Harada Makoto, Adam Jonathan, Covic Marcela, Ge Jianhong, Brandmaier Stefan, Muschet Caroline, Huang Jialing, Han Siyu, Rommel Martina, Rotter Markus, Heier Margit, Mohney Robert P, Krumsiek Jan, Kastenmüller Gabi, Rathmann Wolfgang, Zou Zhongmei, Zukunft Sven, Scheerer Markus F, Neschen Susanne, Adamski Jerzy, Gieger Christian, Peters Annette, Ankerst Donna P, Meitinger Thomas, Alderete Tanya L, de Angelis Martin Hrabe, Suhre Karsten, Wang-Sattler Rui
Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
German Center for Diabetes Research (DZD), Neuherberg, Germany.
Cardiovasc Diabetol. 2024 Jun 12;23(1):199. doi: 10.1186/s12933-024-02288-x.
Metformin and sodium-glucose-cotransporter-2 inhibitors (SGLT2i) are cornerstone therapies for managing hyperglycemia in diabetes. However, their detailed impacts on metabolic processes, particularly within the citric acid (TCA) cycle and its anaplerotic pathways, remain unclear. This study investigates the tissue-specific metabolic effects of metformin, both as a monotherapy and in combination with SGLT2i, on the TCA cycle and associated anaplerotic reactions in both mice and humans.
Metformin-specific metabolic changes were initially identified by comparing metformin-treated diabetic mice (MET) with vehicle-treated db/db mice (VG). These findings were then assessed in two human cohorts (KORA and QBB) and a longitudinal KORA study of metformin-naïve patients with Type 2 Diabetes (T2D). We also compared MET with db/db mice on combination therapy (SGLT2i + MET). Metabolic profiling analyzed 716 metabolites from plasma, liver, and kidney tissues post-treatment, using linear regression and Bonferroni correction for statistical analysis, complemented by pathway analyses to explore the pathophysiological implications.
Metformin monotherapy significantly upregulated TCA cycle intermediates such as malate, fumarate, and α-ketoglutarate (α-KG) in plasma, and anaplerotic substrates including hepatic glutamate and renal 2-hydroxyglutarate (2-HG) in diabetic mice. Downregulated hepatic taurine was also observed. The addition of SGLT2i, however, reversed these effects, such as downregulating circulating malate and α-KG, and hepatic glutamate and renal 2-HG, but upregulated hepatic taurine. In human T2D patients on metformin therapy, significant systemic alterations in metabolites were observed, including increased malate but decreased citrulline. The bidirectional modulation of TCA cycle intermediates in mice influenced key anaplerotic pathways linked to glutaminolysis, tumorigenesis, immune regulation, and antioxidative responses.
This study elucidates the specific metabolic consequences of metformin and SGLT2i on the TCA cycle, reflecting potential impacts on the immune system. Metformin shows promise for its anti-inflammatory properties, while the addition of SGLT2i may provide liver protection in conditions like metabolic dysfunction-associated steatotic liver disease (MASLD). These observations underscore the importance of personalized treatment strategies.
二甲双胍和钠-葡萄糖协同转运蛋白2抑制剂（SGLT2i）是治疗糖尿病患者高血糖的基础疗法。然而，它们对代谢过程的具体影响，尤其是对柠檬酸（TCA）循环及其回补途径的影响仍不清楚。本研究调查了二甲双胍单药治疗以及与SGLT2i联合治疗对小鼠和人类TCA循环及相关回补反应的组织特异性代谢作用。
通过比较二甲双胍治疗的糖尿病小鼠（MET）和溶剂处理的db/db小鼠（VG），初步确定二甲双胍特异性的代谢变化。然后在两个人群队列（KORA和QBB）以及一项针对未使用过二甲双胍的2型糖尿病（T2D）患者的KORA纵向研究中评估这些发现。我们还比较了MET组与接受联合治疗（SGLT2i + MET）的db/db小鼠。代谢谱分析在治疗后对血浆、肝脏和肾脏组织中的716种代谢物进行了分析，使用线性回归和Bonferroni校正进行统计分析，并辅以通路分析以探究其病理生理学意义。
二甲双胍单药治疗显著上调了糖尿病小鼠血浆中TCA循环中间产物，如苹果酸、富马酸和α-酮戊二酸（α-KG），以及回补底物，包括肝脏中的谷氨酸和肾脏中的2-羟基戊二酸（2-HG）。还观察到肝脏中牛磺酸下调。然而，添加SGLT2i后逆转了这些作用，如下调循环中的苹果酸和α-KG，以及肝脏中的谷氨酸和肾脏中的2-HG，但上调了肝脏中的牛磺酸。在接受二甲双胍治疗的人类T2D患者中，观察到代谢物有显著的全身改变，包括苹果酸增加但瓜氨酸减少。小鼠中TCA循环中间产物的双向调节影响了与谷氨酰胺分解、肿瘤发生、免疫调节和抗氧化反应相关的关键回补途径。
本研究阐明了二甲双胍和SGLT2i对TCA循环的特定代谢后果，反映了对免疫系统的潜在影响。二甲双胍因其抗炎特性显示出前景，而添加SGLT2i可能在代谢功能障碍相关脂肪性肝病（MASLD）等情况下提供肝脏保护。这些观察结果强调了个性化治疗策略的重要性。
