Gs/Gq signaling switch in ß cells defines incretin effectiveness in diabetes.
J Clin Invest
; 130(12): 6639-6655, 2020 12 01.
Article
em En
| MEDLINE
| ID: mdl-33196462
ABSTRACT
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 ß 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+ (KATP) channels play a crucial role in coupling the systemic metabolic status to ß cell electrical activity for insulin secretion. Here, we have shown that persistent membrane depolarization of ß cells due to genetic (ß cell-specific Kcnj11-/- mice) or pharmacological (long-term exposure to sulfonylureas) inhibition of the KATP 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 ß cells of pancreatic islets chronically treated with high glucose. Thus, a Gs/Gq signaling switch in ß cells exposed to chronic hyperglycemia underlies the differential insulinotropic potential of incretins in diabetes.
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MEDLINE
Assunto principal:
Transdução de Sinais
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Cromograninas
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Subunidades alfa Gs de Proteínas de Ligação ao GTP
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Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP
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Diabetes Mellitus Experimental
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Células Secretoras de Insulina
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Incretinas
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article