Activity of a pancreatic β-cell-specific two-chain product of the IGF-II gene: Vesiculin

Abstract

The search for an islet β-cell growth factor has been paramount in recent diabetes research as the ability to regenerate and/or protect the functioning β-cell population of a patient would result in a great advancement for diabetes treatment. Insulin-like growth factor (IGF)-I and -II are known to have crucial roles in fetal growth and prenatal development, including development of the pancreas where IGF-II expression is much higher than IGF-I and there is growing evidence that IGF-II increases β-cell proliferation and survival in-vitro and in-vivo. IGF-II-like immunoreactivity has previously been seen in β-cells of adult rat, dogs and human pancreas. Vesiculin, a two chain product of the IGF-II gene, was discovered during screening for the source of IGF-II-like-immunoreactivity in β-cells. Considering its presence in the secretory granule, its structure and its homology to insulin and IGF-II, it seems likely to contribute to the mechanisms by which β-cells regulate metabolism in health and disease. Our hypothesis is that Vesiculin may be the long sought-after islet β-cell specific growth factor that could enable regeneration of β-cells, whose degeneration and death cause both major forms of diabetes. Accordingly we have had this peptide synthesized for further characterisation in-vivo and in-vitro. The blood glucose lowering activity of the peptide has been tested alongside IGF-II and insulin in mice. We have also used isolated rat soleus muscle to compare stimulation of radiolabelled glucose conversion to muscle glycogen. The proliferative potential of vesiculin and IGF-II is being assessed in various β-cell lines (rodent and human) in the presence of varying glucose concentrations, in the presence or absence of GLP-1 and also in the presence of IGF-1R inhibitors. Beta-cell survival in the face of toxic preparations of human amylin/IAPP is also being measured. This data will be informative for developing pilot trials of vesiculin as a therapeutic agent in our proprietary human amylin/IAPP transgenic mouse model which is an excellent model for type 2 diabetes. In-vivo data has shown that murine synthetic vesiculin, like IGF-II has blood glucose lowering effects in mice with approximately 100x more peptide to elicit the same response. Ex-vivo experiments have also revealed that both human synthetic Insulin and synthetic murine vesiculin stimulate glucose conversion to muscle glycogen in isolated rat muscle with similar potencies. Findings to be presented will also include data from on-going in-vitro assessment on the proliferative and cytoprotective roles of both IGF-II and vesiculin as well as receptor specificities.