E.J.C. Koene¹, J. Basset-Sagarminaga¹, K. Brouwers², J. Mevenkamp², Y.M.H. Op den Kamp-Bruls², E. Phielix¹, V.B. Schrauwen-Hinderling², P. Schrauwen ¹, M.C.G.J. Brouwers³

¹Department of Nutrition and Movement Science, NUTRIM research school, Maastricht University, Maastricht, Netherlands ²Department of Radiology and Nuclear Medicine, Maastricht University Medical Center+, Maastricht, Netherlands, ³Department of Internal Medicine, Division of Endocrinology and Metabolic Disease, CARIM research school, Maastricht University Medical Center, Maastricht+, Netherlands. e.koene@maastrichtuniversity.nl

Background: Previous studies have shown that fructose intake is associated with metabolic dysfunction-associated steatotic liver disease (MASLD), which is a risk factor for type 2 diabetes (T2D). Of interest, experimental studies demonstrated that pharmacological inhibition of ketohexokinase (KHK), the first committed step in fructose metabolism which converts fructose to fructose-1-phosphate, effectively lowers de novo lipogenesis and intrahepatic lipid (IHL) content, which have recently been confirmed in phase II clinical studies. Here, we investigated the effect of a KHK inhibitor, PF-06835919, on insulin sensitivity.

Methods: We conducted a randomized double-blind, placebo-controlled cross-over trial in which fifteen overweight/obese participants with MASLD (IHL ≥ 5.56%) were treated with PF-06835919 (300 mg, once daily) and placebo. Each 6-week treatment arm was evaluated by assessment of: 1) in vivo intrahepatic fructose phosphorylation (measured with ³¹P- Magnetic Resonance Spectroscopy (MRS) after an oral fructose load) 2) IHL content (quantified with ¹H-MRS), and 3) insulin sensitivity (M-value assessed with two-step hyperinsulinemic-euglycemic clamp).

Results: Hepatic phosphomonoester concentration increased upon an oral fructose load in the placebo arm, which was completely abolished after PF-06835919 treatment (p<0.001), showing that the drug inhibits normal fructose metabolism. IHL content was lower after PF-06835919 versus placebo (absolute difference: -2.5 %; 95% CI: -3.3, -1.8; p<0.001). Body weight remained stable between both periods (difference: 0.37 kg; 95% CI: -0.12, 0.83 kg; p=0.12). Whole body insulin sensitivity (M-value) was significantly higher (p=0.007) after 6 weeks of PF-06835919 (mean: 5.2 mg/kg/min) as compared to placebo (mean: 4.4 mg/kg/min).

Conclusion: Six weeks of KHK inhibition suppresses intrahepatic fructose metabolism, reduces IHL content, and improves insulin sensitivity.