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Insulin-regulated serine and lipid metabolism drive peripheral neuropathy.

Citation
Handzlik, M. K., et al. “Insulin-Regulated Serine And Lipid Metabolism Drive Peripheral Neuropathy.”. Nature, pp. 118-124.
Center UCSD-UCLA
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Author Michal K Handzlik, Jivani M Gengatharan, Katie E Frizzi, Grace H McGregor, Cameron Martino, Gibraan Rahman, Antonio Gonzalez, Ana M Moreno, Courtney R Green, Lucie S Guernsey, Terry Lin, Patrick Tseng, Yoichiro Ideguchi, Regis J Fallon, Amandine Chaix, Satchidananda Panda, Prashant Mali, Martina Wallace, Rob Knight, Marin L Gantner, Nigel A Calcutt, Christian M Metallo
Abstract

Diabetes represents a spectrum of disease in which metabolic dysfunction damages multiple organ systems including liver, kidneys and peripheral nerves. Although the onset and progression of these co-morbidities are linked with insulin resistance, hyperglycaemia and dyslipidaemia, aberrant non-essential amino acid (NEAA) metabolism also contributes to the pathogenesis of diabetes. Serine and glycine are closely related NEAAs whose levels are consistently reduced in patients with metabolic syndrome, but the mechanistic drivers and downstream consequences of this metabotype remain unclear. Low systemic serine and glycine are also emerging as a hallmark of macular and peripheral nerve disorders, correlating with impaired visual acuity and peripheral neuropathy. Here we demonstrate that aberrant serine homeostasis drives serine and glycine deficiencies in diabetic mice, which can be diagnosed with a serine tolerance test that quantifies serine uptake and disposal. Mimicking these metabolic alterations in young mice by dietary serine or glycine restriction together with high fat intake markedly accelerates the onset of small fibre neuropathy while reducing adiposity. Normalization of serine by dietary supplementation and mitigation of dyslipidaemia with myriocin both alleviate neuropathy in diabetic mice, linking serine-associated peripheral neuropathy to sphingolipid metabolism. These findings identify systemic serine deficiency and dyslipidaemia as novel risk factors for peripheral neuropathy that may be exploited therapeutically.

Year of Publication
2023
Journal
Nature
Volume
614
Issue
7946
Number of Pages
118-124
Date Published
02/2023
ISSN Number
1476-4687
DOI
10.1038/s41586-022-05637-6
Alternate Journal
Nature
PMID
36697822
PMCID
PMC9891999
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