Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Agilent Technologies, Chromatography Mass Spectrometry Sales Department, Life Science and Applied Markets Group, Tokyo, Japan.
J Cachexia Sarcopenia Muscle. 2022 Feb;13(1):574-588. doi: 10.1002/jcsm.12814. Epub 2021 Dec 2.
Diabetes mellitus increases the excretion of urinary glucose from the renal glomeruli due to elevated blood glucose levels. In the renal tubules, SGLT2 is expressed and reabsorbs the excreted urinary glucose. In the pathogenesis of diabetes mellitus, glucose reabsorption by SGLT2 is increased, and SGLT2 inhibitors improve hyperglycaemia by inhibiting this reabsorption. When urinary glucose excretion is enhanced, glucose supply to skeletal muscle may be insufficient and muscle protein catabolism may be accelerated. On the other hand, SGLT2 inhibitors not only ameliorate hyperglycaemia but also improve fatty acid metabolism in muscle, which may prevent muscle atrophy.
Eight-week-old male db/m mice or db/db mice were fed a standard diet with or without the SGLT2i luseogliflozin (0.01% w/w in chow) for 8 weeks. Mice were sacrificed at 16 weeks of age, and skeletal muscle and serum lipidomes, as well as skeletal muscle transcriptome, were analysed.
Administration of SGLT2i led to not only decreased visceral fat accumulation (P = 0.004) but also increased soleus muscle weight (P = 0.010) and grip strength (P = 0.0001). The levels of saturated fatty acids, especially palmitic acid, decreased in both muscles (P = 0.017) and sera (P = 0.041) upon administration of SGLT2i, while the content of monosaturated fatty acids, especially oleic acid, increased in both muscle (P < 0.0001) and sera (P = 0.009). Finally, the accumulation of transcripts associated with fatty acid metabolism, such as Scd1, Fasn, and Elovl6, and of muscle atrophy-associated transcripts, such as Foxo1, Mstn, Trim63, and Fbxo32, decreased following SGLT2i administration.
Intramuscular fatty acid metabolism and gene expression were influenced by the extracellular lipidome, which was modified by SGLT2i. Hence, secondary effects, other than the hypoglycaemic effects of SGLT2i, might lead to the alleviation of sarcopenia.
由于血糖升高，糖尿病会导致肾脏肾小球中尿糖排泄增加。在肾小管中，SGLT2 表达并重吸收排泄的尿糖。在糖尿病的发病机制中，SGLT2 的葡萄糖重吸收增加，SGLT2 抑制剂通过抑制这种重吸收来改善高血糖。当尿糖排泄增加时，骨骼肌的葡萄糖供应可能不足，肌肉蛋白分解可能加速。另一方面，SGLT2 抑制剂不仅改善高血糖，还改善肌肉中的脂肪酸代谢，从而防止肌肉萎缩。
16 周龄雄性 db/m 小鼠或 db/db 小鼠给予标准饮食，或在标准饮食中添加 SGLT2i 卢格列净（饮食中 0.01%w/w）喂养 8 周。16 周龄时处死小鼠，分析骨骼肌和血清脂质组以及骨骼肌转录组。
SGLT2i 的给药不仅导致内脏脂肪堆积减少（P=0.004），还导致比目鱼肌重量增加（P=0.010）和握力增强（P=0.0001）。SGLT2i 给药后，两种肌肉（P=0.017）和血清（P=0.041）中饱和脂肪酸，尤其是棕榈酸水平降低，而单不饱和脂肪酸，尤其是油酸水平升高，两种肌肉（P<0.0001）和血清（P=0.009）。最后，脂肪酸代谢相关基因如 Scd1、Fasn 和 Elovl6，以及肌肉萎缩相关基因如 Foxo1、Mstn、Trim63 和 Fbxo32 的转录本积累减少。
细胞外脂质组受 SGLT2i 影响，从而影响肌肉内的脂肪酸代谢和基因表达。因此，除了 SGLT2i 的降血糖作用外，其他的次级作用可能会导致肌肉减少症的缓解。
