title: Recessive mutations in the cancer gene Ataxia Telangiectasia Mutated (ATM), at a locus previously associated with metformin response, cause dysglycaemia and insulin resistance.
abstract: OBJECTIVE
  To investigate glucose and insulin metabolism in participants with ataxia telangiectasia in the absence of a diagnosis of diabetes.
  
  
  METHODS
  A standard oral glucose tolerance test was performed in participants with ataxia telangiectasia (n = 10) and in a control cohort (n = 10). Serial glucose and insulin measurements were taken to permit cohort comparisons of glucose-insulin homeostasis and indices of insulin secretion and sensitivity.
  
  
  RESULTS
  During the oral glucose tolerance test, the 2-h glucose (6.75 vs 4.93 mmol/l; P = 0.029), insulin concentrations (285.6 vs 148.5 pmol/l; P = 0.043), incremental area under the curve for glucose (314 vs 161 mmol/l/min; P = 0.036) and incremental area under the curve for insulin (37,720 vs 18,080 pmol/l/min; P = 0.03) were higher in participants with ataxia telangiectasia than in the controls. There were no significant differences between groups in fasting glucose, insulin concentrations or insulinogenic index measurement (0.94 vs 0.95; P = 0.95). The Matsuda index, reflecting whole-body insulin sensitivity, was lower in participants with ataxia telangiectasia (5.96 vs 11.03; P = 0.019) than in control subjects.
  
  
  CONCLUSIONS
  Mutations in Ataxia Telangiectasia Mutated (ATM) that cause ataxia telangiectasia are associated with elevated glycaemia and low insulin sensitivity in participants without diabetes. This indicates a role of ATM in glucose and insulin metabolic pathways.
authors.affiliation: Division of Cardiovascular and Diabetes Medicine, Medical Research Institute, University of Dundee, Dundee, UK.
authors.forename: P J
authors.initials: PJ
authors.lastname: Connelly
authors.affiliation: Division of Cardiovascular and Diabetes Medicine, Medical Research Institute, University of Dundee, Dundee, UK.
authors.forename: N
authors.initials: N
authors.lastname: Smith
authors.affiliation: Papworth Hospital NHS Foundation Trust, Cambridge, UK.
authors.forename: R
authors.initials: R
authors.lastname: Chadwick
authors.affiliation: Papworth Hospital NHS Foundation Trust, Cambridge, UK.
authors.forename: A R
authors.initials: AR
authors.lastname: Exley
authors.affiliation: Papworth Hospital NHS Foundation Trust, Cambridge, UK.
authors.forename: J M
authors.initials: JM
authors.lastname: Shneerson
authors.affiliation: Division of Cardiovascular and Diabetes Medicine, Medical Research Institute, University of Dundee, Dundee, UK.
authors.forename: E R
authors.initials: ER
authors.lastname: Pearson
mesh_terms: D000328:Adult; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics*; D054316:Biomarkers, Pharmacological; D001786:Blood Glucose / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D052138:Genes, Neoplasm; D005808:Genes, Recessive; D056426:Genetic Loci / Q000187:drug effects; D044882:Glucose Metabolism Disorders / Q000235:genetics*; D005951:Glucose Tolerance Test; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics; D008687:Metformin / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide
chemical_list: D054316:Biomarkers, Pharmacological; D001786:Blood Glucose; D008687:Metformin; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins