Affinage

GIP

Gastric inhibitory polypeptide · UniProt P09681

Length
153 aa
Mass
17.1 kDa
Annotated
2026-06-10
100 papers in source corpus 27 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GIP (glucose-dependent insulinotropic polypeptide) is an intestinal incretin hormone whose release from K-cells couples nutrient sensing to systemic metabolic, skeletal, and central control through its dedicated seven-transmembrane Gαs-coupled receptor GIPR, which raises intracellular cAMP upon ligand binding and discriminates GIP from related secretin-family peptides (PMID:7589426). Within pancreatic β-cells GIPR potentiates glucose-induced insulin secretion, a response requiring N-glycosylation of the receptor's extracellular domain for plasma-membrane expression and receptor stability (PMID:22412906), and dependent on β-arrestin 2, which mediates GIP-induced F-actin depolymerization without engaging cAMP/PKA or ERK (PMID:37897727); GIPR transcription is itself controlled by PPARγ acting at a promoter PPRE, linking adipokine signaling to incretin sensitivity (PMID:20332343). Beyond the pancreas, GIP acts directly on adipocytes to drive insulin-cooperative glucose uptake and fed-state lipid storage while promoting fasting-state lipolysis (PMID:38878772) and, through adipocyte GIPR, activates SERCA-mediated futile calcium cycling that increases thermogenesis and energy expenditure (PMID:39642881); in primary human osteoclasts it suppresses osteoclastogenesis and bone resorption via Src/cAMP/Akt/NFκB/NFATc1 signaling (PMID:36747334), a function confirmed in humans where GIPR antagonism reverses GIP-driven suppression of bone resorption (PMID:31622777, PMID:32730920, PMID:32077470). Central GIPR signaling is required for the weight-reducing and anorectic effects of GIP and GLP-1/GIP co-agonism (PMID:33571454), and GIPR-expressing GABAergic neurons in the area postrema/NTS mediate suppression of GLP-1R-agonist-induced nausea and emesis (PMID:34380697). GIP is rapidly inactivated by N-terminal cleavage by DPP-IV (PMID:19748062), and selective antagonism with GIP(3-30)NH2 establishes the receptor's causal role in insulin secretion and bone resorption in humans (PMID:28948296). Pharmacologically, dual GIP/GLP-1 agonists such as tirzepatide mimic native GIP at GIPR while showing biased, internalization-sparing agonism at GLP-1R (PMID:32730231, PMID:33556643).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1995 High

    Establishing the molecular identity and signaling output of the GIP receptor answered how GIP transduces its hormonal signal, defining it as a Gαs-coupled GPCR specific for GIP.

    Evidence Molecular cloning from human insulinoma cDNA, stable expression in CHL fibroblasts, radioligand binding and cAMP assays with a secretin-family specificity panel

    PMID:7589426

    Open questions at the time
    • No structural model of ligand engagement at this stage
    • Calcium signaling absent in fibroblasts but not tested in native cell types
  2. 2007 High

    Discovery of a dominant-negative truncated GIPR splice variant explained how receptor surface availability is tuned and linked isoform balance to GIP sensitivity in obesity.

    Evidence Co-expression of truncated and wild-type GIPR with cAMP and surface-expression assays, RT-PCR and islet secretion in diet-induced obese mice

    PMID:17971513

    Open questions at the time
    • Mechanism of reduced surface expression of wild-type receptor not resolved
    • Human relevance of the splice variant ratio not established
  3. 2010 High

    Defining PPARγ control of GIPR transcription and the GIP-driven LPL induction pathway connected receptor expression and adipocyte lipid handling to nuclear regulatory programs.

    Evidence ChIP, siRNA, luciferase reporters in INS-1 cells, pancreas-specific PPARγ KO mice; and LPL promoter reporter, ChIP, siRNA and co-IP in GIPR-expressing cells

    PMID:20332343 PMID:20693566

    Open questions at the time
    • Whether insulin-context switching between cAMP/PKA and PI3-K/PKB pathways occurs in vivo unresolved
    • Direct demonstration of PPARγ-GIPR axis driving human GIP resistance not shown
  4. 2012 High

    Identifying N-glycosylation of the GIPR extracellular domain answered why receptor surface expression and insulinotropic function depend on post-translational processing, and uncovered GIP-GLP-1 receptor heteromerization.

    Evidence Site-directed mutagenesis of Asn sites, surface expression and half-life assays, INS-1 insulin secretion, and BRET

    PMID:22412906

    Open questions at the time
    • Functional consequence of the GIP-GLP-1 heteromer in native cells unknown
    • Whether glycosylation is dynamically regulated not addressed
  5. 2017 High

    Development of the selective antagonist GIP(3-30)NH2 enabled causal interrogation of GIPR in humans, proving GIP's dominant contribution to glucose-stimulated insulin secretion; and ectopic GIPR genomics explained GIP-dependent Cushing's syndrome.

    Evidence Receptor specificity panel in COS-7 cells plus randomized crossover hyperglycemic clamp in healthy men; and aCGH, FISH and methylation analysis of adrenocortical lesions

    PMID:28931750 PMID:28948296

    Open questions at the time
    • Single-center genomic analysis of adrenal lesions
    • Antagonist effects on non-pancreatic tissues not yet mapped at this stage
  6. 2019 High

    Establishing direct GIP action in primary human osteoclasts and confirming it with human antagonist studies answered how GIP couples nutrient intake to skeletal homeostasis.

    Evidence Primary human osteoclast/osteoblast cultures, RNA-seq, signaling and bioenergetics assays with GIPR antagonist; and randomized crossover clamp with GIP ± GIP(3-30)NH2 measuring CTX/P1NP

    PMID:31622777 PMID:36747334

    Open questions at the time
    • Long-term skeletal consequences of GIP signaling not established
    • Relative contribution of each signaling arm (Src/cAMP/Akt/NFκB) not quantified
  7. 2019 High

    Tissue-specific GIPR deletion in brown adipose tissue and myeloid cells revealed peripheral GIPR roles in thermogenic fuel use and adipose inflammation beyond the pancreas.

    Evidence BAT-specific and myeloid-specific Gipr knockout mice with metabolic phenotyping, direct cell treatment, and genetic epistasis with S100A8/A9 co-deletion

    PMID:31451430 PMID:32694806

    Open questions at the time
    • Whether the myeloid-GIPR-S100A8/A9 axis operates in humans unknown
    • Reconciliation of GIPR agonism versus deficiency both yielding metabolic benefit unresolved
  8. 2020 High

    Quantifying the endogenous incretin contribution to postprandial physiology and characterizing tirzepatide's biased agonism clarified GIP's physiological footprint and the pharmacology of dual agonists.

    Evidence Four-arm randomized antagonist crossover study in healthy men; and receptor occupancy, cAMP, β-arrestin and internalization assays with primary islet secretion

    PMID:32077470 PMID:32730231 PMID:32730920

    Open questions at the time
    • Mechanism of additive glucose effects of GIP and GLP-1 not molecularly dissected
    • Tissue selectivity of tirzepatide engagement at clinical doses incompletely mapped
  9. 2021 High

    Defining CNS and hindbrain GIPR functions answered how central GIPR signaling mediates weight loss, food-intake suppression, hypothalamic inflammation, and protection from GLP-1-induced nausea.

    Evidence CNS-specific and humanized Gipr knockout mice with cFos imaging; snRNA-seq of AP/NTS with multi-species behavioral pharmacology; ICV GIP with RNA-seq, antibody and KO loss-of-function; and structural homology modeling with mutagenesis

    PMID:32603429 PMID:33571454 PMID:33891864 PMID:34380697

    Open questions at the time
    • Crystal/cryo-EM structure of GIPR-ligand complex not available (homology model only)
    • Mechanism linking GABAergic GIPR neurons to anti-emetic output not resolved
    • CNS hypothalamic inflammation findings are single-lab and Medium confidence
  10. 2023 High

    Dissecting β-arrestin 2 dependence distinguished GIPR from GLP-1R signaling logic, showing ARRB2 is required for GIP-potentiated insulin secretion via F-actin remodeling rather than cAMP.

    Evidence β-arrestin 2 knockout mouse islets and ARRB2-reduced human islets with cAMP/PKA, ERK, F-actin and insulin secretion assays

    PMID:37897727

    Open questions at the time
    • Molecular link between ARRB2 and F-actin depolymerization not defined
    • Relevance to non-islet GIPR-expressing tissues untested
  11. 2024 High

    Adipocyte and K-cell gain-of-function models, fed/fasted adipocyte pharmacology, and a hepatocyte negative-control study refined where GIPR agonism acts to drive weight loss and energy expenditure.

    Evidence Inducible adipocyte-specific GIPR transgenic mice with SERCA calcium cycling analysis; chemogenetic K-cell activation with GIPR antibody blockade; human adipocyte fed/fasted functional assays plus DIO mouse lipid challenge; and direct GLP-1R/GIPR agonist treatment of human hepatocytes/HSCs

    PMID:38653401 PMID:38878772 PMID:39607493 PMID:39642881

    Open questions at the time
    • Mechanism of the 'metabolic memory' weight-loss persistence unknown
    • Whether intestinal K-cell-driven anorexia operates in humans untested
    • Hepatic absence of effect is a negative result requiring dose/context boundaries

Open questions

Synthesis pass · forward-looking unresolved questions
  • How GIPR agonism and GIPR loss-of-function can both yield metabolic benefit, and the high-resolution structural basis of agonist versus antagonist binding, remain unresolved.
  • No experimental atomic structure of the GIPR-ligand complex
  • Reconciliation of agonist-vs-antagonist metabolic benefit paradox unresolved
  • Human translation of CNS and adipocyte mouse mechanisms incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0060089 molecular transducer activity 1
Localization
GO:0005576 extracellular region 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 3
Partners
ARRB2DPP4GIPRGLP1R

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 The human GIP receptor is a 466 amino acid seven-transmembrane domain G-protein coupled receptor that, when stably expressed in fibroblast CHL cells, couples to adenylate cyclase increasing intracellular cAMP (EC50 ~1.29×10⁻¹³ M for human GIP 1-42). The receptor accepts human GIP 1-42 and porcine GIP 1-30 as high-affinity ligands (Kd ~10⁻⁸ M) but shows no response to secretin, glucagon, GLP-1, VIP, PHI, or PACAP. GIP-1-42 stimulation did not increase intracellular calcium in transfected cells. Molecular cloning from human insulinoma cDNA library, stable transfection into CHL fibroblasts, radioligand binding assay, cAMP accumulation assay, intracellular calcium measurement FEBS letters High 7589426
2010 GIP (in the presence of insulin) increases LPL gene expression and LPL promoter activity in human adipocytes through a pathway involving PI3-K, PKB, and AMPK-dependent phosphorylation of CREB at Ser133 and nuclear localization of the CREB coactivator TORC2. CREB and TORC2 bind to a cAMP-response element (-II) in the human LPL promoter, and siRNA knockdown of either CREB or TORC2 reduces LPL expression. The cAMP/PKA pathway was not activated by GIP in the presence of insulin. LPL promoter-luciferase reporter assay in GIP receptor-expressing HEK-293 cells, phosphorylation assays, siRNA knockdown, chromatin immunoprecipitation, co-immunoprecipitation Journal of lipid research High 20693566
2007 A novel GIPR splice variant retaining intron 8 produces a C-terminally truncated GIPR. When co-expressed with wild-type GIPR in transfected cells, this truncated isoform does not produce cAMP in response to GIP but inhibits GIP-induced cAMP production through wild-type GIPR (dominant negative effect), coinciding with reduced wild-type GIPR cell-surface expression. In diet-induced obese mice, the ratio of truncated GIPR to total GIPR mRNA was reduced by ~32%, correlating with increased GIP-induced cAMP and insulin secretion (hypersensitivity). Transfection of truncated and wild-type GIPR constructs into cells, cAMP assay, cell surface receptor expression assay, RT-PCR in islets from HFD mice, ex vivo islet insulin secretion assay American journal of physiology. Endocrinology and metabolism High 17971513
2012 Each of the N-terminal extracellular Asn residues of the human GIP receptor is glycosylated when expressed in CHO cells. N-glycosylation enhances cell-surface expression and function of the GIPR more strongly than the GLP-1 receptor, primarily by reducing receptor degradation in the endoplasmic reticulum and lengthening receptor half-life. N-glycosylation is required for GIP receptor plasma membrane expression and efficient GIP-potentiated glucose-induced insulin secretion from INS-1 cells. Co-expression of a glycosylation-deficient GIP receptor mutant with wild-type GLP-1 receptor rescues its surface expression, and BRET data indicate formation of a GIP-GLP-1 receptor heteromer. Site-directed mutagenesis of Asn glycosylation sites, cell-surface expression assays, receptor half-life measurement, INS-1 insulin secretion assay, BRET PloS one High 22412906
2017 GIP(3-30)NH2 is a selective, efficacious GIPR antagonist in humans. In COS-7 cells it neither bound nor activated related receptors (GLP-1R, GLP-2R, glucagon R, secretin R, GHRH R). During hyperglycemic clamp in healthy men, co-infusion of GIP(3-30)NH2 reduced GIP-induced insulin secretion by 82% and returned glucose requirements to placebo levels. GIP(3-30)NH2 had no effect alone on glucagon, GLP-1, or lipid parameters. In vitro receptor binding and cAMP accumulation in transfected COS-7 cells; randomized double-blind crossover hyperglycemic clamp study in humans with co-infusion of GIP and GIP(3-30)NH2 Diabetologia High 28948296
2010 PPARγ binds to a PPAR response element (PPRE) in the GIP receptor (GIP-R) promoter and regulates GIP-R transcription. Pancreas-specific PPARγ knockout mice show ~70% reduction in islet GIP-R protein. Thiazolidinedione activation of PPARγ in normal mouse islets causes ~3-fold increase in GIP-R protein and doubles insulin secretion in response to glucose+GIP. Hyperglycemia in ZF rats reduces both PPARγ and GIP-R protein, suggesting this pathway mediates GIP resistance in type 2 diabetes. Chromatin immunoprecipitation, siRNA, luciferase promoter assay in INS-1 cells, pancreas-specific PPARγ knockout mice, islet immunohistochemistry and protein expression Diabetes High 20332343
2020 Tirzepatide (dual GIP/GLP-1 receptor agonist) mimics native GIP at the GIP receptor but shows biased agonism at the GLP-1 receptor, favoring cAMP generation over β-arrestin recruitment, and produces weaker GLP-1 receptor internalization than native GLP-1. β-arrestin1 limits the insulin response to GLP-1 but not to GIP or tirzepatide in primary islets, suggesting that tirzepatide's GLP-1 receptor bias enhances insulin secretion. Receptor occupancy analysis shows greater engagement of tirzepatide at GIPR than GLP-1R at clinical doses. Receptor occupancy calculation, cAMP signaling assays, β-arrestin recruitment assays, receptor internalization assays, primary islet insulin secretion with β-arrestin1 manipulation JCI insight High 32730231
2021 CNS GIPR signaling is required for the weight-reducing and food-intake-suppressing effects of GIP and GLP-1/GIP co-agonism. CNS-specific Gipr knockout mice and humanized GIPR knockin mice with CNS-hGIPR deletion on HFD show decreased body weight and improved glucose metabolism. Acute central and peripheral administration of acyl-GIP increases cFos neuronal activity in hypothalamic feeding centers, coinciding with decreased body weight and food intake. The superior metabolic effect of GLP-1/GIP co-agonism relative to GLP-1 is extinguished in CNS-Gipr KO mice. CNS-specific Gipr knockout mice, humanized GIPR knockin mice with CNS deletion, intracerebroventricular and peripheral administration of acyl-GIP, cFos immunohistochemistry, body weight and food intake measurements, epistasis with CNS-Gipr KO Cell metabolism High 33571454
2021 GIPR activation attenuates GLP-1R agonist-induced nausea and emesis while maintaining reduced food intake and body weight. Single-nuclei RNA sequencing of the area postrema/nucleus tractus solitarius (AP/NTS) identifies distinct neuronal populations expressing GIPR (predominantly GABAergic neurons) and GLP-1R (predominantly excitatory neurons). GIPR agonism in these GABAergic neurons blocks emetic and illness behaviors in multiple species. Behavioral pharmacology (emesis/nausea assays in mice, rats, musk shrews), single-nuclei RNA sequencing of AP/NTS, species comparison across three mammalian species Diabetes High 34380697
2018 GIP directly stimulates osteopontin (OPN) protein expression in a dose-dependent manner in rat primary adipocytes. A loss-of-function variant of GIPR (rs10423928) that reduces exon 9-containing receptor isoform (required for transmembrane activity) is associated with lower adipose tissue OPN mRNA and better insulin sensitivity in obese individuals. GIP treatment of primary rat adipocytes with OPN protein measurement, human genetic association of GIPR variant with adipose OPN mRNA and insulin sensitivity measures Diabetes Medium 23349498
2019 GIP directly reduces osteoclast activity through multiple signaling pathways (Src, cAMP, Akt, p38, NFκB) impairing nuclear translocation of NFATc1 and NFκB, inhibiting osteoclastogenesis, delaying bone resorption, and increasing osteoclast apoptosis in primary human osteoclasts. GIP also improves osteoblast survival. GIPR is robustly expressed in mature human osteoclasts (confirmed by RNA-seq and in situ hybridization). All effects are abolished by the GIPR antagonist GIP(3-30)NH2. Primary human osteoclast and osteoblast cultures, RNA-seq, in situ hybridization, LANCE cAMP assay, AlphaLISA phosphorylation assays, intracellular calcium imaging, confocal microscopy for NFATc1/NFκB localization, Seahorse bioenergetics, GIPR antagonist blockade European journal of endocrinology High 36747334
2019 Using GIP(3-30)NH2, GIP receptor antagonism in healthy men reduces GIP-induced suppression of the bone resorption marker CTX by ~51% during hyperglycemic clamp, and attenuates GIP-stimulated P1NP (bone formation marker) and PTH suppression. These effects are GIPR-mediated. Randomized double-blind placebo-controlled crossover study, hyperglycemic clamp with GIP ± GIP(3-30)NH2 infusion, CTX and P1NP measurements Bone High 31622777
2020 Endogenous GIP (during a mixed meal) contributes ~22–25% to postprandial suppression of bone resorption (CTX) in healthy humans, as demonstrated by GIPR antagonism with GIP(3-30)NH2. Endogenous GLP-1 had no detectable effect on bone resorption. Combined GIP and GLP-1 receptor antagonism additively impaired postprandial glycemic control and insulin secretion, indicating their effects on glucose homeostasis are additive. Only GIP affected gallbladder motility. Randomized double-blind placebo-controlled crossover study with four-arm design (GIP antagonist, GLP-1 antagonist, both, placebo) during OGTT and mixed meal test in healthy men Bone / The Journal of clinical endocrinology and metabolism High 32077470 32730920
2018 Myeloid cell-specific GIPR deficiency in HFD-fed mice leads to greater weight gain, insulin resistance, hepatic steatosis, impaired energy expenditure, reduced WAT beiging, and myelopoiesis. GIP directly downregulates S100A8 expression in adipose tissue macrophages, and co-deletion of GIPR and S100A8/A9 in immune cells ameliorates the metabolic phenotype. This identifies a myeloid-GIPR-S100A8/A9 signaling axis coupling nutrient signals to inflammation and adaptive thermogenesis. Myeloid-specific Gipr knockout mice, HFD feeding, metabolic phenotyping, gene expression in WAT macrophages, direct GIP treatment of macrophages, genetic epistasis with S100A8/A9 co-deletion Nature metabolism High 32694806
2019 GIPR is expressed in murine brown adipose tissue (BAT). GIP directly increases Il6 mRNA and IL-6 secretion in BAT cells. BAT-specific (Myf5 domain) Gipr knockout mice exhibit higher body temperature during acute cold challenge, lower respiratory exchange ratio, and impaired lipid tolerance at room temperature. At 4°C, GiprBAT-/- mice show lower body weight and higher iBAT oxygen consumption, indicating the BAT GIPR links to thermogenic fuel utilization and oxygen consumption. BAT cell culture with GIP treatment, siRNA knockdown of Gipr in BAT cells with gene expression, BAT-specific (GiprBAT-/-) knockout mice, metabolic cage phenotyping, cold challenge, ex vivo iBAT oxygen consumption Molecular metabolism High 31451430
2023 β-arrestin 2 (ARRB2) mediates distinct roles in GLP-1R versus GIPR signaling in pancreatic β cells. For GIPR, ARRB2 is required for GIP-potentiated insulin secretion in both mouse and human islets. The GIPR-ARRB2 axis does not regulate cAMP/PKA or ERK signaling but mediates GIP-induced F-actin depolymerization. In contrast, for GLP-1R, ARRB2 dampens insulin secretion at physiological doses. The dual agonist tirzepatide does not require ARRB2 for insulin secretion potentiation. β-arrestin 2 knockout mouse islets, human islets with reduced ARRB2 (diabetogenic conditions), pharmacological assays for cAMP/PKA and ERK, F-actin staining, insulin secretion assays Cell reports High 37897727
2021 Spatiotemporal analysis shows that GLP-1/GIP dual agonists MAR709 and tirzepatide induce diminished ligand-induced receptor internalization at both GIP and GLP-1 receptors compared to native agonists, while preserving maximal cAMP production despite partial Gαs recruitment. GLP-1R co-localization with Rab11-associated recycling endosomes was not different between MAR709 and GLP-1R mono-agonists. BRET-based Gαs recruitment and internalization assays, live-cell HILO microscopy for receptor trafficking, comparison across mono- and dual-agonists Molecular metabolism High 33556643
2021 GIP administered centrally (ICV) increases hypothalamic proinflammatory markers (Il-6, Socs3) and activates IκB kinase-β (IKKβ) inflammatory signaling. GIP also reduces anorectic insulin actions in the brain and diminishes insulin-induced phosphorylation of Akt and GSK3β in the hypothalamus. An antagonistic GIPR antibody and GIPR deficiency both significantly reduce proinflammatory cytokines and Socs3 in the hypothalamus during HFD feeding. ICV GIP administration in mice, unbiased RNA sequencing of GIP-stimulated hypothalami, GIPR antibody treatment, GIPR knockout mice, phospho-Akt and phospho-GSK3β Western blot, cytokine measurement Endocrinology Medium 32603429
2024 GIPR induction exclusively in adipocytes activates SERCA-mediated futile calcium cycling in white adipose tissue, increasing lipid oxidation, thermogenesis, and energy expenditure. Adipocyte-specific GIPR induction protects mice from diet-induced obesity and causes ~35% weight loss in obese mice. A 'metabolic memory' effect maintains weight loss after the transgene is switched off. Inducible adipocyte-specific GIPR transgenic mouse model, calcium flux assays, thermogenesis and energy expenditure measurement, body composition analysis, SERCA pathway interrogation Cell metabolism High 39642881
2024 Long-acting GIPR agonism in human adipocytes and diet-induced obese mice: in the fed (insulin-present) state, GIPR agonism enhances insulin signaling, augments glucose uptake, and increases glucose-to-glycerol conversion cooperatively with insulin. In the fasted (insulin-absent) state, GIPR agonism increases lipolysis. In vivo, a long-acting GIPR agonist reduces circulating triglycerides during oral lipid challenge and increases lipoprotein-derived fatty acid uptake into adipose tissue. Human adipocyte functional assays (glucose uptake, glycerol production, lipolysis), DIO mouse model with long-acting GIPR agonist treatment, oral lipid challenge with triglyceride and fatty acid tracer measurement Cell metabolism High 38878772
2021 GIP receptor agonism blocks emesis and attenuates illness behaviors (nausea surrogates) elicited by GLP-1R activation in mice, rats, and musk shrews, while maintaining GLP-1R agonist-induced reduction in food intake, body weight, and improved glucose tolerance. The area postrema/NTS of the hindbrain mediates these effects, and GIPR is most highly expressed in GABAergic neurons in this region. Multi-species pharmacological experiments (mice, rats, musk shrews), snRNA-seq of AP/NTS, GIPR agonist co-administration with GLP-1R agonists, food intake and emesis behavioral assays Diabetes High 34380697
2021 Structural and mutational analysis of the GIP receptor using a homology model of GIPR based on GLP-1R, combined with molecular dynamics and in vitro mutagenesis, identifies R183(2.60), R190(2.67), and R300(5.40) as key residues for GIPR activation. Disruption of a K293(ECL2)–E362(ECL3) salt bridge by GIPR antagonists strongly reduces GIPR activation. GIP(1-30)NH2 and GIP(1-42) have different binding modes compared with antagonists GIP(3-30)NH2 and GIP(5-30)NH2. Homology modeling, molecular dynamics simulation, in vitro site-directed mutagenesis with cAMP and binding assays Structure Medium 33891864
2017 Ectopic GIPR expression in adrenocortical adenomas causing GIP-dependent Cushing's syndrome occurs through monoallelic transcriptional activation of the GIPR gene. In some adrenal lesions, this is driven by somatic chromosomal duplications in the 19q13.32 region containing the GIPR locus, with rearrangements juxtaposing cis-acting regulatory sequences (including glucocorticoid response elements) to the translocated GIPR allele, driving its aberrant expression. Array-comparative genomic hybridization, RNA/DNA FISH, RRBS DNA methylation analysis, molecular analysis of adrenocortical lesions from 14 patients JCI insight Medium 28931750
2009 GIP is rapidly inactivated primarily by N-terminal cleavage by dipeptidyl peptidase IV (DPP IV/CD26) on the cell surface of endothelial and epithelial cells, generating inactive metabolites. Cleavage by neprilysin (neutral endopeptidase) is a minor degradation route. Renal clearance eliminates incretin fragments but is of less importance for regulating incretin bioactivity. Biochemical degradation studies establishing DPP-IV as the primary inactivating enzyme (review synthesizing multiple mechanism studies) Best practice & research. Clinical endocrinology & metabolism Medium 19748062
2024 Stimulating intestinal GIP release via chemogenetic activation (hM3Dq DREADD) of GIP-expressing K-cells in mice increases plasma GIP to postprandial levels and produces a robust inhibition of food intake. This anorectic effect is prevented by peripheral or central injection of antagonistic GIPR antibodies and reproduced when Dq expression is restricted to intestinal K-cells. The effect is maintained in diet-induced obese mice, with chronic K-cell activation reducing food intake and attenuating body weight gain. GIP-Dq DREADD mouse model, chemogenetic K-cell activation, peripheral and central GIPR antibody injection, intersectional Gip-Cre/Villin-Flp model, plasma GIP measurement, food intake and body weight assays Molecular metabolism High 38653401
2015 GLP-1-producing L-cells and GIP-producing K-cells rarely overlap (~5% co-expression) and differ by bombesin receptor-2 expression. Bombesin/neuromedin C stimulates GLP-1 but not GIP secretion, consistent with selective expression of the bombesin receptor-2 in L-cells but not K-cells, as demonstrated in isolated perfused mouse intestine and primary cultured intestinal cells. Transgenic mice with fluorescent markers in GIP-positive and GLP-1-positive cells, secretion assays in isolated perfused mouse intestine and primary cultured intestinal cells, expression analysis of bombesin receptor-2 The Journal of endocrinology High 26483393
2024 GLP-1R/GIPR agonists (liraglutide, acyl-GIP, and MAR709) have no direct actions in human hepatocytes or hepatic stellate cells at concentrations effective for insulin release. None reduced lipid content in oleic/palmitic acid-loaded hepatocytes, nor improved fibrotic marker expression in TGFβ-activated HSCs, nor induced CREB phosphorylation in either cell type. Human hepatocyte and HSC cell lines and primary cells treated with GLP-1R/GIPR agonists; lipid content assay, fibrotic marker expression, CREB phosphorylation assay Cellular and molecular life sciences Medium 39607493

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Biology of incretins: GLP-1 and GIP. Gastroenterology 2816 17498508
2010 GIP and GLP-1, the two incretin hormones: Similarities and differences. Journal of diabetes investigation 562 24843404
2020 Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI insight 381 32730231
2020 How May GIP Enhance the Therapeutic Efficacy of GLP-1? Trends in endocrinology and metabolism: TEM 338 32396843
2021 The evolving story of incretins (GIP and GLP-1) in metabolic and cardiovascular disease: A pathophysiological update. Diabetes, obesity & metabolism 294 34310013
2021 Dual GIP and GLP-1 Receptor Agonist Tirzepatide Improves Beta-cell Function and Insulin Sensitivity in Type 2 Diabetes. The Journal of clinical endocrinology and metabolism 257 33236115
2021 The glucose-dependent insulinotropic polypeptide (GIP) regulates body weight and food intake via CNS-GIPR signaling. Cell metabolism 256 33571454
2000 GIP biology and fat metabolism. Life sciences 228 10666005
2022 LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept. Cell metabolism 226 35985340
2004 GPCR interacting proteins (GIP). Pharmacology & therapeutics 203 15464590
2019 The incretin system in healthy humans: The role of GIP and GLP-1. Metabolism: clinical and experimental 177 31029770
2022 Beyond the pancreas: contrasting cardiometabolic actions of GIP and GLP1. Nature reviews. Endocrinology 175 36509857
2021 GIP Receptor Agonism Attenuates GLP-1 Receptor Agonist-Induced Nausea and Emesis in Preclinical Models. Diabetes 164 34380697
2004 On the physiology of GIP and GLP-1. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 153 15655703
2020 GIP as a Therapeutic Target in Diabetes and Obesity: Insight From Incretin Co-agonists. The Journal of clinical endocrinology and metabolism 150 32459834
2011 Two incretin hormones GLP-1 and GIP: comparison of their actions in insulin secretion and β cell preservation. Progress in biophysics and molecular biology 150 21820006
2021 Effects on weight loss and glycemic control with SAR441255, a potent unimolecular peptide GLP-1/GIP/GCG receptor triagonist. Cell metabolism 145 34932984
2002 Structure-function of the glucagon receptor family of G protein-coupled receptors: the glucagon, GIP, GLP-1, and GLP-2 receptors. Receptors & channels 140 12529935
2009 Glucose-dependent insulinotropic polypeptide (Gastric Inhibitory Polypeptide; GIP). Vitamins and hormones 132 19251046
2005 GIP and GLP-1 as incretin hormones: lessons from single and double incretin receptor knockout mice. Regulatory peptides 131 15780432
2008 Physiology of incretins (GIP and GLP-1) and abnormalities in type 2 diabetes. Diabetes & metabolism 130 18640588
2005 Biological actions of the incretins GIP and GLP-1 and therapeutic perspectives in patients with type 2 diabetes. Diabetes & metabolism 119 16142014
2022 GLP-1 and GIP receptor signaling in beta cells - A review of receptor interactions and co-stimulation. Peptides 116 35065096
2022 Next generation GLP-1/GIP/glucagon triple agonists normalize body weight in obese mice. Molecular metabolism 114 35809773
2010 GIP increases human adipocyte LPL expression through CREB and TORC2-mediated trans-activation of the LPL gene. Journal of lipid research 110 20693566
2017 Central administration of GLP-1 and GIP decreases feeding in mice. Biochemical and biophysical research communications 97 28610922
2022 Effects of Tirzepatide, a Dual GIP and GLP-1 RA, on Lipid and Metabolite Profiles in Subjects With Type 2 Diabetes. The Journal of clinical endocrinology and metabolism 94 34608929
2019 Evaluation of the incretin effect in humans using GIP and GLP-1 receptor antagonists. Peptides 91 31693916
2009 Therapeutic potential for GIP receptor agonists and antagonists. Best practice & research. Clinical endocrinology & metabolism 90 19748067
2019 GIP has neuroprotective effects in Alzheimer and Parkinson's disease models. Peptides 84 31705913
2024 Tirzepatide modulates the regulation of adipocyte nutrient metabolism through long-acting activation of the GIP receptor. Cell metabolism 82 38878772
2021 Spatiotemporal GLP-1 and GIP receptor signaling and trafficking/recycling dynamics induced by selected receptor mono- and dual-agonists. Molecular metabolism 80 33556643
2019 The role of GIP in α-cells and glucagon secretion. Peptides 80 31785304
2017 GIP(3-30)NH2 is an efficacious GIP receptor antagonist in humans: a randomised, double-blinded, placebo-controlled, crossover study. Diabetologia 79 28948296
2003 Glucose-dependent insulinotropic polypeptide (GIP): anti-diabetic and anti-obesity potential? Neuropeptides 79 14607102
2013 Link between GIP and osteopontin in adipose tissue and insulin resistance. Diabetes 78 23349498
2011 Incretin effect: GLP-1, GIP, DPP4. Diabetes research and clinical practice 78 21864749
1995 Molecular cloning, functional expression, and signal transduction of the GIP-receptor cloned from a human insulinoma. FEBS letters 78 7589426
2021 The dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist tirzepatide: a novel cardiometabolic therapeutic prospect. Cardiovascular diabetology 77 34819089
2007 A novel GIP receptor splice variant influences GIP sensitivity of pancreatic beta-cells in obese mice. American journal of physiology. Endocrinology and metabolism 67 17971513
2018 Glucose-dependent insulinotropic polypeptide (GIP) receptor antagonists as anti-diabetic agents. Peptides 65 29412817
2009 Mechanisms underlying the rapid degradation and elimination of the incretin hormones GLP-1 and GIP. Best practice & research. Clinical endocrinology & metabolism 64 19748062
2019 Physiological roles of the GIP receptor in murine brown adipose tissue. Molecular metabolism 61 31451430
2018 GIP regulates inflammation and body weight by restraining myeloid-cell-derived S100A8/A9. Nature metabolism 60 32694806
1986 The receptors of the VIP family peptides (VIP, secretin, GRF, PHI, PHM, GIP, glucagon and oxyntomodulin). Specificities and identity. Peptides 60 3018707
2007 GIP receptor mRNA expression in different fat tissue depots in postmenopausal non-diabetic women. Regulatory peptides 58 17395281
2019 The Effects of Dual GLP-1/GIP Receptor Agonism on Glucagon Secretion-A Review. International journal of molecular sciences 57 31443356
2020 GIP and GLP-1 Receptor Antagonism During a Meal in Healthy Individuals. The Journal of clinical endocrinology and metabolism 56 32077470
2021 The Role of GIP in the Regulation of GLP-1 Satiety and Nausea. Diabetes 54 34176783
2023 GLP-1 and GIP receptors signal through distinct β-arrestin 2-dependent pathways to regulate pancreatic β cell function. Cell reports 53 37897727
2021 The Role of GIP Receptor in the CNS for the Pathogenesis of Obesity. Diabetes 53 34176784
2012 Regulation of GIP and GLP1 receptor cell surface expression by N-glycosylation and receptor heteromerization. PloS one 53 22412906
2009 Immunoassays for the incretin hormones GIP and GLP-1. Best practice & research. Clinical endocrinology & metabolism 52 19748060
2018 High Glycemic Index Metabolic Damage - a Pivotal Role of GIP and GLP-1. Trends in endocrinology and metabolism: TEM 51 29602522
2023 Dual GIP/GLP-1 receptor agonists: New advances for treating type-2 diabetes. Annales d'endocrinologie 48 36639119
2019 Glucose-dependent insulinotropic polypeptide (GIP) and cardiovascular disease. Peptides 48 31689454
2020 The role of endogenous GIP and GLP-1 in postprandial bone homeostasis. Bone 47 32730920
2020 Pharmacological characterization of mono-, dual- and tri-peptidic agonists at GIP and GLP-1 receptors. Biochemical pharmacology 46 32360365
2020 GIP as a Potential Therapeutic Target for Atherosclerotic Cardiovascular Disease-A Systematic Review. International journal of molecular sciences 45 32098413
2003 GIP or not GIP? That is the question. Trends in pharmacological sciences 45 12628351
2006 GIP(Lys16PAL) and GIP(Lys37PAL): novel long-acting acylated analogues of glucose-dependent insulinotropic polypeptide with improved antidiabetic potential. Journal of medicinal chemistry 44 16451070
2023 GIP reduces osteoclast activity and improves osteoblast survival in primary human bone cells. European journal of endocrinology 43 36747334
2015 GLP1- and GIP-producing cells rarely overlap and differ by bombesin receptor-2 expression and responsiveness. The Journal of endocrinology 43 26483393
2010 Physiologic and pharmacologic modulation of glucose-dependent insulinotropic polypeptide (GIP) receptor expression in beta-cells by peroxisome proliferator-activated receptor (PPAR)-gamma signaling: possible mechanism for the GIP resistance in type 2 diabetes. Diabetes 43 20332343
2017 Adrenal GIPR expression and chromosome 19q13 microduplications in GIP-dependent Cushing's syndrome. JCI insight 42 28931750
2004 Physiology of GIP--a lesson from GIP receptor knockout mice. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 40 15655707
2024 The GIP receptor activates futile calcium cycling in white adipose tissue to increase energy expenditure and drive weight loss in mice. Cell metabolism 39 39642881
2022 Therapeutic application of GLP-1 and GIP receptor agonists in Parkinson's disease. Expert opinion on therapeutic targets 38 35584372
2021 Effects of endogenous GIP in patients with type 2 diabetes. European journal of endocrinology 38 33886495
2019 GIP analogues and the treatment of obesity-diabetes. Peptides 38 31756366
2022 GIP and GLP-2 together improve bone turnover in humans supporting GIPR-GLP-2R co-agonists as future osteoporosis treatment. Pharmacological research 37 34995796
2019 GIP and the gut-bone axis - Physiological, pathophysiological and potential therapeutic implications. Peptides 35 31715213
2023 GLP-1/GIP analogs: potential impact in the landscape of obesity pharmacotherapy. Expert opinion on pharmacotherapy 34 36927378
2019 Hypermethylator Phenotype and Ectopic GIP Receptor in GNAS Mutation-Negative Somatotropinomas. The Journal of clinical endocrinology and metabolism 34 30376114
2020 Gut Hormone GIP Induces Inflammation and Insulin Resistance in the Hypothalamus. Endocrinology 33 32603429
2019 GIP's effect on bone metabolism is reduced by the selective GIP receptor antagonist GIP(3-30)NH2. Bone 33 31622777
2019 Molecular interactions of full-length and truncated GIP peptides with the GIP receptor - A comprehensive review. Peptides 33 31809770
2017 Genetic determinants of circulating GIP and GLP-1 concentrations. JCI insight 33 29093273
2019 Recent advances of GIP and future horizons. Peptides 30 31838219
2011 GIP-dependent expression of hypothalamic genes. Physiological research 30 21995902
2004 GIP as a potential therapeutic agent? Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 29 15655720
2006 Expression of ACTH receptor pathway genes in glucose-dependent insulinotrophic peptide (GIP)-dependent Cushing's syndrome. Clinical endocrinology 28 16402925
2021 Single-Cell Mapping of GLP-1 and GIP Receptor Expression in the Dorsal Vagal Complex. Diabetes 27 34176785
2025 Integrated Management of Cardiovascular-Renal-Hepatic-Metabolic Syndrome: Expanding Roles of SGLT2is, GLP-1RAs, and GIP/GLP-1RAs. Biomedicines 26 39857719
2023 GIP receptor agonism blocks chemotherapy-induced nausea and vomiting. Molecular metabolism 26 37245848
2019 GIP analogues augment bone strength by modulating bone composition in diet-induced obesity in mice. Peptides 26 31765668
2022 Effects of Hepatic Impairment on the Pharmacokinetics of the Dual GIP and GLP-1 Receptor Agonist Tirzepatide. Clinical pharmacokinetics 25 35674880
2024 The antiemetic actions of GIP receptor agonism. American journal of physiology. Endocrinology and metabolism 24 38477667
2019 Metabolism of GIP and the contribution of GIP to the glucose-lowering properties of DPP-4 inhibitors. Peptides 24 31706956
2024 Stimulating intestinal GIP release reduces food intake and body weight in mice. Molecular metabolism 23 38653401
2017 Effect of D-Ala2GIP, a stable GIP receptor agonist on MPTP-induced neuronal impairments in mice. European journal of pharmacology 23 28366809
2020 The role of GLP-1/GIP receptor agonists in Alzheimer's disease. Advances in clinical and experimental medicine : official organ Wroclaw Medical University 22 32614526
2024 Secretion of glucagon, GLP-1 and GIP may be affected by circadian rhythm in healthy males. BMC endocrine disorders 21 38481208
2021 Investigating GIPR (ant)agonism: A structural analysis of GIP and its receptor. Structure (London, England : 1993) 21 33891864
2020 GIP and GLP-1 Potentiate Sulfonylurea-Induced Insulin Secretion in Hepatocyte Nuclear Factor 1α Mutation Carriers. Diabetes 21 32518064
2023 Combined GIP receptor and GLP1 receptor agonism attenuates NAFLD in male APOE∗3-Leiden.CETP mice. EBioMedicine 19 37379656
2022 Evidence for Involvement of GIP and GLP-1 Receptors and the Gut-Gonadal Axis in Regulating Female Reproductive Function in Mice. Biomolecules 19 36551163
2024 GLP-1 and GIP agonism has no direct actions in human hepatocytes or hepatic stellate cells. Cellular and molecular life sciences : CMLS 18 39607493
2023 Research Progress on the GIP/GLP-1 Receptor Coagonist Tirzepatide, a Rising Star in Type 2 Diabetes. Journal of diabetes research 18 37096236
2022 Nephroprotective Properties of the Glucose-Dependent Insulinotropic Polypeptide (GIP) and Glucagon-like Peptide-1 (GLP-1) Receptor Agonists. Biomedicines 18 36289848

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