The role of fibroblast growth factor 21 in diabetes and metabolic dysfunction.

Fibroblast growth factor 21 (FGF21) is an endocrine hormone central to metabolic regulation under nutritional and cellular stress. Predominantly synthesized by the liver, FGF21 exerts pleiotropic effects through fibroblast growth factor receptor 1c (FGFR1c) and its co receptor β-Klotho, targeting adipose tissue, skeletal muscle, pancreas, and the central nervous system. In diabetes mellitus, FGF21 enhances insulin sensitivity, stimulates adiponectin secretion, alleviates hepatic steatosis, and protects pancreatic β-cells from oxidative and endoplasmic reticulum stress. These effects are mediated via key molecular pathways, including AMPK, SIRT1, PGC-1α, and mTOR signaling. Interestingly, despite elevated circulating FGF21 levels in obesity and type 2 diabetes, biological responsiveness is diminished-a phenomenon termed FGF21 resistance, characterised by impaired receptor expression, inflammatory signaling interference, and downstream signaling deficits. This review presents an in depth mechanistic overview of FGF21 signaling, its regulatory networks, and implications for glucose and lipid homeostasis, inflammation, mitochondrial health, and autophagy. Additionally, it discusses the development of pharmacologically optimized FGF21 analogs and multi agonists designed to overcome resistance and enhance therapeutic efficacy. As our comprehension of FGF21 biology deepens, elucidation of its molecular processes, resistance phenomena, and pharmacological refinement will be crucial in establishing FGF21 as a fundamental element of precision medicine for metabolic illnesses. The incorporation of FGF21 based strategies with combinatorial pharmacotherapy and tissue targeted delivery methods offers a potential approach to tackle the complicated pathophysiology of diabetes and improve clinical outcomes in affected populations.