmental biology Hyperglucagonemia medicine.drug |
| Popis: | Glucagon hypersecretion from the pancreatic α-cell is a characteristic sign of diabetes, which exacerbates fasting hyperglycemia. Thus, targeting glucagon secretion from α-cells may be a promising approach for combating hyperglucagonemia. We have recently identified stathmin-2 as a protein that resides in α-cell secretory granules, and showed that it regulates glucagon secretion by directing glucagon towards the endolysosomal system in αTC1-6 cells. Here, we hypothesized that disruption of Stmn2-mediated trafficking of glucagon to the endolysosomes contributes to hyperglucagonemia. In isolated islets from male mice treated with streptozotocin (STZ) to induce diabetes, Arg-stimulated secretion of glucagon and Stmn2 was augmented. However, cell glucagon content was significantly increased (pGcg mRNA increased ~4.5 times, while Stmn2 mRNA levels did not change. Using confocal immunofluorescence microscopy, the colocalization of glucagon and Stmn2 in Lamp2A+ lysosomes was dramatically reduced (p+-induced glucagon secretion, suggesting that high glucose may induce glucagon secretion from another lysosomal compartment. Both glucagon and Stmn2 co-localized with Lamp1, which marks secretory lysosomes, in cells cultured in high glucose. We propose that, in addition to enhanced trafficking and secretion through the regulated secretory pathway, the hyperglucagonemia of diabetes may also be due to re-routing of glucagon from the degradative Lamp2A+ lysosome towards the secretory Lamp1+lysosome. |
| Databáze: | OpenAIRE |
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