二甲双胍
糖异生
代谢物
2型糖尿病
分解代谢
化学
内科学
乳酸
酮体
内分泌学
药理学
生物
糖尿病
医学
新陈代谢
细菌
遗传学
作者
Makoto Harada,Siyu Han,Mengya Shi,Jianhong Ge,Shixiang Yu,Jonathan Adam,Jerzy Adamski,Markus F. Scheerer,Susanne Neschen,Martin Hrabě de Angelis,Rui Wang‐Sattler
标识
DOI:10.1016/j.ijbiomac.2024.130962
摘要
Combining a Sodium-Glucose-Cotransporter-2-inhibitor (SGLT2i) with metformin is recommended for managing hyperglycemia in patients with type 2 diabetes (T2D) who have cardio-renal complications. Our study aimed to investigate the metabolic effects of SGLT2i and metformin, both individually and synergistically. We treated leptin receptor-deficient (db/db) mice with these drugs for two weeks and conducted metabolite profiling, identifying 861 metabolites across kidney, liver, muscle, fat, and plasma. Using linear regression and mixed-effects models, we identified two SGLT2i-specific metabolites, X-12465 and 3-hydroxybutyric acid (3HBA), a ketone body, across all examined tissues. The levels of 3HBA were significantly higher under SGLT2i monotherapy compared to controls and were attenuated when combined with metformin. We observed similar modulatory effects on metabolites involved in protein catabolism (e.g., branched-chain amino acids) and gluconeogenesis. Moreover, combination therapy significantly raised pipecolate levels, which may enhance mTOR1 activity, while modulating GSK3, a common target of SGLT2i and 3HBA inhibition. The combination therapy also led to significant reductions in body weight and lactate levels, contrasted with monotherapies. Our findings advocate for the combined approach to better manage muscle loss, and the risks of DKA and lactic acidosis, presenting a more effective strategy for T2D treatment.
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