Lessening Health Inequalities in Type 2 Diabetes Through Innovative Drug Repurposing

Most older type 2 diabetes (T2D) drugs were developed through pre-clinical studies and then trials that model T2D as it is experienced by older white people (1). These drugs tend to be less efficacious in currently difficult-to-treat T2D, such as can often be experienced for example, by younger people and/or ethnic minorities (2, 3). Recently, relative lack of muscle mass, by accelerating onset and severity of insulin resistance, has been highlighted as a new additional target that should be exploited to address currently difficult-to-treat T2D (4, 5, 6, 7, 8). We will use Seahorse methodology to investigate pyruvate kinase (PK) M2 activators as a potential novel therapy for direct alleviation of muscle cell insulin resistance, something that no clinically-approved drug currently achieves.

We will study the mitochondrial impact of PK activators on wild-type L6 cell and those lacking PKM2. We will also study material from knockout and wild-type animals. Seahorse respiratory control experiments will be conducted to determine the effect of PK activators on mitochondrial respiratory capacity, which we know is reduced by lipids in primary tissue as they induce insulin resistance. The outcome will be a clearer understanding of the therapeutic action of these drugs on insulin resistance.

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