Abstract
Aims/hypothesisThe aim of this study was to leverage human genetic data to investigate the cardiometabolic effects of glucose-dependent insulinotropic polypeptide (GIP) signalling.MethodsData 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.ResultsEvidence 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/interpretationThis 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 availabilityAll data used in this study are publicly available. The scripts for the analysis are available at: https://github.com/vkarhune/GeneticallyProxiedGIP.Graphical abstract
Highlights
Glucose-dependent insulinotropic polypeptide is an incretin peptide that stimulates insulin secretion after oral nutrient intake
For the five outcomes of heart failure (HF), BMI, Creactive protein (CRP) levels, HDL-cholesterol (HDL-C) and triacylglycerols, there was evidence for Co-localisation protects at both glucosedependent insulinotropic polypeptide (GIP) and GIP receptor (GIPR)
Our genetic analyses using human data provide consistent support for favourable effects of sustained GIP signalling on BMI, CRP, HDL-C and triacylglycerol levels
Summary
Glucose-dependent insulinotropic polypeptide (or gastric inhibitory polypeptide, GIP) is an incretin peptide that stimulates insulin secretion after oral nutrient intake. Both GIP and glucagon-like peptide 1 (GLP-1) are involved in regulating energy homeostasis [1]. GLP-1 agonism is an established pharmacological target for treating type 2 diabetes and obesity, it is unclear whether pharmacological GIP agonism represents a similar therapeutic opportunity [2]. We leverage human genetic data to investigate the potential of targeting GIP signalling for the treatment of cardiometabolic disease
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
