Affinage

GCG

Pro-glucagon · UniProt P01275

Round 2 corrected
Length
180 aa
Mass
20.9 kDa
Annotated
2026-04-28
130 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GCG encodes preproglucagon, a precursor that is tissue-specifically processed into glucagon, GLP-1, GLP-2, and oxyntomodulin, each acting through distinct receptors to coordinate glucose homeostasis, appetite, and intestinal growth (PMID:6877358, PMID:12554744). Glucagon promotes hepatic glucose output via glycogenolysis and gluconeogenesis (PMID:12626323); GLP-1 stimulates glucose-dependent insulin secretion through cAMP/PKA-mediated closure of KATP channels and activation of nonselective cation channels in beta cells (PMID:8993395), protects beta cells from apoptosis via caspase-3 downregulation and bcl-2 upregulation (PMID:12960095), and suppresses feeding through hypothalamic (DMH) and brainstem (NTS) GLP-1R-expressing circuits that encode satiation independently of peripheral preproglucagon neurons (PMID:8538742, PMID:38935778, PMID:33589843). GLP-1 secretion from intestinal L cells is triggered by luminal glucose via α-gustducin/sweet taste receptor machinery (PMID:17724330) and modulated by leptin (STAT3/Ob-Rb) and IL-6-driven upregulation of proglucagon and PC1/3 in alpha cells (PMID:12540594, PMID:22037645), while GLP-1R signaling efficacy is determined by β-arrestin-1 recruitment and receptor trafficking, with biased agonists that reduce β-arrestin engagement and GLP-1R internalization producing greater insulinotropic responses (PMID:18445652, PMID:29686402, PMID:32730231).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1983 High

    Cloning the preproglucagon cDNA established that glucagon, GLP-1, and GLP-2 arise from a single gene through exon duplication, resolving how structurally related gut-pancreas peptides share a common genetic origin.

    Evidence cDNA cloning and sequence analysis of the human preproglucagon gene

    PMID:6877358

    Open questions at the time
    • Tissue-specific post-translational processing mechanisms were not defined
    • Functions of GLP-1 and GLP-2 were unknown at this point
  2. 1993 High

    Demonstration that GLP-1(7-36 amide) and GLP-1(7-37) are equipotent insulinotropic agents with identical clearance kinetics established the active forms of the peptide and its extremely short plasma half-life (~5–6 min), framing a key pharmacological challenge.

    Evidence Intravenous infusion of both GLP-1 forms in healthy humans with insulin, glucagon, glucose, and clearance measurements

    PMID:8482423

    Open questions at the time
    • The proteolytic enzyme responsible for rapid degradation was not identified in this study
    • Receptor binding kinetics of each form were not compared
  3. 1996 High

    Two foundational mechanisms of GLP-1 action were defined: central GLP-1 was shown to suppress feeding via hypothalamic circuits (blocked by exendin(9-39)), and peripheral GLP-1 was shown to stimulate insulin secretion through both KATP channel closure and nonselective cation channel activation in beta cells.

    Evidence ICV injection with c-fos mapping and receptor antagonist epistasis in rats; patch-clamp electrophysiology and Ca²⁺ imaging in beta cells

    PMID:8538742 PMID:8993395

    Open questions at the time
    • Identity of the specific neuronal populations mediating central anorexia was unresolved
    • Relative contribution of KATP vs. NSCC pathways to insulin secretion in vivo was unclear
  4. 1999 High

    Cloning of the GLP-2 receptor demonstrated that each major proglucagon-derived peptide acts through a distinct GPCR, with GLP-2R showing exquisite ligand specificity (nanomolar affinity for GLP-2 but not GLP-1), explaining how a single precursor gene controls diverse tissue-specific functions.

    Evidence cDNA cloning of rat and human GLP-2R; cAMP and radioligand binding assays; in vivo intestinotrophic activity

    PMID:9990065

    Open questions at the time
    • Downstream signaling cascades of GLP-2R were not characterized
    • Intestinotrophic mechanism beyond receptor activation was unknown
  5. 2003 High

    A cluster of discoveries established GLP-1 as a trophic and antiapoptotic factor for beta cells (via caspase-3/bcl-2), identified leptin-STAT3 signaling as a regulator of L-cell GLP-1 secretion, confirmed DPP-IV as the primary GLP-1-degrading enzyme in vivo, and showed oxyntomodulin suppresses appetite and ghrelin in humans, broadening the functional repertoire of proglucagon-derived peptides.

    Evidence Human islet culture with apoptosis markers; L-cell secretion assays with leptin/STAT3; IV pharmacokinetics in renal insufficiency patients; double-blind crossover OXM infusion in humans

    PMID:12540594 PMID:12960095 PMID:14557443 PMID:14988249

    Open questions at the time
    • Whether GLP-1 antiapoptotic effects are sustained in vivo long-term was untested
    • Molecular mechanism of oxyntomodulin anorexia (receptor identity) was unclear
  6. 2005 High

    GLP-1R signaling was linked to cardioprotection via cAMP/PI3K/MAPK prosurvival pathways phosphorylating BAD, and to beta-cell mass expansion via IRS-2/PI3K/Akt-mediated Foxo1 nuclear exclusion upregulating PDX-1, revealing GLP-1 actions beyond acute insulin secretion.

    Evidence Isolated perfused heart ischemia/reperfusion with kinase inhibitors; cell-based studies of GLP-1R → IRS-2 → PI3K → Akt → Foxo1 → PDX-1

    PMID:15616022 PMID:15671479

    Open questions at the time
    • In vivo relevance of GLP-1 cardioprotection in humans was not established
    • Whether Foxo1 exclusion is necessary or sufficient for beta-cell proliferation was not genetically tested
  7. 2007 High

    The luminal glucose-sensing mechanism for GLP-1 secretion was identified: intestinal L cells employ sweet taste receptors and α-gustducin, the same molecular machinery as lingual taste cells, to detect sugars and trigger GLP-1 release.

    Evidence α-Gustducin knockout mice; NCI-H716 cells; siRNA knockdown; lactisole pharmacological antagonism; glucose tolerance tests

    PMID:17724330

    Open questions at the time
    • Whether this mechanism accounts for the majority of nutrient-stimulated GLP-1 secretion in humans was untested
    • Lipid and amino acid sensing pathways in L cells were not addressed
  8. 2007 High

    Structural understanding of incretin-receptor engagement advanced through binding studies showing GLP-1R uses a two-domain mechanism (ECD captures peptide C-terminus; TMD binds N-terminus for activation), and crystallography of the related GIP receptor ECD–GIP complex confirmed a conserved binding mode across class B GPCRs.

    Evidence Radioligand competition with GLP-1R truncation constructs; crystal structure of GIP receptor ECD bound to GIP(1-42)

    PMID:17635131 PMID:17715056

    Open questions at the time
    • Full-length GLP-1R structure was not yet available
    • Activation-associated conformational transitions were not visualized
  9. 2008 High

    β-Arrestin-1 was identified as a direct GLP-1R interactor that positively mediates GLP-1-stimulated cAMP, ERK/CREB, and insulin secretion, adding an arrestin-dependent signaling arm beyond classical G-protein coupling.

    Evidence Co-immunoprecipitation in INS-1 cells; siRNA knockdown of β-arrestin-1 with cAMP, ERK/CREB, IRS-2, and insulin secretion readouts

    PMID:18445652

    Open questions at the time
    • Whether β-arrestin-1 signals from endosomes vs. plasma membrane was not resolved
    • Contribution to in vivo insulin secretion was not tested
  10. 2011 High

    IL-6 was shown to stimulate GLP-1 production from pancreatic alpha cells by upregulating both proglucagon and prohormone convertase 1/3 expression, providing a mechanism linking exercise-induced IL-6 to enhanced incretin availability.

    Evidence IL-6 administration in mice; alpha-cell and L-cell line culture; IL-6 neutralization; proglucagon and PC1/3 mRNA quantification

    PMID:22037645

    Open questions at the time
    • Quantitative contribution of alpha-cell-derived GLP-1 vs. L-cell-derived GLP-1 to systemic GLP-1 pools was unresolved
    • Signaling pathway downstream of IL-6 receptor in alpha cells was not fully mapped
  11. 2018 High

    Biased agonism at GLP-1R was functionally validated: agonists that reduce β-arrestin recruitment and receptor internalization while retaining cAMP signaling produce superior long-term insulin secretion compared to FDA-approved GLP-1 mimetics, establishing receptor trafficking as a determinant of therapeutic efficacy.

    Evidence Series of biased agonists tested for GLP-1R internalization, recycling, β-arrestin recruitment, and insulin secretion in primary islets; glycemic studies in mice

    PMID:29686402

    Open questions at the time
    • Long-term in vivo consequences of biased agonism on beta-cell mass were not assessed
    • Whether biased agonism also affects central anorectic actions was unknown
  12. 2020 High

    Structural resolution of GLP-1R in multiple states—inactive (crystal structure showing closed ECD), non-peptide agonist-bound (cryo-EM revealing an extracellular binding pocket for TT-OAD2), and positive allosteric modulator-bound (cryo-EM showing molecular-glue mechanism at TM1/TM2)—provided a comprehensive conformational framework for receptor activation and drug design.

    Evidence X-ray crystallography at 3.2 Å; cryo-EM structures; disulfide cross-linking; MD simulations; signaling and insulin secretion assays

    PMID:31915381 PMID:32152292 PMID:32690941

    Open questions at the time
    • Dynamics of GLP-1R activation at the single-molecule level in membranes remain unresolved
    • How allosteric modulator engagement affects receptor trafficking and desensitization in vivo is unknown
  13. 2020 High

    Tirzepatide was shown to exhibit biased agonism at GLP-1R favoring cAMP over β-arrestin, and β-arrestin-1 knockout islets confirmed that β-arrestin-1 limits insulin responses to GLP-1 but not GIP, explaining how dual-agonist design achieves enhanced insulinotropic efficacy.

    Evidence cAMP and β-arrestin signaling assays; GLP-1R internalization; insulin secretion in β-arrestin-1 KO vs. WT mouse islets; receptor occupancy modeling

    PMID:32730231

    Open questions at the time
    • In vivo receptor-level occupancy at therapeutic doses in humans was modeled but not directly measured
    • Contribution of GIP vs. GLP-1 receptor pathways to weight loss was not dissected
  14. 2021 High

    Circuit dissection revealed that preproglucagon NTS neurons (PPGNTS) encode satiation from vagal gastrointestinal distension input and suppress eating independently of peripheral GLP-1R agonist action, demonstrating that central and peripheral GLP-1 systems constitute parallel anorectic pathways.

    Evidence Optogenetic manipulation of PPGNTS neurons; calcium imaging; vagal circuit mapping; genetic ablation; comparison with semaglutide in mice

    PMID:33589843

    Open questions at the time
    • Whether combined PPGNTS activation and GLP-1RA treatment produces synergistic weight loss long-term was untested
    • Molecular identity of the PPGNTS-released mediator(s) (GLP-1 vs. other peptides) was not resolved
  15. 2024 High

    Multiple new GLP-1R-expressing neural circuits were functionally mapped: DMH GLP-1R neurons encode preingestive satiation and interact with ARC NPY/AgRP neurons, while olfactory bulb GLP-1R activation stimulates insulin secretion via a sympathetic brain-to-pancreas axis relayed through the PVN, expanding the known central targets of GLP-1 signaling.

    Evidence Optogenetics and calcium imaging of DMHGLP-1R neurons; stereotaxic OB GLP-1R activation; PVN GABAA inhibition; pancreatic noradrenaline measurement in lean and DIO mice

    PMID:38935778 PMID:39138162

    Open questions at the time
    • Whether DMH or OB circuits are engaged by therapeutic GLP-1RA doses in humans is unknown
    • Molecular mediators downstream of PVN relay to sympathetic outflow are not identified
  16. 2024 High

    Orforglipron, a nonpeptide oral GLP-1R agonist, was shown to bind GLP-1R with 1 nM affinity yet with low intrinsic efficacy and negligible β-arrestin recruitment; CRISPR-Cas9-sensitized Glp1r rats confirmed target engagement in pancreas and brain, establishing the pharmacological basis for oral nonpeptide GLP-1R agonism.

    Evidence Radioligand binding; signal transduction assays; receptor occupancy modeling; humanized GLP-1R mice; CRISPR-sensitized rats; DIO weight loss

    PMID:39693407

    Open questions at the time
    • Long-term metabolic and safety profiles of low-efficacy nonpeptide agonism are not established
    • Whether orforglipron engages the same allosteric site as TT-OAD2 is not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the quantitative contribution of alpha-cell-derived vs. L-cell-derived GLP-1 to systemic incretin pools, the molecular mediators through which PPGNTS neurons suppress eating, the in vivo relevance of GLP-1R allosteric modulator and biased agonist mechanisms to long-term beta-cell mass and weight regulation, and how Gpr17 and other inhibitory GPCRs coordinate with nutrient-sensing pathways to fine-tune GLP-1 secretion.
  • Alpha-cell vs. L-cell GLP-1 contributions not quantified in humans
  • PPGNTS neuron-released mediator identity unresolved
  • Long-term in vivo consequences of biased agonism on beta-cell mass unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 6 GO:0098772 molecular function regulator activity 2
Localization
GO:0005576 extracellular region 4
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-112316 Neuronal System 5 R-HSA-1430728 Metabolism 3 R-HSA-392499 Metabolism of proteins 3
Partners
ARRB1DPP4GCGRGLP1RGLP2RGNAT3IDEIL6

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1983 The human preproglucagon gene (GCG) encodes multiple peptides through exon duplication and divergence, establishing that glucagon, GLP-1, and GLP-2 are all products of a single preproglucagon precursor gene. cDNA cloning and sequence analysis of the human preproglucagon gene Nature High 6877358
1993 The two bioactive forms of GLP-1 (7-36 amide and 7-37) are equipotent in stimulating insulin secretion, suppressing glucagon, and lowering plasma glucose in healthy humans, and share similar metabolic clearance rates (~12–15 pmol/kg·min) and plasma half-lives (~5–6 min), indicating C-terminal amidation does not significantly alter GLP-1 biological activity or metabolism. Intravenous infusion of GLP-1 7-36 amide vs. GLP-1 7-37 in healthy human subjects with measurement of insulin, C-peptide, glucagon, glucose, and metabolic clearance rates Diabetes High 8482423
1996 Central GLP-1 (ICV injection) potently inhibits feeding in fasted rats and activates c-fos expression in the paraventricular nucleus (PVN) of the hypothalamus and central nucleus of the amygdala; the specific GLP-1 receptor antagonist exendin(9-39) blocks these effects and augments feeding in satiated animals, establishing central GLP-1 as a physiological mediator of satiety acting through hypothalamic circuits. Intracerebroventricular (ICV) injection of GLP-1 and exendin(9-39) in rats; food intake measurement; c-fos immunohistochemistry Nature High 8538742
1996 GLP-1 and PACAP depolarize pancreatic beta cells and stimulate insulin secretion through at least two mechanisms: closure of ATP-sensitive K+ channels and activation of nonselective cation channels (NSCCs) carrying predominantly Na+-dependent current; NSCCs are dually regulated by intracellular cAMP and Ca2+, and activation of GLP-1 signaling raises [Ca2+]i and promotes exocytosis of insulin-containing granules. Electrophysiology (patch-clamp), intracellular Ca2+ imaging, and pharmacological manipulation in pancreatic beta cells Annals of the New York Academy of Sciences High 8993395
1999 GLP-2 (a proglucagon-derived peptide) exerts its intestinotrophic actions through a specific G protein-coupled receptor (GLP-2R) expressed in the gut; GLP-2R activation by GLP-2 but not GLP-1 increases cAMP (EC50 = 0.58 nM) and shows saturable high-affinity radioligand binding (Kd = 0.57 nM), demonstrating ligand specificity among proglucagon-derived peptides. cDNA cloning of rat and human GLP-2R; cAMP assays; radioligand binding; in vivo intestinotrophic activity of GLP-2 analogs Proceedings of the National Academy of Sciences of the United States of America High 9990065
2003 Glucagon is the principal counterregulatory hormone that increases hepatic glucose output by simultaneously promoting glycogenolysis and gluconeogenesis while inhibiting glycogenesis and glycolysis, acting through the glucagon receptor; diabetic hyperglucagonemia contributes to pathological hyperglycemia. Review integrating in vivo and in vitro mechanistic studies of glucagon receptor signaling and hepatic glucose metabolism American journal of physiology. Endocrinology and metabolism High 12626323
2003 GLP-1 inhibits apoptosis in freshly isolated human islets by downregulating active caspase-3 and upregulating bcl-2 at both mRNA and protein levels, while enhancing intracellular insulin content and glucose-dependent insulin secretion; this establishes a direct antiapoptotic mechanism of GLP-1 in human beta cells. Culture of human islets with GLP-1 (10 nM); measurement of apoptotic nuclei, caspase-3 and bcl-2 mRNA and protein; insulin content and secretion assays Endocrinology High 12960095
2003 GLP-1 stimulates pancreatic beta-cell proliferation, induces islet neogenesis, promotes differentiation toward a beta-cell phenotype from exocrine or progenitor cells, and exerts antiapoptotic actions preserving beta-cell mass in vivo; GLP-2 analogously stimulates gastrointestinal mucosal cell proliferation and exerts antiapoptotic actions on gut epithelium. Review integrating in vivo genetic models, cell culture experiments, and proglucagon-derived peptide biology Molecular endocrinology (Baltimore, Md.) High 12554744
2003 Leptin directly stimulates GLP-1 secretion from intestinal L cells via the long form of the leptin receptor (Ob-Rb), inducing STAT3 phosphorylation; leptin resistance in diet-induced obese mice is associated with reduced basal GLP-1 and diminished GLP-1 response to oral glucose, linking leptin signaling to GLP-1 secretory regulation. GLP-1 secretion assays in fetal rat intestinal cells, GLUTag and NCI-H716 L-cell lines, and in vivo in rats and ob/ob mice; Western blot for STAT3 phosphorylation; high-fat diet mouse model Diabetes High 12540594
2003 GLP-1 rapidly degrades in plasma with a half-life of ~1–2 min primarily through DPP-IV cleavage; kidneys are important for final elimination of the metabolite GLP-1(9-36 amide), as patients with chronic renal insufficiency show significantly longer half-lives for the metabolite (5.3 vs. 3.3 min) but not for intact GLP-1. Intravenous infusion of GLP-1 in patients with chronic renal insufficiency vs. healthy controls; specific immunoassays for intact and total GLP-1; pharmacokinetic modeling Diabetes High 14988249
2003 Oxyntomodulin (a proglucagon-derived peptide) suppresses appetite and reduces food intake in humans when infused intravenously, and significantly suppresses circulating ghrelin levels (by ~44% of postprandial decrease), identifying oxyntomodulin as a physiological appetite-regulating signal from the GCG locus. Randomized, double-blind, placebo-controlled crossover study with IV OXM infusion in healthy subjects; ad libitum food intake measurement; plasma ghrelin, appetite VAS scores The Journal of clinical endocrinology and metabolism High 14557443
2005 GLP-1 directly protects the heart against ischemia/reperfusion injury via GLP-1 receptor-dependent activation of cAMP, PI3-kinase, and p42/44 MAPK prosurvival pathways, leading to phosphorylation of the proapoptotic peptide BAD; protection is abolished by the GLP-1 receptor antagonist exendin(9-39), Rp-cAMP, LY294002 (PI3K inhibitor), or UO126 (MEK inhibitor). Isolated perfused rat heart and whole animal ischemia/reperfusion models; infarct size measurement; pharmacological inhibition with receptor antagonist and kinase inhibitors; Western blot for phospho-BAD Diabetes High 15616022
2005 GLP-1 receptor activation in pancreatic beta cells promotes nuclear exclusion of Foxo1 through PKB (Akt)-mediated phosphorylation, downstream of IRS-2 and PI3K signaling; this upregulates PDX-1, a master regulator of beta-cell growth and differentiation, providing a mechanism for GLP-1-induced expansion of beta-cell mass. Mechanistic review integrating cell-based studies of GLP-1R → IRS-2 → PI3K → PKB → Foxo1 phosphorylation → PDX-1 upregulation in pancreatic beta cells Science's STKE : signal transduction knowledge environment Medium 15671479
2006 GLP-2 (a proglucagon-derived peptide) stimulates glucagon secretion in humans both in the fasting state and postprandially, enhances intestinal lipid absorption (elevated postprandial triglycerides and free fatty acids), and inhibits pentagastrin-stimulated gastric acid secretion by ~15%, without affecting gastric emptying. Randomized crossover studies in 15 healthy male volunteers each; IV infusion of GLP-2 vs. placebo; plasma glucagon, lipid, and gastric acid measurements; 13C-octanoate breath test for gastric emptying Gastroenterology High 16401467
2006 Insulin-degrading enzyme (IDE) degrades glucagon (as well as insulin, amyloid-β, and amylin) by encapsulating it within an enclosed catalytic chamber formed by IDE-N and IDE-C domains; substrate access requires repositioning of these domains, and the substrate undergoes conformational changes to form beta-sheets with IDE for degradation. Crystal structures of human IDE in complex with substrates including glucagon; in vitro activity assays; mutagenesis disrupting IDE-N/IDE-C contacts increases catalytic activity 40-fold Nature High 17051221
2007 Intestinal L cells express sweet taste receptors and the taste G protein α-gustducin; glucose-stimulated GLP-1 secretion is defective in α-gustducin null mice and in isolated intestinal tissue from these mice; GLP-1 release from NCI-H716 cells is promoted by sugars and the noncaloric sweetener sucralose and blocked by the sweet receptor antagonist lactisole or siRNA for α-gustducin, establishing that L cells 'taste' luminal glucose through the same machinery as lingual taste cells to trigger GLP-1 secretion. α-Gustducin knockout mice; glucose tolerance tests; isolated small bowel GLP-1 secretion assays; NCI-H716 cell line; siRNA knockdown of α-gustducin; pharmacological antagonism with lactisole Proceedings of the National Academy of Sciences of the United States of America High 17724330
2007 GLP-1 binds to its class B GPCR through a two-domain mechanism: the N-terminal extracellular domain (ECD) provides most binding energy for the C-terminal region of GLP-1, while the core transmembrane domain binds the N-terminal region of GLP-1 to transmit the activation signal; in contrast, exendin-4 can bind the isolated ECD with full-receptor affinity, indicating mechanistic differences between GLP-1 and exendin-4 receptor engagement. Peptide binding studies using full-length and truncated GLP-1 receptor variants and truncated ligands; radioligand competition assays Biochemical Society transactions Medium 17635131
2007 Crystal structure of the GIP receptor extracellular domain (ECD) bound to GIP(1-42) reveals that the incretin hormone binds in an alpha-helical conformation within a surface groove of the ECD through predominantly hydrophobic interactions; the N-terminal residues of GIP remain free, consistent with a two-domain binding model conserved across class B GPCRs including GLP-1R. X-ray crystallography of human GIP receptor ECD in complex with GIP(1-42); thermodynamic binding analysis Proceedings of the National Academy of Sciences of the United States of America High 17715056
2008 β-Arrestin-1 physically associates with the GLP-1 receptor (demonstrated by co-immunoprecipitation in INS-1 beta cells) and mediates GLP-1 signaling to insulin secretion; β-arrestin-1 knockdown reduces cAMP production, ERK and CREB activation, IRS-2 expression, and insulin secretion in response to GLP-1, without affecting GLP-1R surface expression or ligand-induced internalization. Co-immunoprecipitation in INS-1 cells; siRNA knockdown of β-arrestin-1; measurement of cAMP, ERK/CREB phosphorylation, IRS-2 expression, and insulin secretion Proceedings of the National Academy of Sciences of the United States of America High 18445652
2011 IL-6 stimulates GLP-1 secretion from both intestinal L cells and pancreatic alpha cells; in alpha cells, IL-6 increases GLP-1 production by upregulating proglucagon (GCG) gene expression and prohormone convertase 1/3 expression, establishing a mechanism by which exercise-elevated IL-6 enhances GLP-1 availability to improve insulin secretion. IL-6 administration in mice and in vitro in L-cell and alpha-cell lines; measurement of GLP-1 secretion, proglucagon mRNA, and prohormone convertase 1/3 expression; IL-6 neutralization experiments; exercise models Nature medicine High 22037645
2012 A major lineage of enteroendocrine cells co-expresses proglucagon (GLP-1), CCK, GIP, PYY, neurotensin, and secretin but not somatostatin throughout the intestine; cell ablation driven by the proglucagon promoter (diphtheria toxin receptor model) markedly reduces not only GLP-1 cells but also PYY, neurotensin, GIP, CCK, and secretin cells, demonstrating that GCG-expressing L cells represent a broad shared lineage of enteroendocrine cells. Transgenic mice with CCK-eGFP reporter; FACS purification and quantitative PCR; LC-MS proteomics; immunohistochemistry; proglucagon-promoter-driven diphtheria toxin receptor cell ablation; single-cell qPCR Endocrinology High 23064014
2016 NTS astrocytes express functional GLP-1 receptors; systemic or central administration of fluorophore-labeled exendin-4 localizes within NTS astrocytes and neurons in a GLP-1R-dependent manner (blocked by exendin(9-39)); GLP-1R agonists activate NTS astrocytes (live-cell calcium signaling) and increase cAMP in astrocytes in vitro; pharmacological inhibition of NTS astrocytes attenuates the anorectic and body-weight-suppressive effects of intra-NTS GLP-1R activation. Fluorophore-labeled GLP-1R agonist localization in vivo; ex vivo and in vitro calcium signaling; cAMP assays in astrocytes; immunohistochemistry; pharmacological inhibition of NTS astrocytes with behavioral readout The Journal of neuroscience : the official journal of the Society for Neuroscience High 27013681
2018 GLP-1 receptor agonists that retain GLP-1R at the plasma membrane (reduced internalization and slower agonist dissociation rates, with reduced β-arrestin recruitment) produce greater long-term insulin release compared to FDA-approved GLP-1 mimetics; this enhanced insulin secretion is dependent on reduced β-arrestin recruitment, establishing a mechanism by which GLP-1R trafficking determines insulinotropic efficacy. Series of biased GLP-1R agonists tested for GLP-1R internalization, recycling, β-arrestin recruitment, and insulin secretion in primary islets; glycemic studies in mice; comparison to panel of FDA-approved GLP-1 mimetics Nature communications High 29686402
2020 Crystal structure of the full-length human GLP-1R in peptide-free inactive state at 3.2 Å reveals a unique closed conformation of the extracellular domain (ECD); disulfide cross-linking validates the physiological relevance of this closed conformation; EM and MD simulations show large ECD conformational dynamics necessary for GLP-1 binding, providing a mechanistic framework for receptor activation. X-ray crystallography (3.2 Å); disulfide cross-linking; electron microscopy; molecular dynamics simulation Nature communications High 32152292
2020 A non-peptide agonist (TT-OAD2) binds the GLP-1 receptor at an unpredicted extracellular pocket distinct from the peptide-binding site, causing reorganization of ECL3 and TM helices 6 and 7 independently of direct interaction with the deep transmembrane pocket; TT-OAD2 shows biased agonism with distinct G-protein activation kinetics compared to peptide agonists, and protrudes beyond the receptor core to interact with lipid/detergent, explaining its distinct activation kinetics. Cryo-EM structure of GLP-1R bound to TT-OAD2; signaling assays (cAMP, β-arrestin); binding competition studies Nature High 31915381
2020 A positive allosteric modulator (LSN3160440) of GLP-1R acts as a 'molecular glue' that cooperatively binds both the receptor and orthosteric ligand GLP-1(9-36), stabilizing the active-state conformation; cryo-EM structure reveals the modulator binds at an interface between TM1 and TM2 high in the helical bundle, allowing access to the peptide ligand; LSN3160440 enhances insulin secretion in a glucose-, ligand-, and GLP-1R-dependent manner. Cryo-EM structure of GLP-1R bound to LSN3160440 + GLP-1 + Gs; insulin secretion assays; pharmacological characterization with multiple ligands; probe-dependence analysis Nature chemical biology High 32690941
2020 Tirzepatide shows biased agonism at the GLP-1 receptor, favoring cAMP generation over β-arrestin recruitment, and drives less GLP-1R internalization compared to native GLP-1; β-arrestin1 limits the insulin response to GLP-1 but not GIP or tirzepatide, and tirzepatide engages the GIP receptor more than the GLP-1R at clinically efficacious doses; these signaling properties together enhance insulin secretion. Receptor occupancy calculations; cAMP and β-arrestin recruitment signaling assays; GLP-1R internalization assays; insulin secretion in primary islets from β-arrestin1 knockout and wild-type mice JCI insight High 32730231
2021 PPGNTS neurons (preproglucagon-expressing neurons in the nucleus tractus solitarii) encode satiation through vagal signaling of gastrointestinal distension and receive vagal input predominantly from oxytocin-receptor-expressing vagal neurons rather than GLP-1 receptor-expressing vagal neurons; PPGNTS neurons are not necessary for eating suppression by GLP-1 receptor agonists, and concurrent PPGNTS neuron activation suppresses eating more potently than semaglutide alone, demonstrating that central and peripheral GLP-1 systems suppress eating via independent gut-brain circuits. Optogenetic manipulation of PPGNTS neurons; calcium imaging; vagal circuit mapping; genetic deletion of PPGNTS neurons; comparison with semaglutide treatment in mice Nature metabolism High 33589843
2022 Intestinal Gpr17 (an orphan GPCR) is co-expressed in GLP-1-expressing enteroendocrine cells and functions as an inhibitory regulator of GLP-1 secretion; Gpr17 knockout or acute intestinal epithelial ablation improves glucose tolerance and GSIS; Gpr17 agonism in vitro reduces voltage-gated calcium currents and decreases cAMP production, the two critical factors regulating GLP-1 secretion; Gpr17 null intestinal organoids show increased GLP-1 (but not GIP) secretion in response to glucose or lipid. Inducible intestinal-specific Gpr17 knockout mice; intestinal organoids; electrophysiology (voltage-gated Ca2+ currents); cAMP assays; GSIS and glucose tolerance tests Cell reports High 34986353
2024 GLP-1 receptor neurons in the dorsomedial hypothalamus (DMH) encode preingestive satiation; optogenetic activation of DMHGLP-1R neurons causes satiation; calcium imaging shows these neurons are activated specifically during eating behavior; GLP-1RA administration selectively increases DMHGLP-1R neuron activity, and these neurons interact with NPY/AgRP neurons of the arcuate nucleus to regulate food intake. Optogenetic manipulation and calcium imaging of DMHGLP-1R neurons in mice; GLP-1RA administration; human and mouse brain sample analysis; food intake measurements Science (New York, N.Y.) High 38935778
2024 GLP-1 receptor activation in the olfactory bulb (OB) stimulates insulin secretion in response to oral glucose via a top-down neural circuit: OB GLP-1R activation reduces noradrenaline content in the pancreas (implicating the sympathetic nervous system), and this effect is relayed through the PVN (abolished by GABAA receptor inhibition in PVN), identifying a novel brain-to-pancreas axis for GLP-1-mediated insulin secretion. Stereotaxic OB GLP-1R activation in lean and diet-induced obese male mice; measurement of pancreatic noradrenaline; α2-adrenergic receptor agonist blockade; GABAA receptor inhibition in PVN; glucose-stimulated insulin secretion assays Nature communications High 39138162
2024 Orforglipron, a nonpeptide oral GLP-1R agonist, binds human GLP-1R with high affinity (Ki = 1 nM), has low intrinsic efficacy for effector activation and negligible β-arrestin recruitment; low GLP-1R occupancy by orforglipron is sufficient to yield a full biological response in vivo; target engagement in pancreas and brain is confirmed using CRISPR-Cas9-sensitized rat Glp1r, demonstrating the pharmacological basis for nonpeptide GLP-1R agonism. Radioligand competition binding ([125I]GLP-1 and [3H]orforglipron); signal transduction assays; receptor occupancy modeling; glucose tolerance tests in humanized GLP-1R mice; CRISPR-Cas9 Glp1r-sensitized rats; DIO weight loss studies Science translational medicine High 39693407

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Biology of incretins: GLP-1 and GIP. Gastroenterology 2797 17498508
1996 A role for glucagon-like peptide-1 in the central regulation of feeding. Nature 1571 8538742
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