Affinage

GNAI2

Guanine nucleotide-binding protein G(i) subunit alpha-2 · UniProt P04899

Round 2 corrected
Length
355 aa
Mass
40.5 kDa
Annotated
2026-04-28
130 papers in source corpus 11 papers cited in narrative 11 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GNAI2 encodes Gαi2, an inhibitory heterotrimeric G protein α subunit that transduces signals from Gi-coupled GPCRs by cycling between GDP-bound (inactive) and GTP-bound (active) states, with RGS proteins accelerating its intrinsic GTPase activity to terminate signaling. Gαi2 mediates inhibition of adenylyl cyclase downstream of receptors such as the platelet ADP receptor P2Y12 (PMID:11196645), and its GDP-bound form is sequestered in caveolae through direct interaction with caveolin (PMID:8621645). RGS-insensitive Gnai2 (G184S) knock-in mice exhibit pleiotropic phenotypes including cardiac enlargement, myeloid expansion, resistance to diet-induced obesity, and enhanced insulin sensitivity, demonstrating that RGS-mediated GTPase regulation of Gαi2 is essential for cardiovascular, hematopoietic, and metabolic homeostasis (PMID:16943428, PMID:17928396). Gαi2 and Gαi3 are jointly required for chemoattractant receptor-driven B cell compartmentalization in secondary lymphoid organs (PMID:23977324), and somatic activating mutations at Arg179 that impair GTPase activity define GNAI2 as a proto-oncogene (gip2) in adrenocortical and ovarian tumors (PMID:2116665).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 1990 High

    Identification of somatic GTPase-impairing mutations (R179C/H) in GNAI2 in human tumors established Gαi2 as a proto-oncogene (gip2) and demonstrated that constitutive activation of Gαi2 can drive tumorigenesis.

    Evidence Direct sequencing of adrenocortical and ovarian tumor DNA with structural analogy to characterized activating mutations in Gαs

    PMID:2116665

    Open questions at the time
    • Downstream effectors mediating oncogenic signaling from constitutively active Gαi2 were not identified
    • Whether R179 mutations are sufficient for tumor initiation or require cooperating alterations was not tested
  2. 1995 High

    The crystal structure of the Gαi1β1γ2 heterotrimer revealed the molecular basis of Gβγ-stabilized GDP binding and GTP-induced subunit dissociation via switch II rearrangement, providing the structural framework for understanding Gαi2 activation and regulation.

    Evidence X-ray crystallography at 2.3 Å resolution of recombinant Gαi1β1γ2

    PMID:8521505

    Open questions at the time
    • Structure was of Gαi1, not Gαi2 directly, though high sequence conservation supports applicability
    • GPCR-bound heterotrimer structure was not determined
  3. 1996 High

    Demonstration that inactive (GDP-bound) Gαi2 directly and preferentially binds caveolin established that Gαi2 is spatially organized within caveolae microdomains in a nucleotide-state-dependent manner.

    Evidence Caveolae purification, GST pulldown, co-immunoprecipitation, and overexpression in intact cells

    PMID:8621645

    Open questions at the time
    • Functional consequence of caveolin–Gαi2 interaction for downstream signaling was not defined
    • Whether caveolae localization is required for all Gαi2-dependent GPCR signaling was not tested
  4. 2001 High

    Cloning of the P2Y12 ADP receptor and demonstration of its coupling to Gi (Gαi2) to inhibit adenylyl cyclase placed Gαi2 at the center of platelet aggregation signaling targeted by major antithrombotic drugs.

    Evidence Receptor cloning, functional reconstitution in oocytes and mammalian cells, human loss-of-function mutation in P2Y12 causing a bleeding disorder

    PMID:11196645

    Open questions at the time
    • Specific requirement for Gαi2 versus other Gαi family members in platelets was not genetically dissected
    • Downstream effectors beyond adenylyl cyclase inhibition in platelet activation were not resolved
  5. 2005 High

    Real-time BRET measurements of GPCR–G protein coupling dynamics in living cells revealed that Gα subunit identity (including Gαi2) determines the magnitude and kinetics of receptor–Gβγ interaction, establishing subunit-selective coupling as a dynamic regulatory mechanism.

    Evidence BRET in live HEK293 cells with tagged GPCR, Gα, Gβ, and Gγ subunits

    PMID:15782186

    Open questions at the time
    • Structural basis for Gαi2-specific coupling selectivity was not defined
    • Whether these kinetic differences translate to physiological signaling differences in native tissues was not assessed
  6. 2006 High

    The RGS-insensitive Gnai2(G184S) knock-in mouse revealed that RGS-mediated GTPase acceleration is essential for Gαi2 homeostasis across multiple organ systems, with loss of RGS regulation causing cardiac enlargement, myeloid expansion, skeletal defects, and behavioral hyperactivity.

    Evidence Genomic knock-in mouse with biochemical verification of RGS insensitivity; multi-organ phenotypic analysis

    PMID:16943428

    Open questions at the time
    • Which specific RGS protein(s) regulate Gαi2 in each affected tissue was not determined
    • Whether phenotypes are cell-autonomous was not resolved
  7. 2007 High

    Extension of the G184S model to metabolic challenge showed that unchecked Gαi2 signaling protects against diet-induced obesity and insulin resistance, establishing the RGS–Gαi2 axis as a metabolic regulator controlling energy expenditure and glucose homeostasis.

    Evidence High-fat diet metabolic challenge of G184S mice; glucose/insulin tolerance tests, indirect calorimetry, body composition analysis

    PMID:17928396

    Open questions at the time
    • The specific GPCR(s) and downstream effectors mediating Gαi2-dependent metabolic effects were not identified
    • Whether the metabolic phenotype originates in CNS, adipose, liver, or muscle was not resolved
  8. 2013 High

    B cell-specific double knockout of Gnai2 and Gnai3 demonstrated that these Gαi subunits are jointly required for chemokine-driven B cell migration, compartmentalization in secondary lymphoid organs, and normal humoral immune responses.

    Evidence B cell-conditional double knockout mice; chemokine migration assays, flow cytometry, immunoglobulin isotype profiling

    PMID:23977324

    Open questions at the time
    • Relative contributions of Gαi2 versus Gαi3 to specific chemokine receptor pathways in B cells were not individually delineated
    • Whether the hyper-IgM-like phenotype reflects a signaling defect or a compartmentalization defect was not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of specific RGS proteins regulating Gαi2 in individual tissues, the tissue-of-origin for the metabolic phenotype of enhanced Gαi2 signaling, and the structural basis for Gαi2-selective GPCR coupling.
  • No tissue-specific conditional Gαi2 gain-of-function models have dissected cell-autonomous roles in metabolism
  • No high-resolution structure of Gαi2 in complex with a GPCR or RGS protein has been reported in this timeline
  • Mechanisms by which constitutively active Gαi2 (gip2 mutations) drive tumorigenesis remain unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003924 GTPase activity 3 GO:0060089 molecular transducer activity 2
Localization
GO:0005829 cytosol 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-109582 Hemostasis 1 R-HSA-168256 Immune System 1
Partners
CAV1GNAI3GNB1GNG2P2RY12
Complex memberships
Gi heterotrimer (Gαi2/Gβ/Gγ)

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1990 Somatic mutations at Arg179 (R179C or R179H) in the alpha subunit of Gi2 (encoded by GNAI2) were identified in adrenocortical tumors and ovarian endocrine tumors. These mutations, analogous to activating mutations in Gαs (gsp), are predicted to inhibit GTPase activity and constitutively activate Gαi2 signaling, defining the GNAI2 gene product as a proto-oncogene (termed gip2). Direct sequencing of human tumor DNA; functional analogy to characterized GTPase-impairing mutations in other G protein alpha subunits Science High 2116665
1995 The crystal structure of the Gαi1β1γ2 heterotrimer (at 2.3 Å) revealed two nonoverlapping regions of contact between Gα and Gβ, with the major interface covering switch II of Gα. GTP-induced rearrangement of switch II drives subunit dissociation during signaling. Alterations in GDP binding in the heterotrimer (relative to free Gα-GDP) explain how Gβγ stabilizes the inactive (GDP-bound) conformation of Gα. This structure is directly applicable to GNAI2 (Gαi2), which shares the same heterotrimer architecture. X-ray crystallography at 2.3 Å resolution of recombinant Gαi1β1γ2 heterotrimer Cell High 8521505
1996 Caveolin, the principal structural component of caveolae, was shown to directly interact with Gαi2 (among other G protein alpha subunits including Gαs and Gαo). Mutationally or pharmacologically activated Gαi subunits lost the interaction with caveolin, demonstrating that inactive (GDP-bound) Gαi2 preferentially binds caveolin. This places Gαi2 within caveolae microdomains in a regulated manner dependent on nucleotide state. Detergent-free caveolae purification, co-fractionation, GST pulldown with recombinant caveolin fragments, co-immunoprecipitation, overexpression in intact cells The Journal of Biological Chemistry High 8621645
2001 The platelet ADP receptor P2Y12 was identified and shown to couple to Gi (Gαi2) to mediate inhibition of adenylyl cyclase. P2Y12 is the target of antithrombotic drugs (ticlopidine, clopidogrel), and its Gi-mediated signaling is required for ADP-induced platelet aggregation via the integrin GPIIb-IIIa pathway. Receptor cloning, expression in Xenopus oocytes and mammalian cells, pharmacological characterization, identification of a patient with a P2Y12 loss-of-function mutation causing a bleeding disorder, inhibition of adenylyl cyclase assays Nature High 11196645
2003 Gαi2 protein was identified as an abundant component of human B cell-derived exosomes by mass spectrometry, demonstrating that Gαi2 is sorted into multivesicular bodies and secreted in exosomes, linking it to extracellular vesicle biology. Purification of B cell-derived exosomes followed by mass spectrometric protein identification The Journal of Biological Chemistry Medium 12519789
2005 Using bioluminescence resonance energy transfer (BRET) in living human cells, basal precoupling of GPCRs to Gαβγ complexes (including Gαi2-containing complexes) was directly monitored in real time. Ligand-induced increases in GPCR–Gβγ interaction occurred with t1/2 ~300 ms, followed by slower receptor desensitization. The identity of the Gα subunit present in the complex strongly influenced the magnitude of agonist-promoted GPCR–Gβγ interaction, demonstrating selectivity in receptor–G protein coupling dynamics. BRET assay in living HEK293 cells with tagged GPCR, Gα, Gβ, and Gγ subunits; real-time kinetic measurements Nature Methods High 15782186
2006 A genomic knock-in of an RGS-insensitive G184S allele of Gnai2 in mice produced a dramatic pleiotropic phenotype affecting multiple organ systems (enlarged heart, markedly enlarged spleen, elevated neutrophil counts, shortened long bones, behavioral hyperactivity, reduced viability, and decreased body weight). The G184S mutation blocks RGS protein binding and GTPase acceleration at Gαi2, demonstrating that RGS-mediated regulation of Gαi2 GTPase activity is required for normal cardiovascular, myeloid, skeletal, and CNS function in vivo. Genomic knock-in mouse model; phenotypic analysis of homozygous and heterozygous mice; biochemical verification of RGS insensitivity Molecular and Cellular Biology High 16943428
2006 A -318C>G SNP in the GNAI2 gene promoter region was found to reduce transcriptional activity 2.5-fold in transfected HEK293 cells. EMSA experiments demonstrated that the -318G allele specifically binds the Sp1 transcription factor (confirmed by Sp1 antibody supershift), while the -318C allele binds YY1. This SNP was associated with higher systolic blood pressure and increased risk of hypertension in Caucasians, linking Sp1-mediated GNAI2 transcriptional regulation to blood pressure control. Promoter-reporter transfection assay (HEK293 cells), electrophoretic mobility shift assay (EMSA) with competition and supershift using anti-Sp1 and anti-YY1 antibodies, association study in 655 individuals Journal of the American Society of Nephrology Medium 16565233
2007 Male homozygous Gαi2(G184S) knock-in mice (expressing RGS-insensitive Gαi2) on a high-fat diet were resistant to weight gain, had decreased body fat, were protected from insulin resistance, and showed increased energy expenditure. Both male and female G184S mice exhibited enhanced insulin sensitivity and glucose tolerance. This demonstrates that RGS protein regulation of Gαi2 signaling plays an important role in controlling body weight, adiposity, and insulin sensitivity. High-fat diet metabolic challenge of Gαi2(G184S) genomic knock-in mice; body composition analysis, glucose tolerance tests, insulin tolerance tests, indirect calorimetry for energy expenditure measurement Diabetes High 17928396
2013 Conditional knockout of both Gαi2 (Gnai2) and Gαi3 (Gnai3) specifically in B lymphocytes caused loss of B cell compartments in spleen, lymph nodes, mucosal sites, and thymus; a partial block in splenic follicular B cell development; near-complete refractoriness to chemokine stimulation; poor responsiveness to B cell antigen receptor engagement; and a hyper-IgM-like syndrome. Bone marrow B cell development and egress remained grossly intact, demonstrating that Gαi2 and Gαi3 are specifically required for chemoattractant receptor signaling that governs B cell compartmentalization and function in secondary lymphoid organs. B cell-specific conditional double knockout mice (Gnai2/Gnai3 deleted in B cells); flow cytometry of lymphoid organs; chemokine migration assays; immunoglobulin isotype analysis; histological analysis of lymphoid architecture PLoS ONE High 23977324
2014 GNAI2 mRNA was decreased in 85.9% of ovarian cancer patients (54% mean reduction; up to 2.8-fold decrease in clear cell carcinoma), with reductions occurring in early-stage cancer but relative increases in advanced cancers. GNAI2 message changes correlated with deregulation of CREB, Fos, Myc, cyclins, Arf, transition from estrogen dependence to independence, and metastatic potential, implicating GNAI2 (which inhibits adenylyl cyclase to decrease intracellular cAMP and regulate CREB) as an upstream driver of ovarian cancer progression. Directed sequencing and qPCR of human ovarian cancer tissue arrays; database mining of multiple GEO datasets (>589 OvCa patients total); correlation analysis Journal of Ovarian Research Low 24423449

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
2005 Towards a proteome-scale map of the human protein-protein interaction network. Nature 2090 16189514
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2001 Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 1139 11196645
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
1995 The structure of the G protein heterotrimer Gi alpha 1 beta 1 gamma 2. Cell 1011 8521505
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
1990 Two G protein oncogenes in human endocrine tumors. Science (New York, N.Y.) 967 2116665
1996 Co-purification and direct interaction of Ras with caveolin, an integral membrane protein of caveolae microdomains. Detergent-free purification of caveolae microdomains. The Journal of biological chemistry 916 8621645
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2003 Proteomic and biochemical analyses of human B cell-derived exosomes. Potential implications for their function and multivesicular body formation. The Journal of biological chemistry 708 12519789
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2008 Large-scale proteomics and phosphoproteomics of urinary exosomes. Journal of the American Society of Nephrology : JASN 607 19056867
2010 GIP and GLP-1, the two incretin hormones: Similarities and differences. Journal of diabetes investigation 551 24843404
2006 Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis. Cell 517 17110338
1994 Structural determinants for activation of the alpha-subunit of a heterotrimeric G protein. Nature 517 8208289
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2010 Systematic analysis of human protein complexes identifies chromosome segregation proteins. Science (New York, N.Y.) 421 20360068
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2020 Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI insight 362 32730231
2005 Real-time monitoring of receptor and G-protein interactions in living cells. Nature methods 346 15782186
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2017 An Approach to Spatiotemporally Resolve Protein Interaction Networks in Living Cells. Cell 328 28388416
2020 How May GIP Enhance the Therapeutic Efficacy of GLP-1? Trends in endocrinology and metabolism: TEM 324 32396843
2016 Identification of Zika Virus and Dengue Virus Dependency Factors using Functional Genomics. Cell reports 306 27342126
2021 The evolving story of incretins (GIP and GLP-1) in metabolic and cardiovascular disease: A pathophysiological update. Diabetes, obesity & metabolism 282 34310013
2021 The glucose-dependent insulinotropic polypeptide (GIP) regulates body weight and food intake via CNS-GIPR signaling. Cell metabolism 244 33571454
2007 GIP receptor antagonism reverses obesity, insulin resistance, and associated metabolic disturbances induced in mice by prolonged consumption of high-fat diet. American journal of physiology. Endocrinology and metabolism 210 17848629
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 174 31029770
2022 Beyond the pancreas: contrasting cardiometabolic actions of GIP and GLP1. Nature reviews. Endocrinology 165 36509857
2021 GIP Receptor Agonism Attenuates GLP-1 Receptor Agonist-Induced Nausea and Emesis in Preclinical Models. Diabetes 156 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 145 32459834
2021 Effects on weight loss and glycemic control with SAR441255, a potent unimolecular peptide GLP-1/GIP/GCG receptor triagonist. Cell metabolism 138 34932984
2009 Glucose-dependent insulinotropic polypeptide (Gastric Inhibitory Polypeptide; GIP). Vitamins and hormones 131 19251046
2008 Physiology of incretins (GIP and GLP-1) and abnormalities in type 2 diabetes. Diabetes & metabolism 128 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 111 35065096
2022 Next generation GLP-1/GIP/glucagon triple agonists normalize body weight in obese mice. Molecular metabolism 107 35809773
2021 GIP mediates the incretin effect and glucose tolerance by dual actions on α cells and β cells. Science advances 106 33712466
2017 Central administration of GLP-1 and GIP decreases feeding in mice. Biochemical and biophysical research communications 96 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 91 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
2014 A naturally occurring GIP receptor variant undergoes enhanced agonist-induced desensitization, which impairs GIP control of adipose insulin sensitivity. Molecular and cellular biology 84 25047836
2019 GIP has neuroprotective effects in Alzheimer and Parkinson's disease models. Peptides 82 31705913
2008 Vaccination against GIP for the treatment of obesity. PloS one 81 18779862
2024 Tirzepatide modulates the regulation of adipocyte nutrient metabolism through long-acting activation of the GIP receptor. Cell metabolism 79 38878772
2019 The role of GIP in α-cells and glucagon secretion. Peptides 79 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 76 21864749
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 75 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
2006 Pleiotropic phenotype of a genomic knock-in of an RGS-insensitive G184S Gnai2 allele. Molecular and cellular biology 67 16943428
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 63 19748062
1985 GIP increases insulin receptor affinity and cellular sensitivity in adipocytes. The American journal of physiology 61 3909828
1986 The receptors of the VIP family peptides (VIP, secretin, GRF, PHI, PHM, GIP, glucagon and oxyntomodulin). Specificities and identity. Peptides 60 3018707
2019 Physiological roles of the GIP receptor in murine brown adipose tissue. Molecular metabolism 59 31451430
2018 GIP regulates inflammation and body weight by restraining myeloid-cell-derived S100A8/A9. Nature metabolism 58 32694806
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 Receptor in the CNS for the Pathogenesis of Obesity. Diabetes 52 34176784
2009 Immunoassays for the incretin hormones GIP and GLP-1. Best practice & research. Clinical endocrinology & metabolism 52 19748060
2021 The Role of GIP in the Regulation of GLP-1 Satiety and Nausea. Diabetes 51 34176783
2020 Tirzepatide: a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) dual agonist in development for the treatment of type 2 diabetes. Expert review of endocrinology & metabolism 51 33030356
2018 High Glycemic Index Metabolic Damage - a Pivotal Role of GIP and GLP-1. Trends in endocrinology and metabolism: TEM 51 29602522
2023 GLP-1 and GIP receptors signal through distinct β-arrestin 2-dependent pathways to regulate pancreatic β cell function. Cell reports 49 37897727
2020 The role of endogenous GIP and GLP-1 in postprandial bone homeostasis. Bone 47 32730920
2019 Glucose-dependent insulinotropic polypeptide (GIP) and cardiovascular disease. Peptides 47 31689454
2020 Pharmacological characterization of mono-, dual- and tri-peptidic agonists at GIP and GLP-1 receptors. Biochemical pharmacology 46 32360365
2023 Dual GIP/GLP-1 receptor agonists: New advances for treating type-2 diabetes. Annales d'endocrinologie 45 36639119
2003 GIP or not GIP? That is the question. Trends in pharmacological sciences 45 12628351
2019 Physiology of the Incretin Hormones, GIP and GLP-1-Regulation of Release and Posttranslational Modifications. Comprehensive Physiology 44 31688969
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 42 36747334
2007 Resistance to diet-induced obesity and improved insulin sensitivity in mice with a regulator of G protein signaling-insensitive G184S Gnai2 allele. Diabetes 42 17928396
2004 Physiology of GIP--a lesson from GIP receptor knockout mice. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 40 15655707
2021 Effects of endogenous GIP in patients with type 2 diabetes. European journal of endocrinology 38 33886495
2024 The GIP receptor activates futile calcium cycling in white adipose tissue to increase energy expenditure and drive weight loss in mice. Cell metabolism 36 39642881
2022 Therapeutic application of GLP-1 and GIP receptor agonists in Parkinson's disease. Expert opinion on therapeutic targets 36 35584372
2022 Designing a Dual GLP-1R/GIPR Agonist from Tirzepatide: Comparing Residues Between Tirzepatide, GLP-1, and GIP. Drug design, development and therapy 35 35651477
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
2020 Gut Hormone GIP Induces Inflammation and Insulin Resistance in the Hypothalamus. Endocrinology 33 32603429
2017 Genetic determinants of circulating GIP and GLP-1 concentrations. JCI insight 32 29093273
2019 Recent advances of GIP and future horizons. Peptides 30 31838219
2018 Gut carbohydrate inhibits GIP secretion via a microbiota/SCFA/FFAR3 pathway. The Journal of endocrinology 28 30400014
2023 GIP receptor agonism blocks chemotherapy-induced nausea and vomiting. Molecular metabolism 25 37245848
2022 Effects of Hepatic Impairment on the Pharmacokinetics of the Dual GIP and GLP-1 Receptor Agonist Tirzepatide. Clinical pharmacokinetics 25 35674880
2013 The loss of Gnai2 and Gnai3 in B cells eliminates B lymphocyte compartments and leads to a hyper-IgM like syndrome. PloS one 25 23977324
2020 The pathogenic role of the GIP/GIPR axis in human endocrine tumors: emerging clinical mechanisms beyond diabetes. Reviews in endocrine & metabolic disorders 24 31933128
2025 Integrated Management of Cardiovascular-Renal-Hepatic-Metabolic Syndrome: Expanding Roles of SGLT2is, GLP-1RAs, and GIP/GLP-1RAs. Biomedicines 23 39857719
2019 Metabolism of GIP and the contribution of GIP to the glucose-lowering properties of DPP-4 inhibitors. Peptides 23 31706956
2017 Effect of D-Ala2GIP, a stable GIP receptor agonist on MPTP-induced neuronal impairments in mice. European journal of pharmacology 23 28366809
2024 The antiemetic actions of GIP receptor agonism. American journal of physiology. Endocrinology and metabolism 22 38477667
2019 Blockade of gastric inhibitory polypeptide (GIP) action as a novel means of countering insulin resistance in the treatment of obesity-diabetes. Peptides 22 31733230
1984 The GIP receptor on pancreatic beta cell tumor: molecular identification by covalent cross-linking. Biochemical and biophysical research communications 22 6331448
2021 Investigating GIPR (ant)agonism: A structural analysis of GIP and its receptor. Structure (London, England : 1993) 21 33891864
2020 The role of GLP-1/GIP receptor agonists in Alzheimer's disease. Advances in clinical and experimental medicine : official organ Wroclaw Medical University 21 32614526
2024 Stimulating intestinal GIP release reduces food intake and body weight in mice. Molecular metabolism 20 38653401
2014 Suppression of GNAI2 message in ovarian cancer. Journal of ovarian research 20 24423449
2020 GIP and GLP-1 Potentiate Sulfonylurea-Induced Insulin Secretion in Hepatocyte Nuclear Factor 1α Mutation Carriers. Diabetes 19 32518064
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
2018 Efficacy of targeting bone-specific GIP receptor in ovariectomy-induced bone loss. The Journal of endocrinology 18 30121578
2024 Altered desensitization and internalization patterns of rodent versus human glucose-dependent insulinotropic polypeptide (GIP) receptors. An important drug discovery challenge. British journal of pharmacology 17 38952084
2023 Combined GIP receptor and GLP1 receptor agonism attenuates NAFLD in male APOE∗3-Leiden.CETP mice. EBioMedicine 17 37379656
2022 The GIP/GIPR axis in medullary thyroid cancer: clinical and molecular findings. Endocrine-related cancer 17 35298396
2019 The role of GIP and pancreatic GLP-1 in the glucoregulatory effect of DPP-4 inhibition in mice. Diabetologia 17 31414143
2022 Evidence for Involvement of GIP and GLP-1 Receptors and the Gut-Gonadal Axis in Regulating Female Reproductive Function in Mice. Biomolecules 16 36551163
2018 GLP1 and GIP are involved in the action of synbiotics in broiler chickens. Journal of animal science and biotechnology 16 29416857
2006 The -318 C>G single-nucleotide polymorphism in GNAI2 gene promoter region impairs transcriptional activity through specific binding of Sp1 transcription factor and is associated with high blood pressure in Caucasians from Italy. Journal of the American Society of Nephrology : JASN 16 16565233
2024 Population pharmacokinetics of the GIP/GLP receptor agonist tirzepatide. CPT: pharmacometrics & systems pharmacology 15 38356317
2024 GLP-1 and GIP agonism has no direct actions in human hepatocytes or hepatic stellate cells. Cellular and molecular life sciences : CMLS 15 39607493
2021 Signaling profiles in HEK 293T cells co-expressing GLP-1 and GIP receptors. Acta pharmacologica Sinica 15 34446852
2019 Cardiovascular biology of the GIP receptor. Peptides 15 31812593