Patient-specific effects of metformin on the hepatic metabolism in adolescents with metabolic dysfunction-associated steatotic liver disease (MASLD).

IF 4.8 3区 医学 Q1 GENETICS & HEREDITY
Hermann-Georg Holzhütter, Christian A Hudert, Nikolaus Berndt
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引用次数: 0

Abstract

Metformin is a commonly prescribed antidiabetic drug that inhibits hepatic glucose production (HGP). Recent studies examining the use of metformin for the treatment of children with metabolic dysfunction-associated steatotic liver disease (MASLD) showed controversial results. To evaluate the patient-specific impact of metformin on hepatic glucose, lipid, amino acid, and energy metabolism in a cohort of 70 paediatric patients with biopsy-proven MASH. We parametrized our mathematical model HEPATOKIN1 of liver metabolism with patient-specific proteomics data of liver enzyme abundances and simulated metformin-induced diurnal changes of a large panel of metabolic functions. On average, a single dose (250 mg) of metformin reduced diurnal HGP by 19%. Based on a Z-score of 1, 15% of patients were classified as low responders or high responders. During elevated metformin plasma levels within four after metformin ingestion, energy metabolism, cytosolic and mitochondrial redox potential, urea synthesis and ketone body synthesis were reduced by 10-30%, but averaged over 24 h, these metabolic side effects were not significant. In particular, there was no significant impact of metformin on hepatic fat storage. Baseline lactate and insulin activity at 90 min after glucose challenge (OGTT) correlated significantly with the reduction in HGP and may serve as predictors of effective therapy. On a daily average, metformin selectively affects hepatic glucose production, glycogen storage and lactate uptake, while numerous other metabolic functions are significantly altered only for several hours after administration of the drug. Our method provides a patient-specific analysis of the potential effects of metformin therapy on central hepatic metabolism and may therefore help guide the physician's therapeutic decision.

二甲双胍对青少年代谢功能障碍相关脂肪变性肝病(MASLD)患者肝脏代谢的特异性影响
二甲双胍是一种常用的抗糖尿病药物,可抑制肝脏葡萄糖生成(HGP)。最近关于使用二甲双胍治疗儿童代谢功能障碍相关脂肪变性肝病(MASLD)的研究显示了有争议的结果。评估二甲双胍对70例活检证实为MASH的儿科患者肝脏葡萄糖、脂质、氨基酸和能量代谢的患者特异性影响。我们用肝脏酶丰度的患者特异性蛋白质组学数据来参数化肝脏代谢的数学模型HEPATOKIN1,并模拟二甲双胍诱导的大量代谢功能的日变化。平均而言,单剂量(250毫克)二甲双胍使每日HGP降低19%。根据z得分为1,15%的患者被分为低反应者或高反应者。摄入二甲双胍后4 h内血浆二甲双胍水平升高,能量代谢、胞质和线粒体氧化还原电位、尿素合成和酮体合成降低10-30%,但在24 h内平均降低,这些代谢副作用不显著。特别是,二甲双胍对肝脏脂肪储存没有显著影响。葡萄糖激发后90分钟基线乳酸和胰岛素活性(OGTT)与HGP降低显著相关,可作为有效治疗的预测指标。平均每天,二甲双胍选择性地影响肝脏葡萄糖生成、糖原储存和乳酸摄取,而许多其他代谢功能仅在给药后几小时内发生显著改变。我们的方法为二甲双胍治疗对中枢肝代谢的潜在影响提供了患者特异性分析,因此可能有助于指导医生的治疗决策。
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来源期刊
Journal of Molecular Medicine-Jmm
Journal of Molecular Medicine-Jmm 医学-医学:研究与实验
CiteScore
9.30
自引率
0.00%
发文量
100
审稿时长
1.3 months
期刊介绍: The Journal of Molecular Medicine publishes original research articles and review articles that range from basic findings in mechanisms of disease pathogenesis to therapy. The focus includes all human diseases, including but not limited to: Aging, angiogenesis, autoimmune diseases as well as other inflammatory diseases, cancer, cardiovascular diseases, development and differentiation, endocrinology, gastrointestinal diseases and hepatology, genetics and epigenetics, hematology, hypoxia research, immunology, infectious diseases, metabolic disorders, neuroscience of diseases, -omics based disease research, regenerative medicine, and stem cell research. Studies solely based on cell lines will not be considered. Studies that are based on model organisms will be considered as long as they are directly relevant to human disease.
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