Konings L¹ ², Burggraaf B¹ ², van der Zwan EM ³, Peeters R ², Castro Cabezas M ¹ ² ⁴

¹Dpt of Intern Med, Center for Diabetes and Vasc Med, Franciscus Gasthuis &

Vlietland; ²Dpt of Intern Med, Section of Endocrinology, Erasmus MC, Rotterdam,

³Dpt Clin Chem, Franciscus Gasthuis & Vlietland; ⁴Julius Clinical, Zeist, The Netherlands.

Corresponding author: L. Konings, E-mail: l.konings@franciscus.nl

Background: The Fibroblast Growth Factor (FGF) system is a novel endocrinological system with a role in metabolism. Details on the connection with endocrinological pathways are not well known. We aimed to evaluate the postprandial (pp) changes in FGF-19 and FGF-21 in patients with T2DM in relation to cardiometabolic and endocrinological parameters.

Methods: In this single centre study fourteen male patients with T2DM underwent an 8h standardized oral fat loading test. Every 2hrs FGF-19 and FGF-21 in blood was collected. Low and high pp responders were identified using the area-under-the curve (AUC). Pulse wave velocity (PWV) and carotid (c)IMT were also determined. Results: Fourteen males with a mean age of 64.6±8.6 (x±SD) years and BMI of

29.4±3.9 kg/m² were included. Compared with fasting, the mean concentration of

FGF-19 (109.2 ±126.3 pg/mL) was maximal at 6hrs (289.1±143.5 pg/mL). In contrast, FGF-21 decreased by 32% compared to fasting (423.2±395.5 pg/mL), returning to baseline at later timepoints. Univariate correlations showed that fasting FGF-19 was positively associated with ALAT (Spearman’s rho: 0.54; P=0.05). FGF-21 was positively correlated with waist (r: 0.77; P=0.001) and BMI (r: 0.62; P=0.02). Postprandial FGF-19 and FGF-21 were not associated with glucagon or insulin, neither fasting nor postprandial. Low pp FGF-19 responders had significantly lower ALAT (P=0.014), ASAT (P=0.048), plasma cholesterol (P=0.016), LDL-C (P=0.002), apoB (P=0.03) and lower PWV (P=0.04) versus high responders. Low FGF-21 responders had higher fasting free fatty acids (P= 0.004).

Conclusions: In this study a lower FGF-19 correlated with a better cardiovascular profile and liver status, in contrast to FGF-21, which was associated with obesity indices. Low postprandial FGF-19 responders may have a more beneficial cardiovascular profile, which raises the question whether FGF-19 inhibitors may protect patients against cardiovascular disease.