Diet-induced gene expression of isolated pancreatic islets from a polygenic mouse model of the metabolic syndrome
| Autor: | HG Joost, Giles S.H. Yeo, Zorica Jovanovic, Y. C. L. Tung, Hadi Al-Hasani, Reinhart Kluge, T. Dreja, Axel Rasche, Ralf Herwig |
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| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Male
Candidate gene Multifactorial Inheritance Genome-wide association study Transcription Genetic Endocrinology Diabetes and Metabolism 030209 endocrinology & metabolism Type 2 diabetes Biology Polymerase Chain Reaction Article 03 medical and health sciences Islets of Langerhans Mice 0302 clinical medicine Diet Diabetic medicine Internal Medicine Animals Oxidative phosphorylation Obesity New Zealand obese mouse Gene Glucotoxicity Pancreas Expression profiling 030304 developmental biology Regulation of gene expression Genetics Metabolic Syndrome 0303 health sciences Pancreatic islets Gene Expression Profiling Cell Cycle Gene Amplification Laser capture microdissection medicine.disease 3. Good health Diet Gene expression profiling Kinetics medicine.anatomical_structure Lipotoxicity Gene Expression Regulation Hyperglycemia RNA Cell Division |
| Zdroj: | Diabetologia; Vol 53 Diabetologia |
| ISSN: | 1432-0428 |
| DOI: | 10.1007/s00125-009-1576-4 |
| Popis: | Aims/hypothesis Numerous new genes have recently been identified in genome-wide association studies for type 2 diabetes. Most are highly expressed in beta cells and presumably play important roles in their function. However, these genes account for only a small proportion of total risk and there are likely to be additional candidate genes not detected by current methodology. We therefore investigated islets from the polygenic New Zealand mouse (NZL) model of diet-induced beta cell dysfunction to identify novel genes and pathways that may play a role in the pathogenesis of diabetes. Methods NZL mice were fed a diabetogenic high-fat diet (HF) or a diabetes-protective carbohydrate-free HF diet (CHF). Pancreatic islets were isolated by laser capture microdissection (LCM) and subjected to genome-wide transcriptome analyses. Results In the prediabetic state, 2,109 islet transcripts were differentially regulated (>1.5-fold) between HF and CHF diets. Of the genes identified, 39 (e.g. Cacna1d, Chd2, Clip2, Igf2bp2, Dach1, Tspan8) correlated with data from the Diabetes Genetics Initiative and Wellcome Trust Case Control Consortium genome-wide scans for type 2 diabetes, thus validating our approach. HF diet induced early changes in gene expression associated with increased cell-cycle progression, proliferation and differentiation of islet cells, and oxidative stress (e.g. Cdkn1b, Tmem27, Pax6, Cat, Prdx4 and Txnip). In addition, pathway analysis identified oxidative phosphorylation as the predominant gene-set that was significantly upregulated in response to the diabetogenic HF diet. Conclusions/interpretation We demonstrated that LCM of pancreatic islet cells in combination with transcriptional profiling can be successfully used to identify novel candidate genes for diabetes. Our data strongly implicate glucose-induced oxidative stress in disease progression. Electronic supplementary material The online version of this article (doi:10.1007/s00125-009-1576-4) contains supplementary material, which is available to authorised users. |
| Databáze: | OpenAIRE |
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