Bidirectional regulation of liver sinusoidal clearance by amino acid nanofibers and IGFBP4 complex: effects on HbA1c

Therapies for type 2 diabetes primarily target hyperglycemia; however, complications are also triggered by advanced glycation end products (AGEs). We hypothesize that the anti-diabetic efficacy of insulin-like growth factor-binding protein 4 (IGFBP4) is enhanced when it assembles with a specific amino acid compound-2 (AAC2) into nanostructures. Their effects were examined in vitro and in ob/ob mice treated for 30 days with the AAC2-IGFBP4 complex or its individual components. IGFBP4-mediated glucose uptake in human and mouse preadipocytes was enhanced by complex formation with AAC2. This complex was confirmed by Fourier-transform mid-infrared spectroscopy, electrophoresis, and AFM. In ob/ob mice, the complex prolonged IGFBP4 circulation and amplified the effects of the individual components, resulting in reduced hyperphagia, body weight, and hyperinsulinemia, along with improved insulin sensitivity and glucose tolerance. Notably, HbA1c levels remained at 5.9% in the complex-treated group compared to > 7% in others, with lower plasma AGE levels than in AAC2-treated mice. Transcriptomic and pathway analyses revealed that the complex upregulated genes promoting the fenestrated phenotype of liver sinusoidal endothelial cells (LSECs), facilitating AGE and waste clearance, whereas free AAC2 inhibited this process. We propose a 'scavenger-input' hypothesis in which free AAC2 inhibits, while the AAC2-IGFBP4 complex activates fenestrated phenotype and waste‑clearance capacity in liver sinusoidal endothelial cells (LSECs). Based on our results, AAC2 could serve as an adaptable and inherently therapeutic nanofiber modality that enhances the functional properties of bound proteins, offering multidimensional treatment possibilities for diabetes and other degenerative disorders.