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Abstract：
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
背景：二甲双胍和钠-葡萄糖-协同转运蛋白-2抑制剂（SGLT2i）是治疗糖尿病高血糖的基础疗法。然而,它们对代谢过程的详细影响，特别是在柠檬酸(TCA)循环及其回补途径中，仍然不清楚。这项研究调查了二甲双胍的组织特异性代谢作用，作为单一疗法和与SGLT2i的组合，小鼠和人类的TCA周期和相关的回补反应。
方法：通过比较二甲双胍治疗的糖尿病小鼠（MET）与溶媒治疗的db/db小鼠（VG），初步鉴定了二甲双胍特异性代谢变化。然后在两个人类队列（KORA和QBB）和二甲双胍初治2型糖尿病（T2D）患者的纵向KORA研究中评估了这些发现。我们还比较了MET与联合治疗(SGLT2i+MET)的db/db小鼠。代谢谱分析了来自血浆的716种代谢物，肝脏,和治疗后的肾脏组织，使用线性回归和Bonferroni校正进行统计分析，辅以通路分析，探讨病理生理意义。
结果：二甲双胍单药治疗显著上调TCA循环中间体，如苹果酸，富马酸盐,和血浆中的α-酮戊二酸（α-KG），和回补底物，包括糖尿病小鼠的肝谷氨酸和肾2-羟基戊二酸（2-HG）。还观察到下调的肝牛磺酸。SGLT2i的加入，然而,逆转了这些影响，如下调循环苹果酸和α-KG，肝谷氨酸和肾2-HG，但上调了肝牛磺酸.在接受二甲双胍治疗的人类T2D患者中，观察到代谢物的显着系统性变化，包括苹果酸增加但瓜氨酸减少。小鼠TCA循环中间体的双向调节影响了与谷氨酰胺分解相关的关键回补途径，肿瘤发生，免疫调节，和抗氧化反应。
结论：本研究阐明了二甲双胍和SGLT2i对TCA循环的特定代谢后果，反映对免疫系统的潜在影响。二甲双胍的抗炎特性显示出希望，而SGLT2i的添加可能在代谢功能障碍相关的脂肪变性肝病（MASLD）等疾病中提供肝脏保护。这些观察结果强调了个性化治疗策略的重要性。
方法：通过比较二甲双胍治疗的糖尿病小鼠（MET）与溶媒治疗的db/db小鼠（VG），初步鉴定了二甲双胍特异性代谢变化。然后在两个人类队列（KORA和QBB）和二甲双胍初治2型糖尿病（T2D）患者的纵向KORA研究中评估了这些发现。我们还比较了MET与联合治疗(SGLT2i+MET)的db/db小鼠。代谢谱分析了来自血浆的716种代谢物，肝脏,和治疗后的肾脏组织，使用线性回归和Bonferroni校正进行统计分析，辅以通路分析，探讨病理生理意义。
结果：二甲双胍单药治疗显著上调TCA循环中间体，如苹果酸，富马酸盐,和血浆中的α-酮戊二酸（α-KG），和回补底物，包括糖尿病小鼠的肝谷氨酸和肾2-羟基戊二酸（2-HG）。还观察到下调的肝牛磺酸。SGLT2i的加入，然而,逆转了这些影响，如下调循环苹果酸和α-KG，肝谷氨酸和肾2-HG，但上调了肝牛磺酸.在接受二甲双胍治疗的人类T2D患者中，观察到代谢物的显着系统性变化，包括苹果酸增加但瓜氨酸减少。小鼠TCA循环中间体的双向调节影响了与谷氨酰胺分解相关的关键回补途径，肿瘤发生，免疫调节，和抗氧化反应。
结论：本研究阐明了二甲双胍和SGLT2i对TCA循环的特定代谢后果，反映对免疫系统的潜在影响。二甲双胍的抗炎特性显示出希望，而SGLT2i的添加可能在代谢功能障碍相关的脂肪变性肝病（MASLD）等疾病中提供肝脏保护。这些观察结果强调了个性化治疗策略的重要性。
