Impaired insulin secretion in a mouse model of ataxia telangiectasia.
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.
Miles
Philip D
PD
Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
Treuner
Kai
K
Latronica
Marc
M
Olefsky
Jerrold M
JM
Barlow
Carrolee
C
D000375:Aging / Q000378:metabolism; D000818:Animals; D001260:Ataxia Telangiectasia / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000209:etiology / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D018149:Glucose Intolerance / Q000235:genetics; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics; D000078790:Insulin Secretion; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D007328:Insulin; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases