Insulin-regulated serine and lipid metabolism drive peripheral neuropathy

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 and Christian M. Metallo ()
Additional contact information
Michal K. Handzlik: The Salk Institute for Biological Studies
Jivani M. Gengatharan: The Salk Institute for Biological Studies
Katie E. Frizzi: University of California San Diego
Grace H. McGregor: The Salk Institute for Biological Studies
Cameron Martino: University of California San Diego
Gibraan Rahman: University of California San Diego
Antonio Gonzalez: University of California San Diego
Ana M. Moreno: University of California San Diego
Courtney R. Green: The Salk Institute for Biological Studies
Lucie S. Guernsey: University of California San Diego
Terry Lin: The Salk Institute for Biological Studies
Patrick Tseng: The Salk Institute for Biological Studies
Yoichiro Ideguchi: Scripps Research
Regis J. Fallon: Lowy Medical Research Institute
Amandine Chaix: University of Utah
Satchidananda Panda: The Salk Institute for Biological Studies
Prashant Mali: University of California San Diego
Martina Wallace: University College Dublin
Rob Knight: University of California San Diego
Marin L. Gantner: Lowy Medical Research Institute
Nigel A. Calcutt: University of California San Diego
Christian M. Metallo: The Salk Institute for Biological Studies

Nature, 2023, vol. 614, issue 7946, 118-124

Abstract: Abstract Diabetes represents a spectrum of disease in which metabolic dysfunction damages multiple organ systems including liver, kidneys and peripheral nerves1,2. Although the onset and progression of these co-morbidities are linked with insulin resistance, hyperglycaemia and dyslipidaemia3–7, aberrant non-essential amino acid (NEAA) metabolism also contributes to the pathogenesis of diabetes8–10. Serine and glycine are closely related NEAAs whose levels are consistently reduced in patients with metabolic syndrome10–14, 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 neuropathy15,16. 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.

Date: 2023
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DOI: 10.1038/s41586-022-05637-6

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