Abstract
Abstract
Aims/hypothesis
Evidence that glucose-dependent insulinotropic peptide (GIP) and/or the GIP receptor (GIPR) are involved in cardiovascular biology is emerging. We hypothesised that GIP has untoward effects on cardiovascular biology, in contrast to glucagon-like peptide 1 (GLP-1), and therefore investigated the effects of GIP and GLP-1 concentrations on cardiovascular disease (CVD) and mortality risk.
Methods
GIP concentrations were successfully measured during OGTTs in two independent populations (Malmö Diet Cancer–Cardiovascular Cohort [MDC-CC] and Prevalence, Prediction and Prevention of Diabetes in Botnia [PPP-Botnia]) in a total of 8044 subjects. GLP-1 (n = 3625) was measured in MDC-CC. The incidence of CVD and mortality was assessed via national/regional registers or questionnaires. Further, a two-sample Mendelian randomisation (2SMR) analysis between the GIP pathway and outcomes (coronary artery disease [CAD] and myocardial infarction) was carried out using a GIP-associated genetic variant, rs1800437, as instrumental variable. An additional reverse 2SMR was performed with CAD as exposure variable and GIP as outcome variable, with the instrumental variables constructed from 114 known genetic risk variants for CAD.
Results
In meta-analyses, higher fasting levels of GIP were associated with risk of higher total mortality (HR[95% CI] = 1.22 [1.11, 1.35]; p = 4.5 × 10−5) and death from CVD (HR[95% CI] 1.30 [1.11, 1.52]; p = 0.001). In accordance, 2SMR analysis revealed that increasing GIP concentrations were associated with CAD and myocardial infarction, and an additional reverse 2SMR revealed no significant effect of CAD on GIP levels, thus confirming a possible effect solely of GIP on CAD.
Conclusions/interpretation
In two prospective, community-based studies, elevated levels of GIP were associated with greater risk of all-cause and cardiovascular mortality within 5–9 years of follow-up, whereas GLP-1 levels were not associated with excess risk. Further studies are warranted to determine the cardiovascular effects of GIP per se.
Funder
Foundation for Life and Health in Finland
ALF government grants
Marcus Wallenbergs Stiftelse för Internationellt Vetenskapligt Samarbete
Sydvästra Skånes Diabetesförening
Svenska Sällskapet för Medicinsk Forskning
the Hulda and Conrad Mossfelt Foundation
Närpes Health Care Foundation
Samfundet Folkhälsan
the Lennart Hanssons Memorial Fund
Instituto de Salud Carlos III
Jalmari ja Rauha Ahokkaan Säätiö
Medicinska Fakulteten, Lunds Universitet
Health Care Centers in Vasa, Närpes and Korsholm
Suomen Akatemia
Paavo Nurmen Säätiö
Sigrid Juséliuksen Säätiö
Vetenskapsrådet
Knut och Alice Wallenbergs Stiftelse
Diabetesliitto
Perklén Foundation
Region Skåne
Helsinki University Central Hospital Research Foundation
Municipal Heath Care Center and Hospital in Jakobstad
Skåne University Hospital
Ministry of Education in Finland
Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse
Wallenberg Centre for Molecular Medicine
Crafoordska Stiftelsen
European Commission FP7 Programme
Direktör Albert Påhlssons Stiftelse
Svenska Kulturfonden
the Ollqvist foundation
EU EXGENESIS
Nordic Center of Excellence in Disease Genetics
Hjärt-Lungfonden
Signe ja Ane Gyllenbergin Säätiö
Bo and Kerstin Hjelt Foundation
EU EUFP7-MOSAIC
Suomalainen Lääkäriseura Duodecim
Stiftelsen Ragnhild och Einar LundstrÖms Minne
Publisher
Springer Science and Business Media LLC
Subject
Endocrinology, Diabetes and Metabolism,Internal Medicine