Lipid Metabolic Disorders: a Pivotal Driver in Type 2 Diabetes Mellitus Pathogenesis

This review aims to synthesize recent evidence to clarify the causal and mechanistic roles of lipid metabolism disorders as core drivers of type 2 diabetes mellitus (T2DM), and to summarize emerging therapeutic advances targeting key nodes within pathophysiological cascade, thereby providing an integrated, translational framework for the precision management of T2DM.

Normoglycemic obese individuals with insulin resistance (IR) frequently exhibit elevated plasma free fatty acids (FFAs), triglycerides (TGs), and low-density lipoprotein cholesterol (LDL-C), alongside reduced high-density lipoprotein cholesterol (HDL-C). These observations indicate that dyslipidemia is not merely a comorbidity but an important early driver of T2DM progression. Lipid metabolism disorders initiate a unifying pathological cascade: ectopic lipid spillover induces systemic IR in the liver and skeletal muscle; lipotoxic stress directly compromises pancreatic β-cell function; and progressive disruption of inter-organ axes, including the gut-adipose-liver axis and brain-periphery axis, further exacerbates systemic metabolic deterioration. Recent evidence supports emerging therapeutic strategies, including traditional medicine-based approaches and interventions targeting lipotoxicity and the gut-brain-liver-fat axis to restore metabolic health. Lipid metabolism disorders are not merely complications of T2DM, but critical drivers of disease progression. Adipose dysfunction acts as the initiating event, triggering a pathological cascade that induces systemic IR, impairs pancreatic β-cell function via lipotoxic intermediates, and disrupts inter-organ communication networks. Targeted interventions along this axis therefore represent a promising strategy for precision therapy.