Dysglycemia and liver lipid content determine the relationship of insulin resistance with hepatic OXPHOS capacity in obesity.

IF 26.8 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Journal of Hepatology Pub Date : 2024-08-30 DOI:10.1016/j.jhep.2024.08.012
Sabine Kahl, Klaus Straßburger, Giovanni Pacini, Nina Trinks, Kalliopi Pafili, Lucia Mastrototaro, Bedair Dewidar, Theresia Sarabhai, Sandra Trenkamp, Irene Esposito, Matthias Schlensak, Frank A Granderath, Michael Roden
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Abstract

Background & aims: Hepatic mitochondrial respiration is higher in steatosis, but lower in overt type 2 diabetes. We hypothesized that hepatic OXPHOS capacity increases with a greater degree of insulin resistance in obesity, independent of other metabolic diseases.

Methods: We analysed 65 humans without diabetes (BMI 50±7 kg/m2, HbA1c 5.5±0.4%) undergoing bariatric surgery. MASLD stages were assessed by histology, whole-body insulin sensitivity (PREDIcted-M index) by oral glucose tolerance tests, and maximal ADP-stimulated mitochondrial OXPHOS capacity by high-resolution respirometry of liver samples.

Results: Prediabetes was present in 30 participants, and MASLD in 46 participants. Thereof, 25 had metabolic dysfunction-associated steatohepatitis (MASH), and seven had F2-F3 fibrosis. While simple regression did not detect an association of insulin sensitivity with hepatic OXPHOS capacity, interaction analyses revealed that the regression coefficient of OXPHOS capacity depended on fasting plasma glucose (FPG) and liver lipid content. Interestingly, the respective slopes were negative for FPG ≤100 mg/dl, but positive for FPG >100 mg/dl. Liver lipid content displayed similar behavior, with a threshold value of 24%. Post-challenge glycemia affected the association between insulin sensitivity and OXPHOS capacity normalized for citrate synthase activity. Presence of prediabetes affected hepatic insulin signaling, mitochondrial dynamics and fibrosis prevalence, while the presence of MASLD related to higher biomarkers of hepatic inflammation, cell damage and lipid peroxidation in people with normal glucose tolerance.

Conclusions: Rising liver lipid contents and plasma glucose concentrations, even in the non-diabetic range, are associated with a progressive decline of hepatic mitochondrial adaptation in people with obesity and insulin resistance. CLINTRIALS.

Gov identifier: NCT01477957.

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糖耐量异常和肝脏脂质含量决定了肥胖症患者的胰岛素抵抗与肝脏 OXPHOS 能力之间的关系。
背景和目的:肝脏线粒体呼吸在脂肪变性中较高,但在明显的2型糖尿病中较低。我们假设,肝脏的 OXPHOS 能力会随着肥胖症患者胰岛素抵抗程度的增加而增加,与其他代谢疾病无关:我们分析了 65 名接受减肥手术的非糖尿病患者(BMI 50±7 kg/m2,HbA1c 5.5±0.4%)。通过组织学方法评估 MASLD 阶段,通过口服葡萄糖耐量试验评估全身胰岛素敏感性(PREDIcted-M 指数),通过肝脏样本的高分辨率呼吸测定法评估最大 ADP 刺激线粒体 OXPHOS 能力:结果:30 人患有糖尿病前期,46 人患有 MASLD。其中,25 人患有代谢功能障碍相关性脂肪性肝炎(MASH),7 人患有 F2-F3 纤维化。虽然简单回归没有检测出胰岛素敏感性与肝脏OXPHOS能力之间的关联,但交互分析表明,OXPHOS能力的回归系数取决于空腹血浆葡萄糖(FPG)和肝脏脂质含量。有趣的是,FPG ≤100 mg/dl 时,各自的斜率为负,而 FPG >100 mg/dl 时,斜率为正。肝脏脂质含量的表现类似,临界值为 24%。挑战后的血糖影响了胰岛素敏感性与柠檬酸合成酶活性正常化的 OXPHOS 能力之间的联系。糖尿病前期会影响肝脏胰岛素信号传导、线粒体动力学和肝纤维化的发生率,而糖耐量正常者的肝脏炎症、细胞损伤和脂质过氧化的生物标志物则较高:结论:肝脏脂质含量和血浆葡萄糖浓度的上升(即使在非糖尿病范围内)与肥胖和胰岛素抵抗患者肝脏线粒体适应性的逐渐下降有关。CLINTRIALS.Gov 标识符:NCT01477957。
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来源期刊
Journal of Hepatology
Journal of Hepatology 医学-胃肠肝病学
CiteScore
46.10
自引率
4.30%
发文量
2325
审稿时长
30 days
期刊介绍: The Journal of Hepatology is the official publication of the European Association for the Study of the Liver (EASL). It is dedicated to presenting clinical and basic research in the field of hepatology through original papers, reviews, case reports, and letters to the Editor. The Journal is published in English and may consider supplements that pass an editorial review.
期刊最新文献
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