Allosteric β-Klotho Modulation to Restore FGF21 Sensitivity in Type 2 Diabetes

Introduction: FGF21 resistance in type 2 diabetes (T2DM) limits the metabolic efficacy of endogenous FGF21 despite increased circulating concentrations, implicating impaired β-Klotho (KLB)–FGFR1c signaling as a therapeutically actionable mechanism. Objective : To evaluate the structural, genetic, tissue-specific, and network-level rationale for allosteric KLB modulation as a strategy to restore FGF21 sensitivity in T2DM. Methods : A literature-grounded bioinformatics framework integrated Protein Data Bank structural curation, comparative structural analysis, characterization of the 39F7-defined allosteric site, KLB genetic-variant curation, tissue-specific receptor synthesis, interaction-network construction, and pharmacological feasibility assessment. Results No solved ternary FGF21–FGFR1c–KLB structure was identified. The homologous FGF23–FGFR1c–αKlotho complex was supported as a modeling template by low structural divergence between Klotho homologs. The KL1 Trp-295-centered site represented a noncompetitive activation interface, exemplified by the 39F7 antibody (KD = 86 pM). Five KLB variants were associated with body mass index, hepatic steatosis, or alcohol-related behavior. Tissue synthesis indicated adipose-predominant FGFR1c–KLB engagement for FGF21, whereas hepatic FGFR4–KLB signaling was comparatively weak. Network curation connected KLB with AMPK, SIRT1, PGC-1α, and mTOR, positioning KLB as a convergent structural node linking genetic susceptibility, tissue selectivity, and metabolic signaling. Conclusion : The integrated evidence supports KLB allosteric modulation as a mechanistically plausible approach to enhance endogenous FGF21 responsiveness and potentially overcome receptor-level resistance in T2DM, with particular relevance to adipose tissue, insulin sensitivity, energy expenditure, and cardiometabolic risk reduction in affected metabolic phenotypes. Experimental binding, cellular signaling, structural, pharmacokinetic, and in vivo studies are required to establish efficacy and tissue selectivity.