Differential glucose uptake response to IGF-II and vesiculin in insulin resistant muscle and adipose cells.

Type 2 diabetes (T2D), a significant global health concern, is characterized by insulin resistance and progressive pancreatic β-cell degradation leading to failure of blood glucose regulation. Pancreatic islet hormones are essential for systemic glucose homeostasis, and their dysregulation is implicated in T2D pathogenesis. Characterisation of these hormones has been critical for understanding disease progression and designing therapeutic approaches. Vesiculin is a two-chain peptide derived from insulin-like growth factor-II (IGF-II) via a four-amino-acid excision. Studies of IGF-II and vesiculin revealed comparable insulin-like glucoregulatory activity in mice, however, in insulin-resistant animal models, vesiculin activity remains intact whereas IGF-II activity is impeded, highlighting potential pharmacological relevance for vesiculin. We aimed to compare the glucoregulatory activity of vesiculin and IGF-II in differentiated 3T3-L1 adipocytes and L6-GLUT4myc myoblasts under insulin-sensitive and insulin-resistant conditions to understand tissue specific activities of these peptides. Further we characterised binding efficiency of vesiculin and IGF-II to several IGF binding proteins (IGFBP).  Vesiculin exhibited glucose uptake comparable to IGF-II in both cell types, with similar dose response curves. Vesiculin retained efficacy in insulin-resistant myotubes whereas IGF-II activity was blunted, however, both peptides were not significantly impacted by insulin resistance in adipocytes. Vesiculin also showed a modest synergistic effect with insulin in resistant adipocytes. Additionally, binding assays revealed that vesiculin had significantly lower affinity for IGFBP3 and IGFBP5 compared to IGF-II. These findings demonstrate that vesiculin exhibits a distinct glucoregulatory signalling profile from IGF-II, discernible specifically under insulin-resistant conditions despite their structural similarity.