Background: Diabetes is highly prevalent, and the number of patients with diabetic sarcopenia and cognitive impairment has grown, leading to decreased quality of life. Although the exact mechanisms between sarcopenia and cognitive impairment have not been elucidated, it is speculated that muscle and liver-derived mediators might contribute to brain function. This study examined the molecular mechanisms associated with muscle-brain interaction accompanied by insulin resistance (IR) caused by aberrant energy metabolism via myokines/hepatokines in type 2 diabetes mellitus (T2DM) mice. Methods: T2DM was induced by a high-fat diet and streptozotocin injection. Behavior tests were conducted to analyze grip strength and cognitive function. Histopathological changes in skeletal muscle and brain tissue were examined by hematoxylin and eosin staining and the protein levels of biomarkers related to energy metabolism via myokines/hepatokines were measured by western blot. Results: T2DM caused peripheral and central IR. Furthermore, T2DM led to aberrant energy metabolism through the reduced fibroblast growth factor 21 dependent AMP-activated kinase (AMPK)/surtuin1/proliferator-activated receptor γ coactivator-1α pathway in T2DM. Subsequently, reduced circulating myokines/hepatokines were in accordance with their levels with hippocampal neuronal markers in T2DM mice. Accordingly, skeletal muscle (muscle strength: 2.83 ± 0.39 vs. 2.187 ± 0.51, p = 0.004) and brain function (PAT: 38.5 ± 57.91 vs. 11.556 ± 12.03, p = 0.02) impairment and morphological changes (muscle cross-sectional area: 872.43 ± 242.87 vs. 743.68 ± 169.31, p = 0.01; density of neurons in hippocampus: 145 ± 15.13 vs. 77 ± 35.51, p = 0.05; density of neurons in cortex: 138.333 ± 6.66 vs. 78 ± 17.35, p = 0.05) were shown in T2DM mice. In addition, the working ability demonstrated by Y-maze was positively correlated with % lean mass (p = 0.046, R = 0.3426). Conclusions: T2DM led to aberrant energy in skeletal muscle and brain via myokines/hepatokines. This study suggested that myokines and hepatokines might have potential roles in skeletal muscle and central metabolic functions which can mediate cognitive function in T2DM mice.