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Impaired insulin secretion in a mouse model of ataxia telangiectasia
Philip D Miles1, Kai Treuner, Marc Latronica
1Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
Abstract:
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.
Insights
Ataxia telangiectasia (A-T) is linked to impaired insulin secretion, leading to diabetes mellitus (DM). This study reveals the ATM gene
Area of Science:
- Genetics and Molecular Biology
- Endocrinology and Metabolism
Background:
- Ataxia telangiectasia (A-T) is an autosomal recessive disorder caused by mutations in the ATM gene.
- ATM kinase is crucial for DNA damage response, cell cycle control, and apoptosis, explaining cancer predisposition in A-T patients.
- The molecular basis for glucose intolerance and diabetes mellitus (DM) in A-T remains unclear.
Purpose of the Study:
- To investigate the pathogenesis of DM in a mouse model of A-T.
- To elucidate the role of ATM in glucose metabolism and insulin secretion.
Main Methods:
- Utilized Atm-deficient (Atm-/-) mice as a model for A-T.
- Performed oral glucose tolerance testing (OGTT) on young and aged Atm-/- mice.
- Assessed fasting glucose levels, insulin sensitivity, insulin, and C-peptide levels.
Main Results:
- Young Atm-/- mice exhibited delayed insulin secretion and transient hyperglycemia during OGTT.
- Aged Atm-/- mice displayed significantly elevated blood glucose levels.
- Aged Atm-/- mice showed reduced insulin and C-peptide levels, indicating impaired insulin secretion.
Conclusions:
- The ATM gene plays a significant role in metabolic function.
- Impaired insulin secretion is identified as the primary cause of DM in A-T.
- These findings highlight a novel link between DNA damage response pathways and metabolic regulation.