Restoring hepatic TDAG51 expression improves insulin signalling and reduces weight gain.

Abstract

1.5 million Ontarians, representing 10.2% the population, lived with diabetes in 2015. Treating this number of people with diabetes cost the public healthcare system approximately $6 billion. A staggering 2.3 million Ontarians, representing 13.5% of the population, are projected to have diabetes in the year 2025. This will raise public spending on diabetes to approximately $7.7 billion. Current therapies for Type 2 diabetes only focus on controlling glucose levels and do not target or reverse disease progression and complications, which allows the prevalence of diabetes to continue to rise unchecked. Targeting the source of insulin resistance, as opposed to attempting to control the symptoms of insulin resistance, represents a better strategy for the discovery of novel therapies. We have recently reported that loss of T-Cell Death-Associated Gene 51 (TDAG51) is associated with mature-onset obesity, Type 2 diabetes, and fatty liver. TDAG51 expression is significantly diminished in mice fed a high fat diet, which leads to insulin resistance and obesity, as well as in the leptin-deficient mouse model, a well-established genetic model of Type 2 diabetes and obesity. We have now discovered that restoring TDAG51 protein expression in the livers of TDAG51-null and leptin-deficient mouse models improves response to insulin and reduces total weight gain. We have shown that exogenous TDAG51 protein expression is significantly reduced in two mouse models of insulin resistance compared to healthy controls. The potential for post-translational degradation of TDAG51 protein in insulin-resistant livers is supported by five independent models of fatty liver in which TDAG51 protein expression is diminished while TDAG51 mRNA expression remained unchanged. We have also explored a number of mechanisms by which TDAG51 protein may be regulated post-translationally, and have provided suggestions of how TDAG51 protein may be modified in a fatty liver that would impact its stability. Collectively, we have highlighted the therapeutic potential of increasing liver TDAG51 expression in Type 2 diabetic conditions, and have laid a strong foundation for discovering how TDAG51 expression is regulated.