Inactivation of the Glucose-Dependent Insulinotropic Polypeptide Receptor Improves Outcomes following Experimental Myocardial Infarction

John R. Ussher, Jonathan E. Campbell, Erin E. Mulvihill, Laurie L. Baggio, Holly E. Bates, Brent A. McLean, Keshav Gopal, Megan Capozzi, Bernardo Yusta, Xiemin Cao, Safina Ali, Minsuk Kim, M. Golam Kabir, Yutaka Seino, Jinya Suzuki, Daniel J. Drucker

Research output: Contribution to journalArticlepeer-review

52 Scopus citations


Incretin hormones exert pleiotropic metabolic actions beyond the pancreas. Although the heart expresses both incretin receptors, the cardiac biology of GIP receptor (GIPR) action remains incompletely understood. Here we show that GIPR agonism did not impair the response to cardiac ischemia. In contrast, genetic elimination of the Gipr reduced myocardial infarction (MI)-induced ventricular injury and enhanced survival associated with reduced hormone sensitive lipase (HSL) phosphorylation; it also increased myocardial triacylglycerol (TAG) stores. Conversely, direct GIPR agonism in the isolated heart reduced myocardial TAG stores and increased fatty acid oxidation. The cardioprotective phenotype in Gipr −/− mice was partially reversed by pharmacological activation or genetic overexpression of HSL. Selective Gipr inactivation in cardiomyocytes phenocopied Gipr −/− mice, resulting in improved survival and reduced adverse remodeling following experimental MI. Hence, the cardiomyocyte GIPR regulates fatty acid metabolism and the adaptive response to ischemic cardiac injury. These findings have translational relevance for developing GIPR-based therapeutics. Ussher et al. demonstrate that the GIP receptor is expressed in cardiomyocytes and that direct activation of GIPR signaling regulates cardiac lipid metabolism. GIPR agonism was not deleterious in the context of ischemic cardiac injury; however, germline- or cardiomyocyte-selective loss of GIPR signaling increased survival and reduced adverse ventricular remodeling.

Original languageEnglish
Pages (from-to)450-460.e6
JournalCell Metabolism
Issue number2
StatePublished - 6 Feb 2018

Bibliographical note

Funding Information:
J.R.U. was supported by fellowships from the Canadian Institutes of Health Research (CIHR) and the Alberta Innovates-Health Solutions. J.E.C. has received fellowships from the Banting and Best Diabetes Centre (BBDC) and the CIHR. B.A.M. and H.E.B. received fellowships from the BBDC. H.E.B. received fellowship support from the Canadian Diabetes Association (CDA). S.A. has received a studentship from the BBDC. M.K. has received a fellowship from the CDA. E.E.M. has received fellowships from the CDA and the CIHR. D.J.D. has received funding from: the Heart and Stroke Foundation of Ontario G-14-0005953 , CIHR grants 82700 and 154321 , partial operating grant support from Merck for studies of cardiac GIP action, a Novo Nordisk postdoctoral training program grant, the Canada Research Chair in Regulatory Peptides, and a Banting and Best Diabetes Centre Novo Nordisk Chair in Incretin Biology. HL-1 cells were a generous gift from Dr. William Claycomb. Human heart tissue was provided via Dr. Kenneth B. Margulies at the University of Pennsylvania in Philadelphia, PA. We thank Chris Newgard and Olga Ilkayeva for helpful discussions surrounding analysis of cardiac metabolomics.

Funding Information:
J.R.U. has received a speaker's honorarium for symposia sponsored by Novo Nordisk. E.M. and J.C. have received a speaker's honorarium for symposia sponsored by Merck. Y.S. reports consulting or speaking fees from Novo Nordisk, MSD, Takeda Pharmaceuticals, Sanofi, Taisho Toyama Pharmaceuticals, Eli Lilly and Company, Mitsubishi Tanabe Pharma, Ono Pharmaceutical, Kowa, Astellas Pharma, and Boehringer Ingelheim.

Publisher Copyright:
© 2017 Elsevier Inc.


  • G-protein-coupled receptor
  • cardiovascular
  • diabetes
  • glucose-dependent insulinotropic polypeptide
  • gut peptide
  • hormone sensitive lipase
  • incretin
  • ischemia
  • myocardial infarction
  • obesity


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