Glycolipid metabolism disorder is one of the causes of type 2 diabetes (T2D). Alternate-day fasting (ADF) is an effective dietary intervention to counteract T2D. The present study is aimed to determine the underlying mechanisms of the benefits of ADF metabolic on diabetes-induced glycolipid metabolism disorders in db/db mice. Here, leptin receptor knock-out diabetic mice were subjected to 28 days of isocaloric ADF. We found that ADF prevented insulin resistance and bodyweight gain in diabetic mice. ADF promoted glycogen synthesis in both liver and muscle. ADF also activated recombinant insulin receptor substrate-1 (IRS-1)/protein kinase B (AKT/PKB) signaling，inactivated inflammation related AMP-activated protein kinase (AMPK) and the inflammation-regulating nuclear factor kappa-B (NF-κB) signaling in the liver. ADF also suppressed lipid accumulation by inactivating the expression of peroxisome proliferator–activated receptor gamma (PPAR-γ) and sterol regulatory element-binding protein-1c (SREBP-1c). Furthermore, ADF elevated the expression of fibroblast growth factor 21 (FGF21) and down-stream signaling AMPK/silent mating type information regulation 2 homolog 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) in the liver of diabetic mice. The mitochondrial biogenesis and autophagy were also stimulated by ADF. Interestingly, ADF also enhanced the bile acids (BAs) metabolism by generating more cholic acid (CA), deoxycholic acid (DCA) and tauroursodeoxycholic acid (TUDCA) in db/db mice. In conclusion, ADF could significantly inhibit T2D induced insulin resistance and obesity, promote insulin signaling，reduce inflammation, as well as promote glycogen synthesis and lipid metabolism. It possibly depends on FGF21 and BA metabolism to enhance mitochondrial biosynthesis and energy metabolism.

糖脂代谢异常是2型糖尿病（T2D）的原因之一。隔日禁食（ADF）是一种有效的饮食干预措施，可以抵抗T2D。本研究旨在确定ADF代谢对db / db小鼠中糖尿病诱导的糖脂代谢异常的益处的潜在机制。在此，使瘦素受体敲除的糖尿病小鼠接受等温ADF的28天。我们发现ADF可以预防糖尿病小鼠的胰岛素抵抗和体重增加。ADF促进肝脏和肌肉中糖原的合成。ADF还激活了重组胰岛素受体底物1（IRS-1）/蛋白激酶B（AKT / PKB）信号转导，灭活了炎症相关的AMP激活蛋白激酶（AMPK）和炎症调节核因子kappa-B（NF-κB）。 ）在肝脏中发出信号。ADF还通过使过氧化物酶体增殖物激活的受体γ（PPAR-γ）和固醇调节元件结合蛋白-1c（SREBP-1c）的表达失活来抑制脂质蓄积。此外，ADF提高了成纤维细胞生长因子21（FGF21）的表达和下游信号AMPK /沉默交配类型信息调节2同源物1（SIRT1）/过氧化物酶体增殖物激活受体γcoactivator-1 alpha（PGC-1α）的表达。糖尿病小鼠的肝脏。ADF也刺激线粒体的生物发生和自噬。有趣的是，ADF还通过在db / db小鼠体内产生更多的胆酸（CA），脱氧胆酸（DCA）和牛磺去氧胆酸（TUDCA）来增强胆汁酸（BAs）的代谢。总之，ADF可以显着抑制T2D诱导的胰岛素抵抗和肥胖，促进胰岛素信号传导，减少炎症以及促进糖原合成和脂质代谢。它可能依赖于FGF21和BA代谢来增强线粒体的生物合成和能量代谢。