Precision Exercise in Type 2 Diabetes Mellitus: Targeting Signaling Networks for Lipid Homeostasis

Type 2 diabetes mellitus (T2DM) is frequently complicated by dyslipidemia, which accelerates insulin resistance and the progression of cardiovascular and hepatic diseases. While exercise intervention is a cornerstone of T2DM management, a systems-level understanding of its underlying molecular mechanisms remains incomplete. This article summarizes current evidence to propose that exercise functions as a signaling network regulator, concurrently modulating critical lipid metabolism-related signaling pathways: cyclic adenosine monophosphate (cAMP), phosphatidylinositol 3-kinase-protein kinase B (PI3K-AKT), forkhead box O (FOXO), and mitogen-activated protein kinase (MAPK) signaling pathways. We delineate how dysregulation of these signaling pathways contributes to lipid disorders in T2DM, highlighting their tissue-specific and often bidirectional roles. Subsequently, we detail the molecular adaptations induced by various exercise modalities-from aerobic training to high-intensity intervals-that restore homeostasis of this signaling network. By integrating these findings, we present a novel framework for precision exercise-defined as the tailoring of exercise modality, intensity, and volume based on an individual's predominant signaling pathway disturbance, assessed via circulating or tissue-specific biomarkers. This framework advocates for future exercise prescriptions to be guided by molecular profiling alongside traditional physiological indicators. This mechanistic insight not only deepens our comprehension of exercise physiology but also paves the way for more effective, personalized strategies to combat T2DM and its metabolic complications.