Molecular and physiological dissection of the unexpected metabolic actions of the DNA repair gene ataxia-telangiectasia mutated (ATM).

Metformin is recommended as first line oral therapy in Type 2 diabetes (>200 million people world wide) in all international guidelines. Despite this there is considerable variation in glycemic response to metformin, which cannot be predicted by clinical phenotype or adherence. Although metformin has been used in the clinic for over 60 years the molecular details of its mechanism of action remain passionately debated. Its primary effect was thought to be a reduction in hepatic glucose output by suppression of gluconeogenesis however additional roles on liver, muscle and in particular gut have been proposed. We reported, in Nature Genetics, an association of a locus on chromosome 11 with glycemic response to metformin. This includes the gene for Ataxia telangiectasia mutated (ATM). Although unexpected we have subsequently found that Ataxia Telangiectasia (A-T) is associated with increased risk of diabetes and marked insulin resistance. Of particular interest is recent work by EP in A-T patients that demonstrated a significant endocrine defect in response to oral glucose load. This data implies a role for ATM in nutrient sensing in the gut, and an influence on the vital regulatory incretin and insulin secretion/clearance response. We thus believe it of clear clinical importance for 100’000s of diabetes patients to clarify the mechanisms linking ATM, nutrient sensing and metformin response.