Gastric inhibitory peptide controls adipose insulin sensitivity via activation of cAMP-response element-binding protein and p110β isoform of phosphatidylinositol 3-kinase
Open accessAbstract
Gastric inhibitory peptide (GIP) is an incretin hormone secreted in response to food intake. The best known function of GIP is to enhance glucose-dependent insulin secretion from pancreatic β-cells. Extra-pancreatic effects of GIP primarily occur in adipose tissues. Here, we demonstrate that GIP increases insulin-dependent translocation of the Glut4 glucose transporter to the plasma membrane and exclusion of FoxO1 transcription factor from the nucleus in adipocytes, establishing that GIP has a general effect on insulin action in adipocytes. Stimulation of adipocytes with GIP alone has no effect on these processes. Using pharmacologic and molecular genetic approaches, we show that the effect of GIP on adipocyte insulin sensitivity requires activation of both the cAMP/protein kinase A/CREB signaling module and p110β phosphoinositol-3' kinase, establishing a novel signal transduction pathway modulating insulin action in adipocytes. This insulin-sensitizing effect is specific for GIP because isoproterenol, which elevates adipocyte cAMP and activates PKA/CREB signaling, does not affect adipocyte insulin sensitivity. The insulin-sensitizing activity points to a more central role for GIP in intestinal regulation of peripheral tissue metabolism, an emerging feature of inter-organ communication in the control of metabolism.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Postprandial insulin excursions drive glucose disposal through actions in muscle and adipose tissue, and GIP enhances insulin sensitivity and glucose disposal in adipose tissue.
“Postprandial excursions of insulin drive glucose dis posal through actions in muscle and adipose tissue, along with effects of postprandial excursions in GIP, to enhance insulin sensitivity and augment glucose disposal in adipose tissue (2-5).”
From Effects of Tirzepatide vs Semaglutide on β-Cell Function, Insulin Sensitivity, and Glucose Control During a Meal Test (2024) · cites this paper as [3]
The ‘GIP Potentiates Insulin Action in Adipocytes’ section reports that GIP increased insulin-stimulated glucose uptake in adipocytes, supporting the adipose-tissue part of the claim. The Discussion connects this effect to nutrient disposal after meals. Our copy does not establish the claim about postprandial insulin driving glucose disposal through muscle, and the paper’s own experiments used adipocytes rather than postprandial measurements. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Nauck, M. A., Heimesaat, M. M., Orskov, C., Holst, J. J., Ebert, R., & Creutzfeldt, W. (1993) · Journal of Clinical Investigation · doi:10.1172/jci116186 · Cited by 1,651 · see citing works
STIMULATION OF INSULIN SECRETION BY GASTRIC INHIBITORY POLYPEPTIDE IN MAN. <sup>1</sup>
Dupre, J., Ross, S. A., Watson, D., & Brown, J. C. (1973) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-37-5-826 · Cited by 860 · see citing works
Hormonal stimulation of adenylyl cyclase through Gi-protein βγ subunits
Federman, A. D., Conklin, B. R., Schrader, K. A., Reed, R. R., & Bourne, H. R. (1992) · Nature · doi:10.1038/356159a0 · Cited by 624 · see citing works
Miyawaki, K., Yamada, Y., Yano, H., Niwa, H., Ban, N., Ihara, Y., Kubota, A., Fujimoto, S., Kajikawa, M., Kuroe, A., et al. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.26.14843 · Cited by 454 · see citing works
Activation of Lipoprotein Lipase by Glucose-dependent Insulinotropic Polypeptide in Adipocytes
Kim, S.-J., Nian, C., & McIntosh, C. H. S. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m609088200 · Cited by 216 · see citing works
Song, D. H., Getty–Kaushik, L., Tseng, E., Simon, J., Corkey, B. E., & Wolfe, M. M. (2007) · Gastroenterology · doi:10.1053/j.gastro.2007.09.005 · Cited by 137 · see citing works
Kim, S.-J., Nian, C., & McIntosh, C. H. S. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m704896200 · Cited by 118 · see citing works
Flagged first, then by citations
Research works printed but not linked: 14
- Miyawaki, K., Yamada, Y., Yano, H., Niwa, H., Ban, N., Ihara, Y., Kubota, A., Fujimoto, S., Kajikawa, M., Kuroe, A., Tsuda, K., Hashimoto, H., Ya- mashita, T., Jomori, T., Tashiro, F., Miyazaki, J., and Seino, Y. (1999) Proc. Natl. Acad. Sci. U.S.A. 96, 14843-14847
- Sano, H., Eguez, L., Teruel, M. N., Fukuda, M., Chuang, T. D., Chavez, J. A., Lienhard, G. E., and McGraw, T. E. (2007) Cell Metab. 5, 293-303
- Gonzalez, E., and McGraw, T. E. (2009) Proc. Natl. Acad. Sci. U.S.A. 106, 7004 -7009
- Karylowski, O., Zeigerer, A., Cohen, A., and McGraw, T. E. (2004) Mol. Biol. Cell 15, 870 -882
- Zeigerer, A., Lampson, M. A., Karylowski, O., Sabatini, D. D., Adesnik, M., Ren, M., and McGraw, T. E. (2002) Mol. Biol. Cell 13, 2421-2435
- Lampson, M. A., Racz, A., Cushman, S. W., and McGraw, T. E. (2000) J. Cell Sci. 113, 4065-4076
- Martin, O. J., Lee, A., and McGraw, T. E. (2006) J. Biol. Chem. 281, 484 -490
- Lampson, M. A., Schmoranzer, J., Zeigerer, A., Simon, S. M., and McGraw, T. E. (2001) Mol. Biol. Cell 12, 3489 -3501
- Eguez, L., Lee, A., Chavez, J. A., Miinea, C. P., Kane, S., Lienhard, G. E., and McGraw, T. E. (2005) Cell Metab. 2, 263-272
- Jiang, Z. Y., Zhou, Q. L., Coleman, K. A., Chouinard, M., Boese, Q., and Czech, M. P. (2003) Proc. Natl. Acad. Sci. U.S.A. 100, 7569 -7574
- Gonzalez, E., and McGraw, T. E. (2006) Mol. Biol. Cell 17, 4484 -4493
- Rydel, R. E., and Greene, L. A. (1988) Proc. Natl. Acad. Sci. U.S.A. 85, 1257-1261
- Guillermet-Guibert, J., Bjorklof, K., Salpekar, A., Gonella, C., Ramadani, F., Bilancio, A., Meek, S., Smith, A. J., Okkenhaug, K., and Vanhaesebroeck, B. (2008) Proc. Natl. Acad. Sci. U.S.A. 105, 8292-8297
- Zhao, J. J., Liu, Z., Wang, L., Shin, E., Loda, M. F., and Roberts, T. M. (2005) Proc. Natl. Acad. Sci. U.S.A. 102, 18443-18448
Cited by
Sorted by citations
How May GIP Enhance the Therapeutic Efficacy of GLP-1?
Samms, R. J., Coghlan, M. P., & Sloop, K. W. (2020) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2020.02.006 · Cited by 419 · see citing works
GIPR agonism mediates weight-independent insulin sensitization by tirzepatide in obese mice
Samms, R. J., Christe, M. E., Collins, K. A. L., Pirro, V., Droz, B. A., Holland, A. K., Friedrich, J. L., Wojnicki, S., Konkol, D. L., Cosgrove, R., et al. (2021) · Journal of Clinical Investigation · doi:10.1172/jci146353 · Cited by 256 · see citing works
Kim, S.-J., Nian, C., Karunakaran, S., Clee, S. M., Isales, C. M., & McIntosh, C. H. S. (2012) · PLoS ONE · doi:10.1371/journal.pone.0040156 · Cited by 182 · see citing works
Anti-diabetic drugs and weight loss in patients with type 2 diabetes
Lazzaroni, E., Ben Nasr, M., Loretelli, C., Pastore, I., Plebani, L., Lunati, M. E., Vallone, L., Bolla, A. M., Rossi, A., Montefusco, L., et al. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.105782 · Cited by 182 · see citing works
Tirzepatide for the treatment of adults with type 2 diabetes: An endocrine perspective
De Block, C., Bailey, C., Wysham, C., Hemmingway, A., Allen, S. E., & Peleshok, J. (2023) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.14831 · Cited by 121 · see citing works
Disruption of GIP/GIPR axis in human adipose tissue is linked to obesity and insulin resistance
Ceperuelo-Mallafré, V., Duran, X., Pachón, G., Roche, K., Garrido-Sánchez, L., Vilarrasa, N., Tinahones, F. J., Vicente, V., Pujol, J., Vendrell, J., et al. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-3350 · Cited by 112 · see citing works
Mohammad, S., Patel, R. T., Bruno, J., Panhwar, M. S., Wen, J., & McGraw, T. E. (2014) · Molecular and Cellular Biology · doi:10.1128/mcb.00256-14 · Cited by 104 · see citing works
Self-citationTimper, K., Grisouard, J., Sauter, N. S., Herzog-Radimerski, T., Dembinski, K., Peterli, R., Frey, D. M., Zulewski, H., Keller, U., Müller, B., et al. (2013) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00100.2012 · Cited by 88 · see citing works
Pharmacological antagonism of the incretin system protects against diet-induced obesity
Svendsen, B., Capozzi, M. E., Nui, J., Hannou, S. A., Finan, B., Naylor, J., Ravn, P., D'Alessio, D. A., & Campbell, J. E. (2020) · Molecular Metabolism · doi:10.1016/j.molmet.2019.11.018 · Cited by 67 · see citing works
Nie, Y., Ma, R. C., Chan, J. C. N., Xu, H., & Xu, G. (2012) · The FASEB Journal · doi:10.1096/fj.11-196782 · Cited by 53 · see citing works
Mather, K. J., Mari, A., Heise, T., DeVries, J. H., Hua, M., Urva, S., Coskun, T., Haupt, A., Heine, R. J., Pratt, E., et al. (2024) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgae319 · Cited by 32 · see citing works
- Authors
- Mohammad, S., Ramos, L. S., Buck, J., Levin, L. R., Rubino, F., & McGraw, T. E.
- Affiliations
- Cornell University (US)
- Corresponding author
- McGraw, Timothy E.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2011-12
- Volume
- 286
- Issue
- 50
- Pages
- 43062-43070
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3234864
- OpenAlex
- W2032914675
- Cited by
- 59
- References
- 7
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 5 · 2023: 5 · 2022: 6 · 2021: 3 · 2020: 3 · 2019: 5 · 2018: 3 · 2017: 4 · 2016: 2 · 2015: 3 · 2014: 6 · 2013: 2 · 2012: 4
- FWCI
- 2.89
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK096925, R01DK069982, R01DK052852, DK52852, R56DK069982, R56DK096925, DK 69982)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- glucose-dependent insulinotropic polypeptide, incretins, CREB, CREB signaling, GLUT4 translocation, protein kinase A, isoproterenol, inter-organ communication, adipose tissue
- MeSH terms
- Cyclic AMP, Adipose Tissue, Animals, Electrophoresis, Polyacrylamide Gel, Gastric Inhibitory Polypeptide, Insulin Resistance, Receptor, Insulin, Immunoblotting, Cyclic AMP Response Element-Binding Protein, Adipocytes, 3T3-L1 Cells, Immunoprecipitation, Mice, Class Ia Phosphatidylinositol 3-Kinase
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
