The muscle-brain axis in type 2 diabetes: Molecular pathways linking sarcopenia and cognitive decline

Type 2 diabetes mellitus (T2DM) is increasingly recognized as a shared pathological substrate for both sarcopenia and cognitive decline, particularly Alzheimer’s disease (AD). This review synthesizes current evidence on the converging molecular pathways linking insulin resistance, hyperglycaemia, mitochondrial dysfunction, oxidative stress, and chronic inflammation to muscle wasting and neurodegeneration. Central to this interplay is the muscle–brain axis, a bidirectional communication network mediated by myokines, exercise-induced cytokines that influence metabolic and neural homeostasis. Key myokines such as IGF-1, irisin, BDNF, FGF21, and SPARC promote myogenesis, synaptic plasticity, and neuroprotection, while others including myostatin, IL-8, and GDF-15 exert detrimental effects. Context-dependent molecules such as IL-6, IL-15, lactate, and cathepsin-B show dual roles modulated by aging, inflammation, and metabolic state. Emerging data support that improved glycaemic control, enhanced insulin sensitivity, and sustained physical activity can attenuate both sarcopenia and cognitive decline. This review aims to summarize current evidence describing how insulin resistance, chronic hyperglycaemia, mitochondrial dysfunction, oxidative stress, and inflammation interact to promote both muscle wasting and neurodegeneration. Keywords • The review introduces the muscle–brain axis as a shared mechanism in T2DM, sarcopenia, and dementia. • It summarizes the role of myokines as mediators of muscle–brain endocrine signaling. • It links insulin resistance, mitochondrial dysfunction, and AGEs to dual tissue degeneration. • It discusses IL-6, irisin, IGF-1, and others in modulating neuroplasticity and muscle homeostasis.