Restoring glutamate receptor signaling in pancreatic alpha cells rescues glucagon responses in type 1 diabetes
| Autor: | Alejandro Tamayo, Julia K. Panzer, Alejandro Caicedo |
|---|---|
| Rok vydání: | 2022 |
| Předmět: |
Blood Glucose
medicine.medical_specialty Kainate receptor AMPA receptor Hypoglycemia Glucagon Alpha cell General Biochemistry Genetics and Molecular Biology Diabetes Mellitus Experimental Mice Internal medicine Medicine Animals Humans Insulin alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid business.industry Glutamate receptor Glucagon secretion medicine.disease Endocrinology Diabetes Mellitus Type 1 Receptors Glutamate Glucagon-Secreting Cells Cyclothiazide business medicine.drug |
| Zdroj: | Cell Reports. 41:111792 |
| ISSN: | 2211-1247 |
| DOI: | 10.1016/j.celrep.2022.111792 |
| Popis: | Glucagon secretion from pancreatic alpha cells is crucial to prevent hypoglycemia. For reasons still unknown, people with type 1 diabetes lose this glucoregulatory mechanism and are susceptible to dangerous hypoglycemia. Here we show that alpha cells in living pancreas slices from donors with type 1 diabetes failed to secrete glucagon in response to decreases in glucose concentration, thus mirroring the in vivo unresponsiveness to hypoglycemia. Glucagon content and responses to KCl depolarization were not affected, suggesting that alpha cells retained their secretory potential. By contrast, alpha cells had severely impaired signaling via glutamate receptors of the AMPA/kainate type. Under healthy conditions, activating these receptors was required to elicit full glucagon responses to decreases in glucose levels. In type 1 diabetes, reactivating residual glutamate receptor function with the positive allosteric modulators cyclothiazide and aniracetam restored glucagon secretion in response to hypoglycemia. These positive allosteric modulators are already approved to treat other conditions and could be repurposed to prevent hypoglycemia and improve management of diabetes. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
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