1760-P: Mining Animal Venoms as a Source of Insulinotropic Peptides for Potential Diabetes Therapy

Abstract

T2D development and progression is widely known to be caused by pancreatic beta cell dysfunction, whether in the presence or absence of insulin resistance. There are however limited diabetes drugs that directly target the beta cell. Hence, there is a need to discover yet untapped pathways to increase or rescue beta cell function. Animal venoms provide a rich resource of bioactive compounds, many of which are highly potent and selective. Venom peptides have been harnessed for therapeutic drug development, such as the blockbuster diabetes drug, exenatide, a GLP-1 receptor agonist, being a synthetic form of exendin-4 that was first isolated from the saliva of the Gila monster. We hypothesize that we can further discover and develop new therapeutic agents that promote pancreatic beta cell function based on venom-derived compounds. We studied up to seven animal venoms from snakes, bees and scorpions. Pancreatic beta cells (including EndoC-βH1 cells, human islets, and MIN6 cells) were treated with crude animal venoms from each species and evaluated for insulin secretion capacity. We used a range of doses that elicit insulin secretion without causing cellular damage. Venoms from Apis mellifera (honey bee) and Naja naja (Indian cobra) were shown to robustly stimulate insulin secretion in a dose-dependent manner without affecting cell viability. Treatment with these venoms were also able to rescue diabetic cell models. We prioritized these two venoms for fractionation via gel filtration and reverse phase HPLC. After subsequent screening of the venom sub-fractions in insulin secretion assays, we pinpointed specific sub-fractions responsible for stimulating insulin release. Ongoing work is in progress to identify and validate selected peptides for insulinotropic activity, safety and stability. The insulinotropic peptides (and any modifications) may represent new therapeutic strategies for tackling T2D in future. Disclosure N.Ng: Stock/Shareholder; BetaLife. C.Koh: None. C.Ching: None. P.Gopalakrishnakone: None. A.Teo: None. Funding A*STAR Career Development Fund (202D800020)