Response of Individuals With Ataxia-Telangiectasia to Metformin and Pioglitazone

Metformin is a commonly-prescribed drug, used as first-line medical management of type 2 diabetes mellitus (T2DM), but also off-license in non-diabetics for Polycystic Ovary Syndrome (PCOS). Over 120 million people worldwide are prescribed metformin. Despite this, its mechanism of action is not fully understood. Both tolerance of and response to metformin varies greatly from patient to patient, and highlights the need for further research into the pharmacokinetics and dynamics of the drug.

As a team of diabetes researchers, our group have been interested in the genetics of drug response in diabetes. A Genome Wide Association Study carried out by members of our group highlighted the locus carrying the ATM gene as a potential link to metformin response. We have designed this study to investigate this link clinically. In doing so we hope to guide the management of diabetes in a condition called Ataxia Telangiectasia.

ATM (Ataxia Telangiectasia Mutated) is a gene involved in DNA repair - homozygous recessive mutations in this gene cause Ataxia Telangiectasia (A-T), which is associated with cerebellar ataxia, ocular telangiectasia and lymphoproliferative cancers. The incidence of A-T is between 1 in 40,000 to 1 in 100,000 live births, though this increases dramatically with consanguineous parents. Interestingly, A-T has also been associated with insulin resistance. Both "fatty liver" and diabetes have been documented in this patient group, but there is little research into the link between A-T and these conditions. Approximately 1 in 100 people are carriers of a loss of function mutation in the ATM gene, which is associated with an increased risk of ischaemic heart disease and certain cancers.

Several studies of ATM deficiency in a mouse model have been carried out. Atm -/- mice display an early defect in glucose-stimulated insulin release and later develop hyperglycaemia, and insulin resistance[1]. Unpublished data from the McCrimmon Group at University of Dundee suggest that mice heterozygous for ATM deficiency have impaired fasting glucose, but demonstrated a marked improvement in fasting glucose with metformin. A Cell Reports paper, detailing a mouse model of ATM deficiency, demonstrates insulin resistance in ATM deficient mice, with a lipodystrophic phenotype[2]. This phenotype (paucity of subcutaneous fat, and increased visceral fat) was attenuated by metformin and thiazolidinedione (TZD) use.

A small study published by the Pearson group from University of Dundee, which compared data from oral glucose tolerance tests (OGTTs) in A-T patients versus healthy individuals, confirmed increased insulin resistance in A-T patients[3]. As mentioned above, a genome wide association study, also by the Pearson group, highlights the ATM locus as a potential genetic link to metformin response[4, 5]. With the mouse models and information from genetic studies, this study now aims to assess insulin resistance in this A-T patient group, and to understand how they respond to drugs commonly used to treat insulin resistance / diabetes.