Comparative study of insulin-like activity of vesiculin and IGF-II in insulin resistant cell models

Abstract

Type 2 Diabetes (T2D) is a growing health issue worldwide with the two hallmarks being insulin resistance and progressive degradation of the pancreatic β-cells. Hormones secreted by the pancreas are crucial for the maintenance of normal whole body glucose homeostasis. Defects in the metabolic pathways that lead to the development of T2D are often associated with dysregulation in islet hormone expression and activity. It is therefore important to study and understand the biological function and signalling mechanism of islet hormones. Vesiculin is a newly discovered peptide, derived from Insulin-like growth factor-II (IGF-II) through an excision of four amino acids. This hormone is secreted by the islet β-cells, but in very small amount and thus, it is hypothesised to have an endocrine and/or paracrine function. Previous work has demonstrated that, like IGF-II, vesiculin is able to lower blood glucose in mice. Glucoregulatory activity of vesiculin is comparable to IGF-II. however, in insulin resistant animal models, IGF-II activity was found to be blunted whereas vesiculin was unaltered. In this study, we performed a full in vitro comparison of vesiculin and IGF-II. This established the blood glucose lowering capacity of vesiculin to be comparable to that of IGF-II in insulin sensitive in vitro models of both skeletal muscle and adipose tissue with dose response curves being not significantly different. We also confirmed that vesiculin was able to retain its effect in insulin resistance, where maximal response to IGF-II was significantly reduced. Furthermore, we showed that vesiculin had marginal synergistic effect with insulin, which enhanced insulin stimulation in resistant cells. Similar to insulin, vesiculin also mediated its glucoregulatory activity through the Phosphoinositide 3-kinases phosphorylation pathway. These findings are consistent with results from previous in vitro studies and thus, confirms vesiculin glucoregulatory signalling is distinct from IGF-II in a way that is only revealed in insulin resistant state even though the two peptides are highly similar in structure. Lastly, we also generated an IGF-II knock-out cell model, which can be used for future study to explore the role of vesiculin in the pancreatic islet cells.