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Diabetes results from the loss or malfunction of the beta cells in the pancreas that make insulin. Autoimmunity has been the accepted explanation for type 1 diabetes (T1D) for 40 years, but clinical trials of immunotherapy have proved disappointing, and have not provided a means of prevention. The accelerator hypothesis proposes a different explanation for T1D, based on the tempo of beta cell loss and the environmental factors that drive it. The autoimmune diabetes Accelerator Prevention Trial (adAPT) is testing the accelerator hypothesis, by seeking to establish whether the drug metformin can slow the tempo sufficiently to reduce the incidence of diabetes in children at risk. The trial is sponsored by the University of Exeter, conducted in Scotland by the Tayside Clinical Trials Unit and funded by JDRF. It will report finally in 2022. ==Background== Although immune interventions have proved successful in preventing T1D in animal models, the same has not proved true for humans.〔Bonifacio E. Immunotherapy in type 1 diabetes: a shorter but more winding road. Diabetes 2012;61:2214-15〕 The disparity suggests that the mechanisms may be different, and questions whether the autoimmunity paradigm is appropriate for T1D in man. The accelerator hypothesis〔Wilkin TJ. The Accelerator Hypothesis: weight gain as the missing link between Type I and Type II diabetes Diabetologia 2001;44:914-22〕 offers an alternative account, which is needed to explain the rise in childhood diabetes over the past 40 years,〔Gale EA. Spring harvest? Reflections on the rise of type 1 diabetes. Diabetologia 2005;48:2445-50〕 and the inability of immune-based interventions to prevent it. It views T1D and type 2 diabetes (T2D) as the same disorder of beta cell stress, set against different genetic backgrounds. Stress shortens the life of beta cells,〔Donath MY, Böni-Schnetzler M, Ellingsgaard H, Ehses JA. Islet inflammation impairs the pancreatic beta-cell in type 2 diabetes. Physiology (Bethesda).2009;24:325-31.〕〔Butler AE, Janson J,Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans With type 2 diabetes. Diabetes 2003;52:102–110〕 and the accelerator hypothesis is built, not on difference in type of diabetes, but on variation in tempo of beta cell loss. The rise in insulin demand associated with contemporary living is considered to be the primary accelerator,〔Fourlanos S, Harrison LC, Colman PG. The accelerator hypothesis and increasing incidence of type 1 diabetes. Curr Opin Endocrinol Diabetes Obes 2008;15:321-25〕 and the immune response to it a secondary accelerator that can propel a critical loss into childhood. Where the conventional explanation for T1D has invoked an immune attack on the insulin-producing beta cells by a faulty immune system,〔Devendra D, Liu E, Eisenbarth GS. Type 1 diabetes:recent developments. BMJ 2004;328:750-54.〕 the accelerator hypothesis sees ‘autoimmunity’ as a normal, albeit inflammatory, response to beta cell stress confined to the small minority of the population with reactive immune response or human leukocyte antigen (HLA) genes.〔Wilkin TJ. Autoimmunity:attack, or defence? Autoimmunity 1989;3:57-73〕 If insulin demand is the primary driver, and ‘autoimmunity’ the response, logic suggests that interventions to prevent childhood diabetes should aim at reduction of insulin demand, not suppression of the immune system. ==Design== adAPT is a classic randomised, placebo-controlled trial of metformin in children and young people at risk of T1D. Metformin is a widely used medication that lowers blood glucose levels, reduces insulin demand and thereby reduces beta cell stress. Diabetes is a state in which the homeostatic control of glucose is lost as a result of beta cell failure, and APT seeks to prevent diabetes in children at risk by slowing beta cell loss. The trial is divided into three stages, each seeking evidence of beta cell preservation: ''Stage 1'' to establish whether metformin reduces demand on the beta cell in children at risk of type 1 diabetes as it does in others. Measures will include fasting insulin, HOMA2-IR,〔Levy JC, Matthews DR, Hermans MP. Correct homeostasis model assessment (HOMA) evaluation uses the computer program. Diabetes Care. 1998;21:2191-92〕 indices from continuous glucose monitoring and the behaviour of glucose, insulin, C-peptide and the insulinogenic index during the course of a mixed meal tolerance test(duration four months). ''Stage 2'' to assess the long-term impact of reducing beta cell stress on surrogate markers of glucose control in children at risk of T1D. Measures will be those used in Stage 1 repeated at six-monthly intervals to explore differences and trends in beta cell function and glucose control between and within the active and placebo arms of the trial (36 months). ''Stage 3'' to determine the impact of beta cell preservation on the incidence of cumulative diabetes incidence (60 months). 抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』 ■ウィキペディアで「Accelerator Prevention Trial (adAPT)」の詳細全文を読む スポンサード リンク
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