Glucose-Dependent Insulinotropic Peptide in the High-Normal Range Is Associated With Increased Carotid Intima-Media Thickness

Jujić, Amra; Nilsson, Peter M.; Atabaki‐Pasdar, Naeimeh; Dieden, Anna; Tuomi, Tiinamaija; Franks, Paul W.; Holst, Jens J.; Torekov, Signe S.; Ravassa, Susana; Dı́ez, Javier; Persson, Margaretha; Ahlqvist, Emma; Melander, Olle; Gomez, Maria F.; Groop, Leif; Magnusson, Martin

doi:10.2337/dc20-1318

Cited by 23 publications

(9 citation statements)

References 39 publications

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“…Total plasma GLP-1 concentrations (intact GLP-1 and the metabolite GLP-1 9–36 amide) were determined radio immunologically as described previously 19 (minimum detection limit 1 pmol/L; intra- and inter-assay coefficients of variation < 6.0% and < 15%, respectively). Identical quality controls and identical batches for all reagents in each analysis set were used in a consecutive sample analysis for two months.…”

Section: Methodsmentioning

confidence: 99%

Endogenous incretin levels and risk of first incident cancer: a prospective cohort study

Jujić

Godina

Belting

et al. 2023

Sci Rep

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Concerns have been raised regarding a potentially increased risk of cancer associated with treatment with glucagon-like peptide-1 (GLP-1) receptor agonists. Here, we explored whether fasting and oral glucose tolerance test post-challenge glucose-dependent insulinotropic peptide (GIP) and GLP-1 levels were associated with incident first cancer. Within the cardiovascular re-examination arm of the population-based Malmö Diet Cancer study (n = 3734), 685 participants with a previous cancer diagnosis were excluded, resulting in 3049 participants (mean age 72.2 ± 5.6 years, 59.5% women), of whom 485 were diagnosed with incident first cancer (median follow-up time 9.9 years). Multivariable Cox-regression and competing risk regression (death as competing risk) were used to explore associations between incretin levels and incident first cancer. Higher levels of fasting GLP-1 (462 incident first cancer cases/2417 controls) showed lower risk of incident first cancer in competing risk regression (sub-hazard ratio 0.90; 95% confidence interval 0.82–0.99; p = 0.022). No association was seen for fasting GIP, post-challenge GIP, or post-challenge GLP-1 and incident first cancer. In this prospective study, none of the fasting and post-challenge levels of GIP and GLP-1 were associated with higher risk of incident first cancer; by contrast, higher levels of fasting GLP-1 were associated with lower risk of incident first cancer.

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Section: Methodsmentioning

confidence: 99%

Endogenous incretin levels and risk of first incident cancer: a prospective cohort study

Jujić

Godina

Belting

et al. 2023

Sci Rep

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“…Further, cardiac selective knockout of the GIPR was not protective in experimental models of heart failure ( 25 ). In contrast with these preclinical experimental findings, recent evidence suggests that fasting GIP levels are associated with increased carotid intimal thickening ( 26 ). In addition, evidence from a recent meta-analysis ( 27 ) of two large population-based cohort studies suggests that higher fasting but not postchallenge GIP levels were associated with increased risk of CVD mortality (hazard ratio 1.30; 95% CI 1.11, 1.52; P = 0.001).…”

Section: Introductionmentioning

confidence: 95%

Genetically Predicted Glucose-Dependent Insulinotropic Polypeptide (GIP) Levels and Cardiovascular Disease Risk Are Driven by Distinct Causal Variants in the GIPR Region

et al. 2021

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There is considerable interest in GIPR agonism to enhance the insulinotropic and extrapancreatic effects of GIP, thereby improving glycemic and weight control in type 2 diabetes (T2D) and obesity. Recent genetic epidemiological evidence has implicated higher GIPR-mediated GIP levels in raising coronary artery disease (CAD) risk, a potential safety concern for GIPR agonism. We therefore aimed to quantitatively assess whether the association between higher GIPR-mediated fasting GIP levels and CAD risk is mediated via GIPR or is instead the result of linkage disequilibrium (LD) confounding between variants at the GIPR locus. Using Bayesian multitrait colocalization, we identified a GIPR missense variant, rs1800437 (G allele; E354), as the putatively causal variant shared among fasting GIP levels, glycemic traits, and adiposity-related traits (posterior probability for colocalization [PPcoloc] > 0.97; PP explained by the candidate variant [PPexplained] = 1) that was independent from a cluster of CAD and lipid traits driven by a known missense variant in APOE (rs7412; distance to E354 ∼770 Kb; R2 with E354 = 0.004; PPcoloc > 0.99; PPexplained = 1). Further, conditioning the association between E354 and CAD on the residual LD with rs7412, we observed slight attenuation in association, but it remained significant (odds ratio [OR] per copy of E354 after adjustment 1.03; 95% CI 1.02, 1.04; P = 0.003). Instead, E354’s association with CAD was completely attenuated when conditioning on an additional established CAD signal, rs1964272 (R2 with E354 = 0.27), an intronic variant in SNRPD2 (OR for E354 after adjustment for rs1964272: 1.01; 95% CI 0.99, 1.03; P = 0.06). We demonstrate that associations with GIP and anthropometric and glycemic traits are driven by genetic signals distinct from those driving CAD and lipid traits in the GIPR region and that higher E354-mediated fasting GIP levels are not associated with CAD risk. These findings provide evidence that the inclusion of GIPR agonism in dual GIPR/GLP1R agonists could potentiate the protective effect of GLP-1 agonists on diabetes without undue CAD risk, an aspect that has yet to be assessed in clinical trials.

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“…Following this observation, two prospective studies of independent populations, Malmö Diet Cancer–Cardiovascular Cohort (MDC-CC) and Prevalence, Prediction, and Prevention of Diabetes in Botnia (PPP-Botnia), have demonstrated that high fasting levels of GIP, but not GLP-1, are associated with an increased risk for coronary artery disease, myocardial infarction, and cardiovascular and all-cause death [ 83 ]. In participants of MDC-CC at re-examination, GIP and GLP-1 fasting levels proved to be divergent in association with markers of subclinical atherosclerosis: increased fasting GIP levels were associated with increased intima-media thickness in the common carotid artery and in the carotid bifurcation, while GLP-1 was associated with decreased intima-media thickness in the carotid bifurcation [ 84 ].…”

Section: Gut Molecules and Cardiovascular Diseasesmentioning

confidence: 99%

Gut Molecules in Cardiometabolic Diseases: The Mechanisms behind the Story

Neag

Crăciun

Buzoianu

2023

IJMS

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Atherosclerotic cardiovascular disease is the most common cause of morbidity and mortality worldwide. Diabetes mellitus increases cardiovascular risk. Heart failure and atrial fibrillation are associated comorbidities that share the main cardiovascular risk factors. The use of incretin-based therapies promoted the idea that activation of alternative signaling pathways is effective in reducing the risk of atherosclerosis and heart failure. Gut-derived molecules, gut hormones, and gut microbiota metabolites showed both positive and detrimental effects in cardiometabolic disorders. Although inflammation plays a key role in cardiometabolic disorders, additional intracellular signaling pathways are involved and could explain the observed effects. Revealing the involved molecular mechanisms could provide novel therapeutic strategies and a better understanding of the relationship between the gut, metabolic syndrome, and cardiovascular diseases.

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Glucose-Dependent Insulinotropic Peptide in the High-Normal Range Is Associated With Increased Carotid Intima-Media Thickness

Cited by 23 publications

References 39 publications

Endogenous incretin levels and risk of first incident cancer: a prospective cohort study

Endogenous incretin levels and risk of first incident cancer: a prospective cohort study

Genetically Predicted Glucose-Dependent Insulinotropic Polypeptide (GIP) Levels and Cardiovascular Disease Risk Are Driven by Distinct Causal Variants in the GIPR Region

Gut Molecules in Cardiometabolic Diseases: The Mechanisms behind the Story

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