Holzhütter Hermann-Georg, Hudert Christian A, Berndt Nikolaus
Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Biochemistry, Charitéplatz 1, 10117, Berlin, Germany.
Charité-Universitätsmedizin Berlin, corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Gastroenterology, Nephrology and Metabolic Diseases, Berlin, Germany.
J Mol Med (Berl). 2025 May 27. doi: 10.1007/s00109-025-02551-y.
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代谢功能障碍相关脂肪性肝病（MASLD）儿童的研究结果存在争议。为了评估二甲双胍对70例经活检证实为MASH的儿科患者肝脏葡萄糖、脂质、氨基酸和能量代谢的个体特异性影响。我们用肝脏酶丰度的个体特异性蛋白质组学数据对我们的肝脏代谢数学模型HEPATOKIN1进行参数化，并模拟了二甲双胍诱导的大量代谢功能的昼夜变化。平均而言，单剂量（250毫克）二甲双胍可使昼夜HGP降低19%。基于Z分数为1，15%的患者被分类为低反应者或高反应者。在摄入二甲双胍后4小时内血浆二甲双胍水平升高期间，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了10 - 30%，但在24小时内平均计算，这些代谢副作用并不显著。特别是，二甲双胍对肝脏脂肪储存没有显著影响。葡萄糖耐量试验（OGTT）后90分钟的基线乳酸和胰岛素活性与HGP的降低显著相关，可作为有效治疗的预测指标。平均而言，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数小时内有显著改变。我们的方法提供了二甲双胍治疗对肝脏中心代谢潜在影响的个体特异性分析，因此可能有助于指导医生的治疗决策。
