Introduction Cardiovascular diseases affect an increasing number of people and are one of the major causes of mortality. Over-consumption of fructose, widely used in soft drinks, compromises normal insulin transduction pathways, leading to impaired insulin signalling. Fructose is mainly metabolised by the enzyme ketohexokinase (KHK) in the liver. However, the mechanism underlying fructose-induced insulin resistance and endothelial dysfunction remains unknown. We aimed to investigate the role of KHK in mediating these effects.

Methods C57/BL6 mice were fed with three different diets for 20 weeks, namely low-fat (LFD), high-fat (HFD) and high-fat supplemented with sucrose (HFHS). Glucose and insulin tolerance tests were carried out after 5th, 11th and 16th weeks. Levels of various proteins were assessed by Western blotting. Endothelial function was analysed by measuring isometric tensions in organ bath set-ups.

Results Glucose clearance and insulin sensitivity were decreased after 5, 11 and 16 weeks of HFHS diet. Moreover, fasting glucose and plasma insulin levels of HFHS mice were increased compared to LFD and HFD. IR-beta expression and IRS-1 levels were decreased in HFD and HFHS. Interestingly, KHK expression was elevated in both liver and muscle of HFHS-fed mice. HFHS-fed animals also showed significant endothelial dysfunction.

Conclusions Consumption of sucrose and high fat leads to endothelial dysfunction in this mouse model of diet-induced metabolic syndrome. Elevated levels of KHK may be a factor underlying fructose-induced insulin resistance and endothelial dysfunction. This study improves our understanding of the links between KHK, insulin signalling and cardiovascular diseases.