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Insulin-regulated serine and lipid metabolism drive peripheral neuropathy.
Handzlik MK, Gengatharan JM, Frizzi KE, McGregor GH, Martino C, Rahman G,
Gonzalez A, Moreno AM, Green CR, Guernsey LS, Lin T, Tseng P, Ideguchi Y, Fallon
RJ, Chaix A, Panda S, Mali P, Wallace M, Knight R, Gantner ML, Calcutt NA,
Michal Handzlik on 2/14/2023
Volume : Pages
614 : 118 - 124
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.
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Financial support for this work was provided by the NIDDK Mouse Metabolic Phenotyping Centers (National MMPC, RRID:SCR_008997,
) under the MICROMouse Program, grants DK076169.
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