ArticleMolecular metabolism2015
Chronic hyperglycemia downregulates GLP-1 receptor signaling in pancreatic β-cells via protein kinase A.
Article in Molecular metabolism, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 71 citations in OpenAlex.
- Glucagon-like peptide-1: a critical link between gut microbiota dysbiosis and degenerative musculoskeletal diseases.Gut microbes · 2026Review
- Harmine selectively enhances human beta cell identity markers and function via protein kinase A pathways.Diabetologia · 2026Article
- Luseogliflozin restores GIP responsiveness in diabetic male mice with preserved β-cell function.Physiological reports · 2026Article
- DNA-based delivery of incretin receptor agonists using MYO Technology leads to durable weight loss in a diet-induced obesity model.Molecular therapy. Nucleic acids · 2026Article
- The molecular mechanisms of incretin resistance in Type 2 Diabetes Mellitus (T2DM).Nutrition & diabetes · 2026Review
- Signaling architecture of the glucagon-like peptide-1 receptor.The Journal of clinical investigation · 2026Review
- Decoding incretin resistance: a mechanistic framework to reclassify therapeutic variability for GLP-1 receptor agonist therapy.Amino acids · 2025Review
- The dual GLP-1 and GIP receptor agonist tirzapetide provides an unintended interaction with the β-adrenoceptors and plays a role in glucose metabolism in hyperglycemic or senescent cardiac cells.Cardiovascular diabetology · 2025Article
- Cardioprotective effects of semaglutide on isolated human ventricular myocardium.European journal of heart failure · 2025Article
- GHRH in diabetes and metabolism.Reviews in endocrine & metabolic disorders · 2025Review
- The Emerging Role of Adropin in Neurological Health: A Systematic Review.Iranian journal of public health · 2025Review
- Effects of GLP-1 and GIP on cholinergic-induced contractility in isolated jejunal muscle from obese patients with and without type 2 diabetes mellitus.Frontiers in physiology · 2025Article
- Modern Challenges in Type 2 Diabetes: Balancing New Medications with Multifactorial Care.Biomedicines · 2024Review
- Adropin: A crucial regulator of cardiovascular health and metabolic balance.Metabolism open · 2024Review
- GLP1R and GIPR expression and signaling in pancreatic alpha cells, beta cells and delta cells.Peptides · 2024Article
- Incretin and Pancreatic β-Cell Function in Patients with Type 2 Diabetes.Endocrinology and metabolism (Seoul, Korea) · 2023Review
- The past, present, and future physiology and pharmacology of glucagon.Cell metabolism · 2022Review
- RNA aptamers specific for transmembrane p24 trafficking protein 6 and Clusterin for the targeted delivery of imaging reagents and RNA therapeutics to human β cells.Nature communications · 2022Article
- β-Cell Knockout of SENP1 Reduces Responses to Incretins and Worsens Oral Glucose Tolerance in High-Fat Diet-Fed Mice.Diabetes · 2021Article
- GRK2 regulates GLP-1R-mediated early phase insulin secretion in vivo.BMC biology · 2021Article
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
objectiveGlucagon-like peptide 1 (GLP-1) enhances insulin secretion and protects β-cell mass. Diabetes therapies targeting the GLP-1 receptor (GLP-1R), expressed in numerous tissues, have diminished dose-response in patients with type 2 diabetes compared with healthy human controls. The aim of this study was to determine the mechanistic causes underlying the reduced efficacy of GLP-1R ligands.
methodsUsing primary mouse islets and the β-cell line MIN6, outcomes downstream of the GLP-1R were analyzed: Insulin secretion; phosphorylation of the cAMP-response element binding protein (CREB); cAMP responses. Signaling systems were studied by immunoblotting and qRT-PCR, and PKA activity was assayed. Cell surface localization of the GLP-1R was studied by confocal microscopy using a fluorescein-tagged exendin-4 and GFP-tagged GLP-1R.
resultsRodent β-cells chronically exposed to high glucose had diminished responses to GLP-1R agonists including: diminished insulin secretory response; reduced phosphorylation of (CREB); impaired cAMP response, attributable to chronically increased cAMP levels. GLP-1R signaling systems were affected by hyperglycemia with increased expression of mRNAs encoding the inducible cAMP early repressor (ICER) and adenylyl cyclase 8, reduced PKA activity due to increased expression of the PKA-RIα subunit, reduced GLP-1R mRNA expression and loss of GLP-1R from the cell surface. To specifically examine the loss of GLP-1R from the plasma membrane a GLP-1R-GFP fusion protein was employed to visualize subcellular localization. Under low glucose conditions or when PKA activity was inhibited, GLP-1R-GFP was found at the plasma membrane. Conversely high glucose, expression of a constitutively active PKA subunit, or exposure to exendin-4 or forskolin led to GLP-1R-GFP internalization. Mutation of serine residue 301 of the GLP-1R abolished the glucose-dependent loss of the receptor from the plasma membrane. This was associated with a loss of an interaction between the receptor and the small ubiquitin-related modifier (SUMO), an interaction that was found to be necessary for internalization of the receptor.
conclusionsThese data show that glucose acting, at least in part, via PKA leads to the loss of the GLP-1R from the cell surface and an impairment of GLP-1R signaling, which may underlie the reduced clinical efficacy of GLP-1R based therapies in individuals with poorly controlled hyperglycemia.
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