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Genetic predisposition for beta cell fragility underlies type 1 and type 2 diabetes.

ABSTRACT: Type 1 (T1D) and type 2 (T2D) diabetes share pathophysiological characteristics, yet mechanistic links have remained elusive. T1D results from autoimmune destruction of pancreatic beta cells, whereas beta cell failure in T2D is delayed and progressive. Here we find a new genetic component of diabetes susceptibility in T1D non-obese diabetic (NOD) mice, identifying immune-independent beta cell fragility. Genetic variation in Xrcc4 and Glis3 alters the response of NOD beta cells to unfolded protein stress, enhancing the apoptotic and senescent fates. The same transcriptional relationships were observed in human islets, demonstrating the role of beta cell fragility in genetic predisposition to diabetes.

SUBMITTER: Dooley J

PROVIDER: S-EPMC5584070 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Genetic predisposition for beta cell fragility underlies type 1 and type 2 diabetes.

Dooley James J Tian Lei L Schonefeldt Susann S Delghingaro-Augusto Viviane V Garcia-Perez Josselyn E JE Pasciuto Emanuela E Di Marino Daniele D Carr Edward J EJ Oskolkov Nikolay N Lyssenko Valeriya V Franckaert Dean D Lagou Vasiliki V Overbergh Lut L Vandenbussche Jonathan J Allemeersch Joke J Chabot-Roy Genevieve G Dahlstrom Jane E JE Laybutt D Ross DR Petrovsky Nikolai N Socha Luis L Gevaert Kris K Jetten Anton M AM Lambrechts Diether D Linterman Michelle A MA Goodnow Chris C CC Nolan Christopher J CJ Lesage Sylvie S Schlenner Susan M SM Liston Adrian A

Nature genetics 20160321 5

Type 1 (T1D) and type 2 (T2D) diabetes share pathophysiological characteristics, yet mechanistic links have remained elusive. T1D results from autoimmune destruction of pancreatic beta cells, whereas beta cell failure in T2D is delayed and progressive. Here we find a new genetic component of diabetes susceptibility in T1D non-obese diabetic (NOD) mice, identifying immune-independent beta cell fragility. Genetic variation in Xrcc4 and Glis3 alters the response of NOD beta cells to unfolded protei ...[more]

PMID: 26998692

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Project description:BackgroundThis Mendelian randomization (MR) study aimed to explore the causal relationship between the genetic predisposition to type 2 diabetes mellitus (T2DM) and aortic dissection (AD), and to assess associations with genetically predicted glycemic traits. The study sought to verify the inverse relationship between T2DM and AD using a more robust and unbiased method, building on the observational studies previously established.Materials and methodsThe study employed a two-sample and multivariable MR approach to analyze genetic data from the DIAbetes Meta-ANalysis of Trans-Ethnic association studies (DIAMANTE) with 74,124 cases and 824,006 controls, and the Meta-Analyses of Glucose and Insulin-Related Traits Consortium (MAGIC) involving up to 196,991 individuals. For AD data, FinnGen Release 10 was used, including 967 cases and 381,977 controls. The research focused on three foundational MR assumptions and controlled for confounders like hypertension. Genetic instruments were selected for their genome-wide significance, and multiple MR methods and sensitivity analyses were conducted.ResultsThe study revealed no significant effect of genetic predisposition to T2DM on the risk of AD. Even after adjusting for potential confounders, the results were consistent, indicating no causal relationship. Additionally, glycemic traits such as fasting glucose, fasting insulin, and HbA1c levels did not show a significant impact on AD susceptibility. The findings remained stable across various MR models and sensitivity analyses. In contrast, genetic liability to T2DM and glycemic traits showed a significant association with coronary artery disease (CAD), aligning with the established understanding.ConclusionContrary to previous observational studies, this study concludes that genetic predisposition to T2DM does not confer protection against AD. These findings underscore the imperative for further research, particularly in exploring the preventative potential of T2DM treatments against AD and to facilitate the development of novel therapeutic interventions.

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Genetic predisposition for beta cell fragility underlies type 1 and type 2 diabetes.

Publications

Genetic predisposition for beta cell fragility underlies type 1 and type 2 diabetes.

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