Response of Individuals With Ataxia-Telangiectasia to Metformin and Pioglitazone

Summary

This study aims to investigate the link between the Ataxia Telangiectasia Mutated (ATM) gene and metformin response. This link has been identified from large studies of the human genome, and this study aims to confirm this link in a clinical study. The ATM gene is involved in DNA repair - if a person inherits a "faulty" copy of this gene from both their parents, they have a genetic condition called Ataxia-telangiectasia (A-T). A-T is associated with, among other things, a resistance to insulin, which causes fatty liver and diabetes. This study will recruit people who have A-T, but have not developed diabetes, and compare this group to "healthy" controls, i.e. people who do not have A-T or diabetes. The study will compare how the groups respond to two drugs used to treat diabetes (metformin and pioglitazone), with the intention that this will guide the management of diabetes in A-T. This is an, open label unblinded study recruiting 15 people with A-T and 15 age and gender matched controls. Each participant will have three study visits to the Clinical Research Centre at Ninewells hospital in Dundee - one at baseline, a second after 8 weeks of metformin and the final visit after eight weeks of pioglitazone. During each visit we will carry out a number of investigations to study the insulin resistance of A-T and how it responds to metformin and pioglitazone.

Timeline

Start

2016-09-29

Primary completion

2017-08-30

Completion

2017-08-30

Publications

• Background Miles PD, Treuner K, Latronica M, Olefsky JM, Barlow C. Impaired insulin secretion in a mouse model of ataxia telangiectasia. Am J Physiol Endocrinol Metab. 2007 Jul;293(1):E70-4. doi: 10.1152/ajpendo.00259.2006. Epub 2007 Mar 13.
• Background Takagi M, Uno H, Nishi R, Sugimoto M, Hasegawa S, Piao J, Ihara N, Kanai S, Kakei S, Tamura Y, Suganami T, Kamei Y, Shimizu T, Yasuda A, Ogawa Y, Mizutani S. ATM Regulates Adipocyte Differentiation and Contributes to Glucose Homeostasis. Cell Rep. 2015 Feb 17;10(6):957-967. doi: 10.1016/j.celrep.2015.01.027. Epub 2015 Feb 12.
• Background Connelly PJ, Smith N, Chadwick R, Exley AR, Shneerson JM, Pearson ER. Recessive mutations in the cancer gene Ataxia Telangiectasia Mutated (ATM), at a locus previously associated with metformin response, cause dysglycaemia and insulin resistance. Diabet Med. 2016 Mar;33(3):371-5. doi: 10.1111/dme.13037. Epub 2015 Dec 24.
• Background GoDARTS and UKPDS Diabetes Pharmacogenetics Study Group; Wellcome Trust Case Control Consortium 2; Zhou K, Bellenguez C, Spencer CC, Bennett AJ, Coleman RL, Tavendale R, Hawley SA, Donnelly LA, Schofield C, Groves CJ, Burch L, Carr F, Strange A, Freeman C, Blackwell JM, Bramon E, Brown MA, Casas JP, Corvin A, Craddock N, Deloukas P, Dronov S, Duncanson A, Edkins S, Gray E, Hunt S, Jankowski J, Langford C, Markus HS, Mathew CG, Plomin R, Rautanen A, Sawcer SJ, Samani NJ, Trembath R, Viswanathan AC, Wood NW; MAGIC investigators; Harries LW, Hattersley AT, Doney AS, Colhoun H, Morris AD, Sutherland C, Hardie DG, Peltonen L, McCarthy MI, Holman RR, Palmer CN, Donnelly P, Pearson ER. Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes. Nat Genet. 2011 Feb;43(2):117-20. doi: 10.1038/ng.735. Epub 2010 Dec 26.
• Background van Leeuwen N, Nijpels G, Becker ML, Deshmukh H, Zhou K, Stricker BH, Uitterlinden AG, Hofman A, van 't Riet E, Palmer CN, Guigas B, Slagboom PE, Durrington P, Calle RA, Neil A, Hitman G, Livingstone SJ, Colhoun H, Holman RR, McCarthy MI, Dekker JM, 't Hart LM, Pearson ER. A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetes: a replication and meta-analysis of five cohorts. Diabetologia. 2012 Jul;55(7):1971-7. doi: 10.1007/s00125-012-2537-x. Epub 2012 Mar 28.

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