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Publication
Integrated lipidomic and transcriptomic analyses identify altered nerve
triglycerides in mouse models of prediabetes and type 2 diabetes.
Authors O'Brien PD, Guo K, Eid SA, Rumora AE, Hinder LM, Hayes JM, Mendelson FE, Hur J,
Feldman EL
Submitted By Submitted Externally on 2/12/2020
Status Published
Journal Disease models & mechanisms
Year 2019
Date Published 12/1/2019
Volume : Pages Not Specified : Not Specified
PubMed Reference 31822493
Abstract Peripheral neuropathy (PN) is a complication of prediabetes and type 2 diabetes
(T2D). Increasing evidence suggests that factors besides hyperglycaemia
contribute to PN development, including dyslipidaemia. The objective of this
study was to determine differential lipid classes and altered gene expression
profiles in prediabetes and T2D mouse models in order to identify the
dysregulated pathways in PN. Here, we used high-fat diet (HFD)-induced
prediabetes and HFD/streptozotocin (STZ)-induced T2D mouse models that develop
PN. These models were compared to HFD and HFD/STZ mice that were subjected to
dietary reversal. Both untargeted and targeted lipidomic profiling, and gene
expression profiling were performed on sciatic nerves. Lipidomic and
transcriptomic profiles were then integrated using complex correlation analyses,
and biological meaning was inferred from known lipid-gene interactions in the
literature. We found an increase in triglycerides (TGs) containing saturated
fatty acids. In parallel, transcriptomic analysis confirmed the dysregulation of
lipid pathways. Integration of lipidomic and transcriptomic analyses identified
an increase in diacylglycerol acyltransferase 2 (DGAT2), the enzyme required for
the last and committed step in TG synthesis. Increased DGAT2 expression was
present not only in the murine models but also in sural nerve biopsies from
hyperlipidemic diabetic patients with PN. Collectively, these findings support
the hypothesis that abnormal nerve-lipid signalling is an important factor in
peripheral nerve dysfunction in both prediabetes and T2D.




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