Global Transcriptional Programs in Peripheral Nerve Endoneurium and DRG Are Resistant to the Onset of Type 1 Diabetic Neuropathy in Ins2Akita/+ 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 Ins2Akita/+ 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 Ins2Akita/+ 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 Ins2Akita/+ mice and sex-matched littermate controls. Our phenotypic analysis of Ins2Akita/+ 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.

Soluble epoxide hydrolase inhibition alleviates neuropathy in Akita (Ins2 Akita) mice

“…The use of t -TUCB has previously demonstrated dose dependent action in reducing in pain in diabetic animals [12]. Here Male 8WK mice were compared with male 12WK mice because male Akita heterozygotes are known to exhibit robust hyperglycemia and neuropathy prior to this age [20]. Little electrophysiological data exists for the females although the Akita females here exhibit hyperglycemia well above 200 mg/dl at 12 weeks (Table 1).…”

Altered Distribution of Juxtaparanodal Kv1.2 Subunits Mediates Peripheral Nerve Hyperexcitability in Type 2 Diabetes Mellitus

“…Nerve conduction velocity recordings and ex vivo compound action potential (CAP) recordings have been performed as previously described (Cartoni et al, 2010;de Preux Charles et al, 2010). For pharmacological analysis, the isolated nerves were exposed to the drugs between 30 min and 1 h until the effects seemed stable.…”

Glia-neuron energy metabolism in health and diseases: New insights into the role of nervous system metabolic transporters

“…Alterations in GLUT function can occur in acquired diseases, as well. Diabetic conditions can affect both GLUT localization (Bakirtzi et al, 2009) and activity (for example, GLUT4 activity in the periphery is impaired under type 2 diabetes) (Pearson-Leary and McNay, 2016); however, expression levels of GLUTs in glial or neuronal cells does not appear to be altered by diabetic conditions (de Preux Charles et al,2010; Hur et al, 2011; Pande et al, 2011). Schwann cells, which metabolically support axons in the PNS, are crucial cell types in the pathogenesis of diabetic neuropathy (Zenker et al, 2013; Mizisin, 2014; Feldman et al, 2017; Goncalves et al, 2017).…”