Leveraging human genetic data to investigate the cardiometabolic effects of glucose-dependent insulinotropic polypeptide signalling
Open accessAbstract
Aims/hypothesis: The aim of this study was to leverage human genetic data to investigate the cardiometabolic effects of glucose-dependent insulinotropic polypeptide (GIP) signalling. Methods: Data were obtained from summary statistics of large-scale genome-wide association studies. We examined whether genetic associations for type 2 diabetes liability in the GIP and GIPR genes co-localised with genetic associations for 11 cardiometabolic outcomes. For those outcomes that showed evidence of co-localisation (posterior probability >0.8), we performed Mendelian randomisation analyses to estimate the association of genetically proxied GIP signalling with risk of cardiometabolic outcomes, and to test whether this exceeded the estimate observed when considering type 2 diabetes liability variants from other regions of the genome. Results: Evidence of co-localisation with genetic associations of type 2 diabetes liability at both the GIP and GIPR genes was observed for five outcomes. Mendelian randomisation analyses provided evidence for associations of lower genetically proxied type 2 diabetes liability at the GIP and GIPR genes with lower BMI (estimate in SD units −0.16, 95% CI −0.30, −0.02), C-reactive protein (−0.13, 95% CI −0.19, −0.08) and triacylglycerol levels (−0.17, 95% CI −0.22, −0.12), and higher HDL-cholesterol levels (0.19, 95% CI 0.14, 0.25). For all of these outcomes, the estimates were greater in magnitude than those observed when considering type 2 diabetes liability variants from other regions of the genome. Conclusions/interpretation: This study provides genetic evidence to support a beneficial role of sustained GIP signalling on cardiometabolic health greater than that expected from improved glycaemic control alone. Further clinical investigation is warranted. Data availability: All data used in this study are publicly available. The scripts for the analysis are available at: https://github.com/vkarhune/GeneticallyProxiedGIP . Graphical abstract:
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?
Recent data provides human genetic evidence that supports a beneficial role of sustained GIP signaling on cardiometabolic health outcomes, notably a lower BMI.
“However, recent data provides human genetic evidence that supports a beneficial role of sustained GIP signaling on cardiometabolic health outcomes, notably a lower BMI [69].”
From Next generation GLP-1/GIP/glucagon triple agonists normalize body weight in obese mice (2022) · cites this paper as [69]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 15 · Cited by 28
Research works printed but not linked: 10
- [1]Gribble FM Reimann F Function and mechanisms of enteroendocrine cells and gut hormones in metabolism Nat Rev Endocrinol 2019 15 4 226 237 10.1038/s41574-019-0168-8 30760847 · DOI · Paper page
- [2]Nauck MA Meier JJ Incretin hormones: their role in health and disease Diabetes Obes Metab 2018 20 S1 5 21 10.1111/dom.13129 29364588 · DOI · Paper page
- [4]Gill D, Georgakis M, Walker V et al (2021) Mendelian randomization for studying the effects of perturbing drug targets [version 2; peer review: 3 approved, 1 approved with reservations]. Wellcome Open Res 6(16). 10.12688/wellcomeopenres.16544.2 PMC7903200 33644404 · DOI
- [5]Bailey CJ GIP analogues and the treatment of obesity-diabetes Peptides 2020 125 170202 10.1016/j.peptides.2019.170202 31756366 · DOI
- [7]Rosenstock J Wysham C Frías JP Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial Lancet 2021 398 10295 143 155 10.1016/S0140-6736(21)01324-6 34186022 · DOI · Paper page
- [8]Killion EA Chen M Falsey JR Chronic glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism desensitizes adipocyte GIPR activity mimicking functional GIPR antagonism Nat Commun 2020 11 1 1 17 10.1038/s41467-020-18751-8 33020469 PMC7536395 · DOI · Paper page
- [9]Mroz PA Finan B Gelfanov V Optimized GIP analogs promote body weight lowering in mice through GIPR agonism not antagonism Mol Metab 2019 20 51 62 10.1016/j.molmet.2018.12.001 30578168 PMC6358549 · DOI · Paper page
- [10]Scirica BM Bhatt DL Braunwald E Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus N Engl J Med 2013 369 14 1317 1326 10.1056/NEJMoa1307684 23992601 · DOI · Paper page
- [12]Jujić A Atabaki-Pasdar N Nilsson PM Glucose-dependent insulinotropic peptide and risk of cardiovascular events and mortality: a prospective study Diabetologia 2020 63 1043 1054 10.1007/s00125-020-05093-9 31974732 PMC7145777 · DOI
- [13]Bergmann NC Gasbjerg LS Heimbürger SM No acute effects of exogenous glucose-dependent Insulinotropic polypeptide on energy intake, appetite, or energy expenditure when added to treatment with a long-acting glucagon-like peptide 1 receptor agonist in men with type 2 diabetes Diabetes Care 2020 43 3 588 596 10.2337/dc19-0578 31949084 · DOI · Paper page
- Authors
- Karhunen, V., Daghlas, I., Zuber, V., Vujkovic, M., Olsen, A. K., Knudsen, L. B., Haynes, W. G., Howson, J. M. M., & Gill, D.
- Affiliations
- Imperial College London (GB)
- Harvard University (US)
- University of Cambridge (GB)
- Novo Nordisk (Denmark) (DK)
- University of Oxford (GB)
- University of London (GB)
- Corresponding author
- Karhunen, Ville
- Gill, Dipender
- ORCID
- Venue
- Diabetologia
- Published
- 2021-09-09
- Volume
- 64
- Issue
- 12
- Pages
- 2773-2778
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- PMC
- PMC8563538
- OpenAlex
- W3196975298
- Cited by
- 28
- References
- 15
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 8 · 2023: 2 · 2022: 6
- FWCI
- 2.26
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Diabetologia (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- St George's Online Research Archive (St George's University of London) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion, other-oa)
- Funders
- National Institute for Health and Care Research (CL-2020-16-001)
- British Heart Foundation (RE/18/4/34215)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Keywords
- glucose-dependent insulinotropic polypeptide, cardiometabolic outcomes, Mendelian randomization, body mass index, C-reactive protein, triglycerides, HDL cholesterol, glycemic control
- MeSH terms
- Human Genetics, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Gastric Inhibitory Polypeptide, Glucose, Humans, Receptors, Gastrointestinal Hormone, Genome-Wide Association Study
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
