Early disruption of nerve mitochondrial and myelin lipid homeostasis in obesity-induced diabetes.

Juan P Palavicini,Xianlin Han,Jung A Woo,Xinming Wang,David E Kang,Nicolas Musi,Juan Chen,Chunyan Wang,Jianing Wang,Chao Qin,Jeffrey L Dupree,Eric Baeuerle

doi:10.1172/jci.insight.137286

Juan P Palavicini, Xianlin Han + Show 10 more

Open Access

https://doi.org/10.1172/jci.insight.137286

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Abstract

Diabetic neuropathy is a major complication of diabetes. 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.

Highlights

Diabetic peripheral neuropathy, the most common complication of diabetes mellitus, is a neurodegenerative disease of the PNS that represents a significant source of morbidity and mortality associated with diabetes [1, 2]
Whereas in most membranes PE is primarily present in its diacyl form, myelin is characterized by a high content of plasmalogen PE containing dominant oleic acid (18:1) [28, 29]
Obesity-induced prediabetes is associated with global losses of myelin lipids that are not driven by hyperglycemia, dysinsulinemia, or insulin resistance

Summary

Introduction

The most common complication of diabetes mellitus, is a neurodegenerative disease of the PNS that represents a significant source of morbidity and mortality associated with diabetes [1, 2]. The signs and symptoms of diabetic neuropathy vary, depending on the type of neuropathy and which nerves are affected (peripheral nerves, autonomic nerves, and/or cranial nerves), ranging from pain and numbness in the extremities to major organ dysfunction. There are no approved disease-modifying therapies for diabetic neuropathy. Diabetes has been associated with disturbances in the CNS, including cerebrovascular lesions and cognitive dysfunction [3,4,5,6]. Diabetes is a well-established risk factor for vascular dementia and Alzheimer’s disease [7,8,9,10,11]

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