Background and aims
Dietary fructose consumption has increased substantially in recent decades and is associated with higher incidence of obesity, type 2 diabetes (T2D) and other non-communicable diseases. However, causality and underlying mechanisms remain to be elucidated. Therefore, the ‘Effect of dietary fructose on fructose kinetics in type 2 diabetes’ (ERIE) trial is being performed. The trial aims to investigate fructose metabolism, including microbial fermentation, and its effects in T2D individuals, through examining oral fructose handling in T2D subjects receiving a high- or low-fructose diet.

Materials and methods
The ERIE trial, a double-blinded, isocaloric randomized controlled trial, aims to recruit 40 non-insulin dependent T2D participants on stable metformin therapy. Participants are randomly assigned to group A or B, receiving either a high- (100g/day) or a low-fructose (30g/day) diet for 4 weeks. Primary endpoints include changes in oral fructose handling, assessed through a fructose challenge test (FCT) by ingesting 1g/kg bodyweight unlabeled fructose and 120mg ¹³C₆-labeled fructose, in relation to metabolic markers such as HOMA-IR. Preliminary data from up to 18 participants were analyzed using multiple non-parametric tests, comparing deltas (Δ) of pre- and post-intervention results between both groups.

Results
In groups A and B, 45.5% and 28.6% of participants were female, respectively. Median age [IQR] was 65 years [56-68] in group A and 60 years [59-66] in group B. Median BMI [IQR] was 29.3 kg/m² [27.1-33.8] in group A and 29.9 kg/m² [27.9-32.2] in group B. Group B exhibited a significantly faster peripheral appearance of ¹³C₆-fructose and reached higher concentrations after 30 minutes with a median Δ [IQR] of 0.93 µM [0.89-1.45], compared to 0.02 µM [-0.46-0.45] in group A (p=0.012). Concurrently, group B showed a trend towards increased peripheral appearance of unlabeled fructose with a median Δ [IQR] of 207.70 µM [144.26-271.14] after 30 minutes, compared to 1.14 µM [-25.19-72.78] in group A (p=0.178). Uric acid levels in group B exhibited a significant rise throughout the FCT, with a median Δ [IQR] of 49.0 µM/l [41.5-69.5] after 150 minutes, compared to -8.0 µM/l [-14.0-23.0] in group A (p=<0.001). No changes in glucose levels were observed in either group, with current inclusion numbers.

Conclusion
The accelerated and heightened peripheral appearance of fructose in group B, compared to group A, following ingestion of an equivalent oral fructose dose pre- and post-intervention, suggests altered fructose absorption in group B. This aligns with a significant increase in uric acid levels in group B, indicating enhanced hepatic fructose metabolism. These results show that varying levels of fructose consumption affect acute fructose metabolism. Prolonged exposure to high fructose levels in the intestine may induce an upregulation of intestinal GLUT-5, facilitating increased fructose absorption. This can have negative metabolic effects by elevating fructose levels reaching the liver, thereby augmenting hepatic fructose metabolism. This can lead to increased uric acid production and fatty acid synthesis. Despite the trial's blinding, preliminary data suggest that group B adhered to the high fructose diet. These results provide novel insights into fructose metabolism in individuals with T2D, highlighting potential deleterious metabolic consequences likely associated with increased fructose consumption.