H. Chen^1,2; E.J.C. Koene³; K.H. M. Roumans³; M.P.H. van de Waarenburg^1,2; M. van Oeteren^1,2; V.B. Schrauwen-Hinderling^3,4; P. Schrauwen⁵; C.G. Schalkwijk^1,2; P.I.H.G. Simons¹, M.C.G.J. Brouwers¹

1. Department of Internal Medicine, Division of Endocrinology and Metabolic Diseases, Maastricht University Medical Center, Maastricht, The Netherlands. 2. Laboratory for Metabolism and Vascular Medicine, Division of General Internal Medicine, Department of Internal Medicine, Maastricht University, Maastricht, The Netherlands. 3. Department of Nutrition and Movement Sciences, Maastricht University, Maastricht, The Netherlands. 4. Department of Radiology and Nuclear Medicine, Maastricht University Medical Center, Maastricht, The Netherlands. 5. Clinical Epidemiology, Leiden University Medical Center, the Netherlands

Email: huadong.chen@maastrichtuniversity.nl

Background: There is experimental and epidemiological evidence suggesting that sex hormone-binding globulin (SHBG) plays a causal role in the pathogenesis of type 2 diabetes. Previous experimental studies have demonstrated that carbohydrate-induced de novo synthesis of palmitate inhibits hepatic SHBG secretion. In the present study we used data from pharmacological and dietary intervention studies to investigate how these substrates, i.e. fructose, glucose and saturated fatty acids, affect serum SHBG in humans.

Methods: Data were derived from three intervention studies in individuals with (high risk of) MASLD:1) a randomized, double-blind, placebo-controlled cross-over trial of pharmacological inhibition of the first step of fructose metabolism, by inhibition of ketohexokinase (KHK); 2) a double-blind, randomized controlled trial of fructose versus glucose supplementation on a background of a 6-week fructose-restricted diet; 3) a randomized cross-over trial of a 4-week diet rich in fructose versus saturated fatty acids (SFA).

Results: all participants showed an increase in serum SHBG with pharmacological inhibition of KHK compared to placebo (+7.4 nmol/L, 95%CI:5.4;11.8). Fructose supplementation did not affect serum SHBG differently as compared to glucose supplementation (+2.0 nmol/L, 95%CI: -1.1;5.3), nor were there any statistically significant differences between the fructose-rich and SFA-rich diet (-2.1 nmol/L, 95%CI: -8.2;1.1).

Conclusion: This study shows that KHK-mediated fructose metabolism is causally related to serum SHBG levels in humans. Dietary fructose, glucose and SFAs do not appear to have a differential effect on serum SHBG.