Oral Presentation The Annual Scientific Meeting of the Australian Diabetes Society and the Australian Diabetes Educators Association 2013

Dissecting insulin resistance using gene expression signatures (#89)

Ken Walder 1
  1. Deakin University, Waurn Ponds, VIC, Australia

We used a novel strategy to identify a Gene Expression Signature (GES) that reflects the overall state of insulin resistance in both cells and patients. The GES was developed in 3T3-L1 adipocytes that were made ‘insulin resistant’ by treatment with TNFα and then reversed with a salicylate and a thiazolidinedione (‘re-sensitised’). The biological relevance of the GES was demonstrated by identifying individuals with a higher degree of insulin resistance based on their GES expression profile (P < 0.001). Next we used the GES to screen a small molecule library to identify potential new therapeutic agents for type 2 diabetes, identifying a hit family of compounds including VVP808, which was then shown to have anti-diabetic efficacy in diet induced obese (DIO) mice, db/db mice and STZ rats. Next we conducted a multi-centre, randomized, double-blinded, placebo-controlled clinical proof-of-concept study evaluating the safety and efficacy of VVP808 in patients with type 2 diabetes. Study participants were treated with VVP808 (40 mg twice daily; n=37) or placebo (n=39) for 24 weeks. The primary efficacy endpoint of the clinical trial was a reduction in HbA1c from baseline in the VVP808 group vs. placebo group after 24 weeks of treatment. The clinical study achieved its protocol-specified primary efficacy endpoint (p<0.05). The drug was safe and well-tolerated, with no drug-related serious adverse events. Furthermore, the study identified potential additional clinical benefits of VVP808, including weight loss in a specific subset of patients and improvements in markers of liver function (reduced ALT, p<0.05). We subsequently showed that VVP808 lowered liver lipid levels in db/db mice, and reduced the hepatic expression of genes involved in lipid biogenesis in diet-induced obese mice, suggesting that VVP808 may be particularly beneficial in diabetic patients with fatty liver disease.