Roughly half of individuals with kind 1 or kind 2 diabetes expertise peripheral neuropathy — weak point, numbness, and ache, primarily within the arms and ft. The situation happens when excessive ranges of sugar circulating within the blood injury peripheral nerves. Now, working with mice, Salk Institute researchers have recognized one other issue contributing to diabetes-associated peripheral neuropathy: altered amino acid metabolism.
The crew discovered that diabetic mice with low ranges of two associated amino acids, serine and glycine, are at larger threat for peripheral neuropathy. What’s extra, the researchers have been capable of alleviate neuropathy signs in diabetic mice by supplementing their diets with serine.
The examine, printed January 25, 2023 in Nature, provides to rising proof that some often-underappreciated, “non-essential” amino acids play necessary roles within the nervous system. The findings might present a brand new strategy to establish individuals at excessive threat for peripheral neuropathy, in addition to a possible therapy choice.
“We have been stunned that dialing up and down a non-essential amino acid had such a profound impact on metabolism and diabetic issues,” says senior writer Christian Metallo, a professor in Salk’s Molecular and Cell Biology Laboratory. “It simply goes to point out that what we consider as dogma can change below totally different circumstances, akin to in illness situations.” Metallo led the examine with first writer Michal Handzlik, a postdoctoral researcher in his lab.
Amino acids are the constructing blocks that make up proteins and specialised fats molecules known as sphingolipids, that are plentiful within the nervous system. Low ranges of the amino acid serine drive the physique to include a distinct amino acid in sphingolipids, which adjustments their construction. These atypical sphingolipids then accumulate, which can contribute to peripheral nerve injury. Whereas the crew noticed this accumulation in diabetic mice, the identical amino acid swap and sphingolipid adjustments happen in a uncommon human genetic illness marked by peripheral sensory neuropathy, indicating that the phenomenon is constant throughout many species.
To find out whether or not long-term, power serine deficiency drives peripheral neuropathy, Metallo’s crew fed mice both management or serine-free diets together with both low-fat or high-fat diets for as much as 12 months. The researchers have been stunned to seek out that low serine, together with a high-fat food plan, accelerated the onset of peripheral neuropathy within the mice. In distinction, serine supplementation in diabetic mice slowed the development of peripheral neuropathy, and the mice fared higher.
The researchers additionally examined the compound myriocin, which inhibits the enzyme that switches out serine for one more amino acid as sphingolipids are assembled. Myriocin therapy diminished peripheral neuropathy signs in mice fed a high-fat, serine-free food plan. These findings underscore the significance of amino acid metabolism and sphingolipid manufacturing within the upkeep of a wholesome peripheral nervous system.
Serine deficiency has additionally been related to varied neurodegenerative issues. For instance, Metallo and collaborators beforehand discovered a hyperlink between altered serine and sphingolipid metabolism in sufferers with macular telangiectasia kind 2, a situation that causes imaginative and prescient loss. In mice, diminished serine led to elevated ranges of atypical retinal sphingolipids and diminished imaginative and prescient. Serine is at present being examined in scientific trials for its security and efficacy in treating macular telangiectasia and Alzheimer’s illness.
Peripheral neuropathy is usually managed with dietary adjustments to scale back blood sugar ranges, in addition to ache relievers, bodily remedy, and mobility aids, akin to canes and wheelchairs. Meals naturally wealthy in serine embody soybeans, nuts, eggs, chickpeas, lentils, meat, and fish, and serine dietary supplements are cheap and out there over-the-counter.
But the researchers say it is untimely to advise individuals with diabetes to take serine dietary supplements to stop neuropathy.
“You’d doubtless must take loads to make a distinction, and never everybody wants additional serine,” Metallo says. “We’d like extra time to grasp serine physiology in people and discover potential downsides to supplementation.”
To this finish, Metallo and Handzlik are actually creating a serine tolerance take a look at, much like a glucose tolerance take a look at used to diagnose diabetes.
“We need to establish these at highest threat for peripheral neuropathy so we are able to deal with solely those that may profit most,” says Handzlik.
Different authors included: Jivani M. Gengatharan, Grace H. McGregor, and Courtney R. Inexperienced of the Salk Institute and UC San Diego; Katie E. Frizzi, Cameron Martino, Gibraan Rahman, Antonio Gonzalez, Ana M. Moreno, Lucie S. Guernsey, Prashant Mali, Rob Knight, and Nigel A. Calcutt of UC San Diego; Terry Lin, Patrick Tseng, and Satchidananda Panda of the Salk Institute; Yoichiro Ideguchi of Scripps Analysis; Regis J. Fallon and Marin L. Gantner of the Lowy Medical Analysis Institute; Amandine Chaix of the College of Utah; and Martina Wallace of College School Dublin in Eire.
The work was funded by the Nationwide Institutes of Well being (grants R01CA234245, DK076169, R01AG065993, P30
DK120515), a Camille and Henry Dreyfus Instructor-Scholar Award, the Lowy Medical Analysis Institute, and the American Coronary heart Affiliation (grant 18CDA34110292).