ArticleThe Journal of clinical investigation2020
Gs/Gq signaling switch in β cells defines incretin effectiveness in diabetes.
Article in The Journal of clinical investigation, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers.
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60 citing papers in PubMed, 93 citations in OpenAlex.
- Differential effects of imeglimin and metformin on insulin and incretin secretion-An exploratory randomized controlled trial.Diabetes, obesity & metabolism · 2025Trial
- Type IIB PKA serves as the primary effector of Gs-coupled receptor-potentiated insulin secretion in mice by orchestrating ion channels and granule phenotype.Diabetologia · 2026Article
- Metabolic state determines the brain and direct islet effects of liraglutide on enhanced insulin secretion.Diabetologia · 2026Article
- Gene expression profiles associated with stimulus-responsive insulin secretion in insulinoma.Endocrine connections · 2026Article
- Luseogliflozin restores GIP responsiveness in diabetic male mice with preserved β-cell function.Physiological reports · 2026Article
- Semaglutide drives weight loss through cAMP-dependent mechanisms in GLP1R-expressing hindbrain neurons.Nature metabolism · 2026Article
- c-Jun N-terminal kinase 3 as a permissive regulator of β-cell incretin responsiveness.Journal of diabetes investigation · 2026Article
- Workload-induced changes to cell state contribute to β-cell failure in diabetes.bioRxiv : the preprint server for biology · 2026Article
- Distinctive molecular architectures of GActa pharmaceutica Sinica. B · 2026Article
- Rewriting Diabetes Therapy: How Incretin Modulation is Transforming Cardiovascular and Renal Outcomes.Diabetes therapy : research, treatment and education of diabetes and related disorders · 2026Review
- Gαs defines the fundamental coupling mechanism of insulin secretion.Journal of diabetes investigation · 2026Article
- Antecedent hypoglycaemia impairs glucagon secretion by enhancing somatostatin-mediated negative feedback control.Nature metabolism · 2026Article
- Spatially diffuse cAMP signalling with oppositely biased GLP-1 receptor agonists in β-cells despite differences in receptor localisation.Molecular metabolism · 2026Article
- The crucial role of potassium ion channels in diabetes mellitus and its complications: A review.Channels (Austin, Tex.) · 2025Review
- Incretin hormones and obesity.The Journal of physiology · 2025Review
- GLP-1/GIP/GCG receptor triagonist (IUB447) enhances insulin secretion via GLP-1 receptor and Gαq signalling pathway in mice.Diabetologia · 2025Article
- Binding kinetics, bias, receptor internalization and effects on insulin secretion in vitro and in vivo of a novel GLP-1R/GIPR dual agonist, HISHS-2001.Diabetes, obesity & metabolism · 2025Article
- Regulation of glucose metabolism by incretins: implications for treatment of type 2 diabetes.Diabetology international · 2025Review
- Evolving incretin-based therapies in Japan: optimizing treatment strategies for diverse clinical and socioeconomical profiles in type 2 diabetes.Diabetology international · 2025Review
- Pyruvate kinase modulates the link between β-cell fructose metabolism and insulin secretion.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025Article
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Authors and funding
18 authors at 5 institutions in 3 countries.
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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 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+ (KATP) 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 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 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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.