Miles Philip D, Treuner Kai, Latronica Marc, Olefsky Jerrold M, Barlow Carrolee
Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
Am J Physiol Endocrinol Metab. 2007 Jul;293(1):E70-4. doi: 10.1152/ajpendo.00259.2006. Epub 2007 Mar 13.
Ataxia telangiectasia (A-T) is an autosomal recessive disease caused by mutations in the A-T mutated (ATM) gene. The gene encodes a serine/threonine kinase with important roles in the cellular response to DNA damage, including the activation of cell cycle checkpoints and induction of apoptosis. Although these functions might explain the cancer predisposition of A-T patients, the molecular mechanisms leading to glucose intolerance and diabetes mellitus (DM) are unknown. We have investigated the pathogenesis of DM in a mouse model of A-T. Here we show that young Atm-deficient mice show normal fasting glucose levels and normal insulin sensitivity. However, oral glucose tolerance testing revealed delayed insulin secretion and resulting transient hyperglycemia. Aged Atm-/- mice show a pronounced increase in blood glucose levels and a decrease in insulin and C-peptide levels. Our findings support a role for ATM in metabolic function and point toward impaired insulin secretion as the primary cause of DM in A-T.
共济失调毛细血管扩张症（A-T）是一种常染色体隐性疾病，由A-T突变（ATM）基因的突变引起。该基因编码一种丝氨酸/苏氨酸激酶，在细胞对DNA损伤的反应中起重要作用，包括激活细胞周期检查点和诱导细胞凋亡。尽管这些功能可能解释了A-T患者的癌症易感性，但导致葡萄糖不耐受和糖尿病（DM）的分子机制尚不清楚。我们已经在A-T小鼠模型中研究了DM的发病机制。在此我们表明，年轻的Atm基因缺陷小鼠空腹血糖水平正常，胰岛素敏感性也正常。然而，口服葡萄糖耐量试验显示胰岛素分泌延迟，并导致短暂性高血糖。老年Atm-/-小鼠的血糖水平显著升高，胰岛素和C肽水平降低。我们的研究结果支持ATM在代谢功能中的作用，并指出胰岛素分泌受损是A-T中DM的主要原因。
