Novel effects of the gastrointestinal hormone secretin on cardiac metabolism and renal function

Sanna Laurila, Eleni Rebelos, Minna Lahesmaa, Lihua Sun, Katharina Schnabl, Tia-Mari Peltomaa, Riku Klén, Mueez U-Din, Miikka-Juhani Honka, Olli Eskola, Anna K Kirjavainen, Lauri Nummenmaa, Martin Klingenspor, Kirsi A Virtanen, Pirjo Nuutila, Sanna Laurila, Eleni Rebelos, Minna Lahesmaa, Lihua Sun, Katharina Schnabl, Tia-Mari Peltomaa, Riku Klén, Mueez U-Din, Miikka-Juhani Honka, Olli Eskola, Anna K Kirjavainen, Lauri Nummenmaa, Martin Klingenspor, Kirsi A Virtanen, Pirjo Nuutila

Abstract

The cardiac benefits of gastrointestinal hormones have been of interest in recent years. The aim of this study was to explore the myocardial and renal effects of the gastrointestinal hormone secretin in the GUTBAT trial (NCT03290846). A placebo-controlled crossover study was conducted on 15 healthy males in fasting conditions, where subjects were blinded to the intervention. Myocardial glucose uptake was measured with [18F]2-fluoro-2-deoxy-d-glucose ([18F]FDG) positron emission tomography. Kidney function was measured with [18F]FDG renal clearance and estimated glomerular filtration rate (eGFR). Secretin increased myocardial glucose uptake compared with placebo (secretin vs. placebo, means ± SD, 15.5 ± 7.4 vs. 9.7 ± 4.9 μmol/100 g/min, 95% confidence interval (CI) [2.2, 9.4], P = 0.004). Secretin also increased [18F]FDG renal clearance (44.5 ± 5.4 vs. 39.5 ± 8.5 mL/min, 95%CI [1.9, 8.1], P = 0.004), and eGFR was significantly increased from baseline after secretin, compared with placebo (17.8 ± 9.8 vs. 6.0 ± 5.2 ΔmL/min/1.73 m2, 95%CI [6.0, 17.6], P = 0.001). Our results implicate that secretin increases heart work and renal filtration, making it an interesting drug candidate for future studies in heart and kidney failure.NEW & NOTEWORTHY Secretin increases myocardial glucose uptake compared with placebo, supporting a previously proposed inotropic effect. Secretin also increased renal filtration rate.

Keywords: gastrointestinal hormone; kidney function; myocardial metabolism; secretin.

Conflict of interest statement

M.K. is an inventor on a patent application from the Technical University of Munich (Publication No. WO/2017/20285; International Application No. PCT/EP2017/062420) addressing the role of secretin receptor agonists and modulators in the regulation of energy homeostasis. This patent is based on the initial discovery that meal-induced secretin inhibits food intake, and this anorexigenic action of secretin depends on the activation of brown fat (6). None of the other authors has any conflicts of interest, financial or otherwise, to disclose.

Figures

Graphical abstract
Graphical abstract
Figure 1.
Figure 1.
Overview of the scanning protocol. Two PET/CT scans were conducted in fasting conditions, in a single-blinded and randomized order, with a placebo (saline) and secretin (secretin pentahydrochloride 1 IU/kg *2) intervention. Arrows indicate the timing of intravenous secretin/placebo infusions. [18F]FDG (150 MBq) was injected at 20 min, after which PET scanning of the neck, and then the thoracic region, was initiated. Indirect calorimetry was conducted for 2 h. Timing of arterialized samples is indicated with test tube figures. Twelve-lead ECG was collected at timepoints 0, 60 and 120 min. CT, computed tomography; [18F]FDG, [18F]2-fluoro-2-deoxy-d-glucose.
Figure 2.
Figure 2.
Myocardial glucose uptake results. A: representative [18F]FDG PET/CT vertical long axis images showing Ki of the heart after secretin and placebo infusions (n = 1). Short axis images are shown in Supplemental Fig. S1. (see https://doi.org/10.6084/m9.figshare.16912807). B: the effect of secretin infusion on myocardial glucose uptake compared with placebo (n = 15). Data were analyzed by Student’s paired t test. C: whole body carbohydrate oxidation (CHO) correlates with myocardial glucose uptake (MGU) after secretin administration (n = 15). Data were analyzed by Pearson correlation. A line has been drawn on the data to indicate a significant association whereas dotted curves represent confidence interval. CT, computed tomography; [18F]FDG, [18F]2-fluoro-2-deoxy-d-glucose.
Figure 3.
Figure 3.
Organ glucose uptake correlations (n = 15). A: brown adipose tissue glucose uptake is strongly associated with myocardial glucose uptake after secretin infusion, while no association is seen during placebo (B). C: skeletal muscle glucose uptake is not associated with myocardial glucose uptake after secretin infusion, while an association exists during placebo (D). Data were analyzed by Pearson correlation. A line has been drawn on the data to indicate a significant association whereas dotted curves represent confidence interval. All units are μmol/100 g/min.
Figure 4.
Figure 4.
Renal function results. A: secretin decreases serum creatinine compared with placebo (n = 10). Values were normalized, dividing by the value of the first time point. Mean values and standard error are shown on graph. Each timepoint was analyzed by paired Wilcoxon signed-rank test. The secretin intervention is shown in orange whereas the placebo intervention is shown in gray. B: eGFR, calculated by Cockroft–Gault equation, was increased by secretin from baseline at 30 minutes, compared with placebo (n = 10). C: [18F]FDG renal clearance was increased after secretin (n = 15). B and C: data were analyzed by Student’s paired t test. [18F]FDG, [18F]2-fluoro-2-deoxy-d-glucose; eGFR, estimated glomerular filtration rate.

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