Development of an Innovative Screening Tool and Identification of Novel ß-Cell Protective Drugs

Abstract

Type 2 diabetes (T2D) is characterised by progressive β-cell failure. While many drugs assist in the management of diabetes, current treatments cannot stop or slow the progression of this failure. In fact, over 50% of people with T2D have poor glycaemic control despite best practice management. Thus a key tool in T2D management would be the development of new drugs that restore adequate insulin secretion, but also protect against the continual deterioration of the β-cells. Previous drug discovery techniques have focused on single targets or pathways, however because β-cell dysfunction is extremely complex, targeting one pathway has proven to be ineffective. One approach that encompasses the intricacy of complex disease is that of gene expression signatures (GES) which have proved to be a valuable tool in other complex diseases.In this study, we developed a β -cell model consisting of three different conditions: 1) normal function/viability (“healthy”), 2) dysfunction/reduced viability (“diabetic”) and 3) successful treatment of dysfunction/reduced viability with a cocktail of known drugs (selected based on their ability to treat different aspects of β-cell dysfunction, “successfully treated”). We then used a comprehensive screening approach using gene expression profiles under these three conditions to generate a β-cell GES consisting of a gene set that robustly and accurately reflects the overall state of the cell. This GES was then used to screen a library of off-patent compounds, with known safety profiles, and the 12 top candidate compounds identified. In vitro testing of these drugs identified that nine significantly improved beta-cell function and survival. Therefore, we have developed a novel platform for T2D β-cell drug discovery and identified several candidate compounds that could prevent the progressive failure of β-cells. These drugs have the potential to be powerful T2D treatments and thereby reduce the burden of T2D and improve quality of life for millions world-wide. Disclosure S. Sithara: None. B. Patel: None. M.K. Ellis: None. T. Crowley: None. K. Walder: None. K. Aston-Mourney: None.