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Global transcriptional programs in peripheral nerve endoneurium and DRG are resistant to the onset of type 1 diabetic neuropathy in Ins2 mice.

ABSTRACT: While the morphological and electrophysiological changes underlying diabetic peripheral neuropathy (DPN) are relatively well described, the involved molecular mechanisms remain poorly understood. In this study, we investigated whether phenotypic changes associated with early DPN are correlated with transcriptional alterations in the neuronal (dorsal root ganglia [DRG]) or the glial (endoneurium) compartments of the peripheral nerve. We used Ins2(Akita/+) mice to study transcriptional changes underlying the onset of DPN in type 1 diabetes mellitus (DM). Weight, blood glucose and motor nerve conduction velocity (MNCV) were measured in Ins2(Akita/+) and control mice during the first three months of life in order to determine the onset of DPN. Based on this phenotypic characterization, we performed gene expression profiling using sciatic nerve endoneurium and DRG isolated from pre-symptomatic and early symptomatic Ins2(Akita/+) mice and sex-matched littermate controls. Our phenotypic analysis of Ins2(Akita/+) mice revealed that DPN, as measured by reduced MNCV, is detectable in affected animals already one week after the onset of hyperglycemia. Surprisingly, the onset of DPN was not associated with any major persistent changes in gene expression profiles in either sciatic nerve endoneurium or DRG. Our data thus demonstrated that the transcriptional programs in both endoneurial and neuronal compartments of the peripheral nerve are relatively resistant to the onset of hyperglycemia and hypoinsulinemia suggesting that either minor transcriptional alterations or changes on the proteomic level are responsible for the functional deficits associated with the onset of DPN in type 1 DM.

SUBMITTER: de Preux Charles AS

PROVIDER: S-EPMC2877074 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Global transcriptional programs in peripheral nerve endoneurium and DRG are resistant to the onset of type 1 diabetic neuropathy in Ins2 mice.

de Preux Charles Anne-Sophie AS Verdier Valérie V Zenker Jennifer J Peter Bastian B Médard Jean-Jacques JJ Kuntzer Thierry T Beckmann Jacques S JS Bergmann Sven S Chrast Roman R

PloS one 20100526 5

While the morphological and electrophysiological changes underlying diabetic peripheral neuropathy (DPN) are relatively well described, the involved molecular mechanisms remain poorly understood. In this study, we investigated whether phenotypic changes associated with early DPN are correlated with transcriptional alterations in the neuronal (dorsal root ganglia [DRG]) or the glial (endoneurium) compartments of the peripheral nerve. We used Ins2(Akita/+) mice to study transcriptional changes und ...[more]

PMID: 20520806

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Project description:Aims/hypothesisDiabetic peripheral neuropathy (DPN) and diabetic nephropathy (DN) are two common microvascular complications of type 1 and type 2 diabetes mellitus that are associated with a high degree of morbidity. In this study, using a variety of systems biology approaches, our aim was to identify common and distinct mechanisms underlying the pathogenesis of these two complications.MethodsOur previously published transcriptomic datasets of peripheral nerve and kidney tissue, derived from murine models of type 1 diabetes (streptozotocin-injected mice) and type 2 diabetes (BKS-db/db mice) and their respective controls, were collected and processed using a unified analysis pipeline so that comparisons could be made. In addition to looking at genes and pathways dysregulated in individual datasets, pairwise comparisons across diabetes type and tissue type were performed at both gene and transcriptional network levels to complete our proposed objective.ResultsGene-level analysis identified exceptionally high levels of concordant gene expression in DN (94% of 2,433 genes), but not in DPN (54% of 1,558 genes), between type 1 diabetes and type 2 diabetes. These results suggest that common pathogenic mechanisms exist in DN across diabetes type, while in DPN the mechanisms are more distinct. When these dysregulated genes were examined at the transcriptional network level, we found that the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway was significantly dysregulated in both complications, irrespective of diabetes type.Conclusions/interpretationUsing a systems biology approach, our findings suggest that common pathogenic mechanisms exist in DN across diabetes type, while in DPN the mechanisms are more distinct. We also found that JAK-STAT signalling is commonly dysregulated among all datasets. Using such approaches, further investigation is warranted to determine whether the same changes are observed in patients with diabetic complications.

Dataset Information

Global transcriptional programs in peripheral nerve endoneurium and DRG are resistant to the onset of type 1 diabetic neuropathy in Ins2 mice.

Publications

Global transcriptional programs in peripheral nerve endoneurium and DRG are resistant to the onset of type 1 diabetic neuropathy in Ins2 mice.

Similar Datasets

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