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Transcriptomic comparison of the retina in two mouse models of diabetes.

ABSTRACT: Mouse models of type I diabetes offer the potential to combine genetic approaches with other pharmacological or physiological manipulations to investigate the pathophysiology and treatment of diabetic retinopathy. Type I diabetes is induced in mice through chemical toxins or can arise spontaneously from genetic mutations. Both models are associated with retinal vascular and neuronal changes. Retinal transcriptomic responses in C57BL/6J mice treated with streptozotocin and Ins2(Akita/+) were compared after 3 months of hyperglycemia. Specific gene expression changes suggest a neurovascular inflammatory response in diabetic retinopathy. Genes common to the two models may represent the response of the retina to hyperglycemia, while changes unique to each model may represent time-dependent disease progression differences in the various models. Further investigation of the commonalities and differences between mouse models of type I diabetes may define cause and effect events in early diabetic retinopathy disease progression. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12177-009-9045-3) contains supplementary material, which is available to authorized users.

SUBMITTER: Freeman WM

PROVIDER: S-EPMC2816812 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Transcriptomic comparison of the retina in two mouse models of diabetes.

Freeman Willard M WM Bixler Georgina V GV Brucklacher Robert M RM Walsh Erin E Kimball Scot R SR Jefferson Leonard S LS Bronson Sarah K SK

Journal of ocular biology, diseases, and informatics 20091212 4

Mouse models of type I diabetes offer the potential to combine genetic approaches with other pharmacological or physiological manipulations to investigate the pathophysiology and treatment of diabetic retinopathy. Type I diabetes is induced in mice through chemical toxins or can arise spontaneously from genetic mutations. Both models are associated with retinal vascular and neuronal changes. Retinal transcriptomic responses in C57BL/6J mice treated with streptozotocin and Ins2(Akita/+) were comp ...[more]

PMID: 20157355

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Project description:BackgroundSpinal Muscular Atrophy (SMA), a neuromuscular disorder that leads to weakness in the muscles due to degeneration of motor neurons. Mutations in the survival motor neuron 1 (SMN1) gene leads to the deficiency of SMN protein that causes SMA. The molecular alterations associated with SMA extends across the transcriptome and proteome. Although several studies have examined the transcriptomic profile of SMA, the difference in experimental settings across these studies highlight the need for a comparative meta-analysis to better understand these differences.Methods and dataWe conducted a systematic comparative meta-analysis of publicly available gene expression data from six selected studies to elucidate variations in the transcriptomic landscape across different experimental conditions, including tissue types and mouse models. We used both microarray and RNA-seq datasets, retrieved from Gene Expression Omnibus (GEO) and ArrayExpress (AE). Methods included normalization, differential expression analysis, gene-set enrichment analysis (GSEA), network reconstruction and co-expression analysis.ResultsDifferential expression analysis revealed varying numbers of differentially expressed genes ranging between zero and 1,655 across the selected studies. Notably, the Metallothionein gene Mt2 was common in several of the eight comparisons. This highlights its role in oxidative stress and detoxification. Additionally, genes such as Hspb1, St14 and Sult1a1 were among the top ten differentially expressed genes in more than one comparison. The Snrpa1 gene, involved in pre-mRNA splicing, was upregulated in the spinal cord and has a strong correlation with other differentially expressed genes from other comparisons in our network reconstruction analysis. Gene-set enrichment analysis identified significant GO terms such as contractile fibers and myosin complexes in more than one comparison which highlights its significant role in SMA.ConclusionsOur comparative meta-analysis identified only few genes and pathways that were consistently dysregulated in SMA across different tissues and experimental settings. Conversely, many genes and pathways appeared to play a tissue-specific role in SMA. In comparison with the original studies, reproducibility was rather weak.

Project description:Aims/hypothesisThe aim of this work was to understand the role of non-beta cells in pancreatic islets at early stages of type 2 diabetes pathogenesis.MethodsSpecific clustering was employed to single-cell transcriptome data from islet cells of obese mouse strains differing in their diabetes susceptibility (diabetes-resistant B6.V.Lepob/ob [OB] and diabetes-susceptible New Zealand Obese [NZO] mice) on a diabetogenic diet.ResultsRefined clustering analysis revealed several heterogeneous subpopulations for alpha cells, delta cells and macrophages, of which 133 mapped to human diabetes genes identified by genome-wide association studies. Importantly, a similar non-beta cell heterogeneity was found in a dataset of human islets from donors at different stages of type 2 diabetes. The predominant alpha cell cluster in NZO mice displayed signs of cellular stress and lower mitochondrial capacity (97 differentially expressed genes [DEGs]), whereas delta cells from these mice exhibited higher expression levels of maturation marker genes (Hhex and Sst) but lower somatostatin secretion than OB mice (184 DEGs). Furthermore, a cluster of macrophages was almost twice as abundant in islets of OB mice, and displayed extensive cell-cell communication with beta cells of OB mice. Treatment of beta cells with IL-15, predicted to be released by macrophages, activated signal transducer and activator of transcription (STAT3), which may mediate anti-apoptotic effects. Similar to mice, humans without diabetes possess a greater number of macrophages than those with prediabetes (39 mmol/mol [5.7%] < HbA1c < 46 mmol/mol [6.4%]) and diabetes.Conclusions/interpretationOur study indicates that the transcriptional heterogeneity of non-beta cells has an impact on intra-islet crosstalk and participates in beta cell (dys)function.Data availabilityscRNA-seq data from the previous study are available in gene expression omnibus under gene accession number GSE159211 ( https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE159211 ).

Project description:BackgroundTechnology use, including continuous glucose monitoring (CGM) and insulin pump therapy, is associated with improved outcomes in youth with type 1 diabetes (T1D). In 2017 CGM was universally funded for youth with T1D in Australia. In contrast, pump access is primarily accessed through private health insurance, self-funding or philanthropy. The study aim was to investigate the use of diabetes technology across different socioeconomic groups in Australian youth with T1D, in the setting of two contrasting funding models.MethodsA cross-sectional evaluation of 4957 youth with T1D aged <18 years in the national registry was performed to determine technology use. The Index of Relative Socio-Economic Disadvantage (IRSD) derived from Australian census data is an area-based measure of socioeconomic status (SES). Lower quintiles represent greater disadvantage. IRSD based on most recent postcode of residence was used as a marker of SES. A multivariable generalised linear model adjusting for age, diabetes duration, sex, remoteness classification, and location within Australia was used to determine the association between SES and device use.ResultsCGM use was lower in IRSD quintile 1 in comparison to quintiles 2 to 5 (p<0.001) where uptake across the quintiles was similar. A higher percentage of pump use was observed in the least disadvantaged IRSD quintiles. Compared to the most disadvantaged quintile 1, pump use progressively increased by 16% (95% CI: 4% to 31%) in quintile 2, 19% (6% to 33%) in quintile 3, 35% (21% to 50%) in quintile 4 and 51% (36% to 67%) in the least disadvantaged quintile 5.ConclusionIn this large national dataset, use of diabetes technologies was found to differ across socioeconomic groups. For nationally subsidised CGM, use was similar across socioeconomic groups with the exception of the most disadvantaged quintile, an important finding requiring further investigation into barriers to CGM use within a nationally subsidised model. User pays funding models for pump therapy result in lower use with socioeconomic disadvantage, highlighting inequities in this funding approach. For the full benefits of diabetes technology to be realised, equitable access to pump therapy needs to be a health policy priority.

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Transcriptomic comparison of the retina in two mouse models of diabetes.

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Transcriptomic comparison of the retina in two mouse models of diabetes.

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