Sellami Eya, Evangelista-Silva Paulo Henrique, Jordão Teixeira Caio, Diop Khoudia, Mitchell Patricia, Forato Anhê Fernando
Québec Heart and Lung Institute Research Center, Université Laval - 2725, Ch. Sainte-Foy, Québec, QC, G1V 4G5, Canada; Department of Medicine, Faculty of Medicine, Université Laval - 1050, Av. de la Médecine, Québec, QC, G1V 0A6, Canada; Institute of Nutrition and Functional Foods, Université Laval - 2440 Bd. Hochelaga, Québec, QC, G1V 0A6, Canada.
Québec Heart and Lung Institute Research Center, Université Laval - 2725, Ch. Sainte-Foy, Québec, QC, G1V 4G5, Canada; Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo - 1524, Av. Prof. Lineu Prestes, Sao Paulo, SP, 05508-000, Brazil.
Mol Metab. 2025 Mar;93:102101. doi: 10.1016/j.molmet.2025.102101. Epub 2025 Jan 22.
Increased fructose consumption contributes to type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD), but the mechanisms are ill-defined. Gut nutrient sensing involves enterohormones like Glucagon-like peptide (Glp)2, which regulates the absorptive capacity of luminal nutrients. While glucose is the primary dietary energy source absorbed in the gut, it is unknown whether excess fructose alters gut glucose sensing to impair blood glucose regulation and liver homeostasis.
Mice were fed diets where carbohydrates were either entirely glucose (70 %Kcal) or glucose partially replaced with fructose (8.5 %Kcal). Glp2 receptor (Glp2r) was inhibited with Glp2 (3-33) injections. Glucose tolerance, insulin sensitivity, and gut glucose absorption were concomitantly assessed, and enteric sugar transporters and absorptive surface were quantified by RT-qPCR and histological analysis, respectively.
High fructose feeding led to impairment of blood glucose disposal, ectopic fat accumulation in the liver, and hepatic (but not muscle or adipose tissue) insulin resistance independent of changes in fat mass. This was accompanied by increased gut glucose absorption, which preceded glucose intolerance and liver steatosis. Fructose upregulated glucose transporters and enlarged the gut surface, but these effects were prevented by Glp2r inhibition. Blocking Glp2r prevented fructose-induced impairments in glucose disposal and hepatic lipid handling.
Excess fructose impairs blood glucose and liver homeostasis by rewiring gut glucose sensing and exacerbating gut glucose absorption. Our findings are positioned to inform novel early diagnostic tools and treatments tailored to counter high fructose-induced metabolic derangements predisposing to T2D and MASLD.
果糖摄入量增加会导致2型糖尿病（T2D）和代谢功能障碍相关脂肪性肝病（MASLD），但其机制尚不清楚。肠道营养感知涉及肠促激素，如胰高血糖素样肽（Glp）2，它调节肠腔内营养物质的吸收能力。虽然葡萄糖是肠道吸收的主要膳食能量来源，但尚不清楚过量果糖是否会改变肠道葡萄糖感知，从而损害血糖调节和肝脏内环境稳态。
给小鼠喂食碳水化合物全部为葡萄糖（70%千卡）或部分葡萄糖被果糖替代（8.5%千卡）的饮食。通过注射Glp2（3 - 33）抑制Glp2受体（Glp2r）。同时评估葡萄糖耐量、胰岛素敏感性和肠道葡萄糖吸收，并分别通过RT-qPCR和组织学分析对肠道糖转运体和吸收表面进行定量。
高果糖喂养导致血糖处理受损、肝脏异位脂肪堆积以及肝脏（而非肌肉或脂肪组织）胰岛素抵抗，且与脂肪量变化无关。这伴随着肠道葡萄糖吸收增加，且早于葡萄糖不耐受和肝脏脂肪变性出现。果糖上调了葡萄糖转运体并扩大了肠道表面积，但这些作用可被Glp2r抑制所阻止。阻断Glp2r可防止果糖诱导的葡萄糖处理和肝脏脂质处理受损。
过量果糖通过重塑肠道葡萄糖感知和加剧肠道葡萄糖吸收来损害血糖和肝脏内环境稳态。我们的研究结果有助于为针对高果糖诱导的易导致T2D和MASLD的代谢紊乱的新型早期诊断工具和治疗方法提供信息。
