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Current treatment options alleviate pain but do not stop the progression of the disease. At present, there are no approved disease-modifying therapies. Thus, developing more effective therapies remains a major unmet medical need. Seeking to better understand the molecular mechanisms driving peripheral neuropathy, as well as other neurological complications associated with diabetes, we performed spatiotemporal lipidomics, biochemical, ultrastructural, and physiological studies on PNS and CNS tissue from multiple diabetic preclinical models. We unraveled potentially novel molecular fingerprints underlying nerve damage in obesity-induced diabetes, including an early loss of nerve mitochondrial (cardiolipin) and myelin signature (galactosylceramide, sulfatide, and plasmalogen phosphatidylethanolamine) lipids that preceded mitochondrial, myelin, and axonal structural\/functional defects; started in the PNS; and progressed to the CNS at advanced diabetic stages. Mechanistically, we provided substantial evidence indicating that these nerve mitochondrial\/myelin lipid abnormalities are (surprisingly) not driven by hyperglycemia, dysinsulinemia, or insulin resistance, but rather associate with obesity\/hyperlipidemia. Importantly, our findings have major clinical implications as they open the door to novel lipid-based biomarkers to diagnose and distinguish different subtypes of diabetic neuropathy (obese vs. nonobese diabetics), as well as to lipid-lowering therapeutic strategies for treatment of obesity\/diabetes-associated neurological complications and for glycemic control.<\/jats:p>","DOI":"10.1172\/jci.insight.137286","type":"journal-article","created":{"date-parts":[[2020,11,4]],"date-time":"2020-11-04T11:01:18Z","timestamp":1604487678000},"source":"Crossref","is-referenced-by-count":49,"title":["Early disruption of nerve mitochondrial and myelin lipid homeostasis in obesity-induced diabetes"],"prefix":"10.1172","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9667-8438","authenticated-orcid":true,"given":"Juan P.","family":"Palavicini","sequence":"first","affiliation":[{"name":"Barshop Institute for Longevity and Aging Studies and"},{"name":"Division of Diabetes, Department of 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