Gs/Gq signaling switch in β cells defines incretin effectiveness in diabetes
| Autor: | Quan Zhang, Johan Tolö, Yuko Maejima, Kenju Shimomura, Naoya Murao, Lakshmi Kothegala, Patrik Rorsman, Claudia Guida, Okechi S. Oduori, Norihide Yokoi, Yasuhiro Minami, Shihomi Sakai, Takashi Miki, Belén Chanclón, Kohtaro Minami, Harumi Takahashi, Haiqiang Dou, Susumu Seino |
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| Rok vydání: | 2020 |
| Předmět: |
Blood Glucose
0301 basic medicine medicine.medical_specialty endocrine system medicine.medical_treatment Cell Incretin Stimulation Gastric Inhibitory Polypeptide Incretins Diabetes Mellitus Experimental 03 medical and health sciences Mice 0302 clinical medicine Glucagon-Like Peptide 1 Diabetes mellitus Internal medicine Insulin-Secreting Cells Insulin Secretion medicine Chromogranins GTP-Binding Protein alpha Subunits Gs Animals Humans Insulin Potassium Channels Inwardly Rectifying G protein-coupled receptor Mice Knockout Chemistry Pancreatic islets Depolarization General Medicine medicine.disease 030104 developmental biology medicine.anatomical_structure Endocrinology Diabetes Mellitus Type 2 030220 oncology & carcinogenesis Commentary GTP-Binding Protein alpha Subunits Gq-G11 hormones hormone substitutes and hormone antagonists Research Article Signal Transduction |
| Zdroj: | J Clin Invest |
| ISSN: | 1558-8238 |
| Popis: | By restoring glucose-regulated insulin secretion, glucagon-like peptide-1–based (GLP-1–based) therapies are becoming increasingly important in diabetes care. Normally, the incretins GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) jointly maintain normal blood glucose levels by stimulation of insulin secretion in pancreatic β cells. However, the reason why only GLP-1–based drugs are effective in improving insulin secretion after presentation of diabetes has not been resolved. ATP-sensitive K(+) (K(ATP)) channels play a crucial role in coupling the systemic metabolic status to β cell electrical activity for insulin secretion. Here, we have shown that persistent membrane depolarization of β cells due to genetic (β cell–specific Kcnj11(–/–) mice) or pharmacological (long-term exposure to sulfonylureas) inhibition of the K(ATP) channel led to a switch from Gs to Gq in a major amplifying pathway of insulin secretion. The switch determined the relative insulinotropic effectiveness of GLP-1 and GIP, as GLP-1 can activate both Gq and Gs, while GIP only activates Gs. The findings were corroborated in other models of persistent depolarization: a spontaneous diabetic KK-Ay mouse and nondiabetic human and mouse β cells of pancreatic islets chronically treated with high glucose. Thus, a Gs/Gq signaling switch in β cells exposed to chronic hyperglycemia underlies the differential insulinotropic potential of incretins in diabetes. |
| Databáze: | OpenAIRE |
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