Florine H.M. Westerbeke¹, Ilias Attaye¹, Melany Rios-Morales¹, Max Nieuwdorp^1,2.
¹ Department of Experimental Vascular Medicine, Amsterdam University Medical Center, Amsterdam. ² Diabeter Center Amsterdam.
f.h.m.westerbeke@amsterdamumc.nl

Background
Dietary fructose consumption has increased substantially and has been associated with increased incidence of obesity, type 2 diabetes (T2D) and other non-communicable diseases. However, causality and underlying mechanisms remain to be elucidated. This trial aims to investigate fructose metabolism and its effects in individuals with T2D.

Methods
The ERIE-trial is a double-blind, isocaloric randomised controlled trial involving non-insulin-dependent T2D participants on stable metformin use, who were allocated to group A or B, reflecting either a high- or low-fructose diet for 4 weeks. Primary endpoints include changes in oral fructose handling assessed through a fructose challenge test pre- and post-intervention, involving oral ingestion of 1g/kg bodyweight unlabeled fructose and 120mg ¹³C₆-labeled fructose.

Results

Group B exhibited a trend towards faster and increased peripheral appearance of unlabeled fructose, reaching higher concentrations with a median Δ [IQR] of 66.8 µM [12.5-180.8], compared to -46.3 µM [-125.9-44.4] in group A (p=0.082) after 120 minutes. Uric acid levels in group B exhibited a significant rise, reaching its peak concentration after 30 minutes with a median Δ [IQR] of 38.0 µM [29.0-77.0], compared to 12.0 µM [-6.0-23.0] in group A (p=0.002).

Conclusion
The trend towards an accelerated and heightened peripheral appearance of fructose in group B suggests altered fructose absorption. This is consistent with the significantly increased uric acid levels in group B, indicating enhanced hepatic fructose metabolism. Prolonged exposure to high fructose levels in the intestine may induce an upregulation of intestinal GLUT 5, facilitating increased fructose absorption and elevating fructose levels reaching the liver, hereby augmenting hepatic fructose metabolism. This potentially causes increased uric acid production and fatty acid synthesis. Despite the trial’s blinding, preliminary data strongly suggest group B adhered to the high fructose diet. The results demonstrate that varying levels of fructose consumption affect acute fructose metabolism in T2D individuals and highlight potential deleterious metabolic consequences likely associated with increased fructose consumption.

This research is funded by a ZonMw Vici grant 2020 (09150182010020).