Researchers from University of Arizona have come up with a new study that shows that increasing the amount of glucose that could be transformed into energy could help persons with amyotrophic lateral sclerosis (ALS) by improving their mobility and increasing their survival rates. The study is published online in the latest issue of the journal eLife and is titled, “Glycolysis upregulation is neuroprotective as a compensatory mechanism in ALS.”
Glucose monitoring via blood test. Image Credit: Proxima Studio / Shutterstock
ALS is a crippling disease which affects metabolism. There is rapid loss of weight ue to hypermetabolsim explained researchers. After diagnosis, the average life expectancy is around 2 to 5 years, write the researchers. As the disease progresses, the patient fails to eat and drink and slowly even fails to breathe by themselves. Daniela Zarnescu, UA professor of molecular and cellular biology and senior author on the study said, “ALS is a devastating disease. It renders people from functioning one day to rapidly and visibly deteriorating.”
Study author Ernesto Manzo, a UA alumnus and postdoctoral researcher in the Department of Molecular and Cellular Biology explained that this form of hyperthermia could be a continued vicious cycle. At rest, those with ALS tend to use more energy compared to those who do not have ALS. In addition, there is a a difficulty in utilizing the available glucose in these individuals, explain the researchers. Glucose is the main source of energy for the body, they add. Manzo said, “This project was a way to parse out those details,” explaining that how exactly glucose metabolism was affected by ALS was not known.
Results from the study showed that when the neurons affected by ALS were fed more glucose, they turned it into energy. This energy helped the neurons to survive longer and also perform better, the team wrote. They thus speculate that if the neurons could be supplied with more glucose, they may survive longer and function better. Manzo said, “These neurons were finding some relief by breaking down glucose and getting more cellular energy.”
According to Zarnescu previous studies have looked at the effects of ALS on the whole body and this is the first time that they are looking at the cellular level. Zarnescu said, “The fact that we uncovered a compensatory mechanism surprised me. These desperate, degenerating neurons showed incredible resilience. It is an example of how amazing cells are at dealing with stress.” Zarnescu said that till date the metabolic changes within the ALS affected neurons has not been clearly understood. She added, “It's difficult to study, in part because of limited accessibility to the nervous system,” explaining that neurons could not be studied separately in the labs and within the body’s system, their metabolic differences were not fully understood. To overcome this, the team used fruitflies or Drosophila as a model to study the neurons. Manzo said, “Fruit flies can teach us a lot about human diseases.” They used a specific fruit fly model that had “TDP-43 proteinopathy”.
For this study Manzo and Zarnescu used high-powered microscopes to look at the motor neurons of fruit flies while they were still larvae. They provided more glucose and saw the reaction of the neurons. As the glucose amounts rose, the neurons tended to live longer and perform better. As the glucose levels fell, the larvae moved slowly, the team wrote.
As a next step the team performed a pilot clinical trial on humans with ALS. They noted that a high carbohydrate diet could help those with ALS. High levels of carbohydrates can mean more glucose to the neurons, they wrote. Zarnescu said, “Our data essentially provide an explanation for why that approach might work. My goal is to convince clinicians to perform a larger clinical trial to test this idea.”
Authors led by Siobhan Kirk from the Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane couple of months back published an article titled, “Biomarkers of Metabolism in Amyotrophic Lateral Sclerosis,” in the March 2019 issue of Frontiers of Neurology.
They looked at several biomarkers of metabolism in ALS. Relevant to the above study, they also wrote about glucose metabolism in ALS. The team reviewed articles saying that glucose metabolism in the brains of those with ALS has been studied using “fluorodeoxyglucose F18 positron emission tomography (F18-PET)”. Studies have shown that there is a decrease in glucose use in the primary motor cortex of the brain in these patients. Glucose levels are raised in the CSF meaning that there us more glucose uptake in the spinal cord, they write. Glucose level variation could be a marker for diagnosis, they explain.
The team wrote, “Alterations in glucose metabolism in ALS extend beyond the central nervous system (CNS).” They add that studies have shown that those with ALS have “significant increase in blood glucose levels following the provision of a glucose load when compared to age- and sex-matched controls.” One in three ALS patient meets the criteria for impaired glucose tolerance and possible insulin resistance they wrote.
- Glycolysis upregulation is neuroprotective as a compensatory mechanism in ALS, Ernesto Manzo, Ileana Lorenzini, Dianne Barrameda, Abigail G O'Conner, Jordan M Barrows, Alexander Starr, Tina Kovalik, Benjamin E Rabichow, Erik M Lehmkuhl, eLife 2019;8:e45114 DOI: 10.7554/eLife.45114, https://elifesciences.org/articles/45114
- Biomarkers of Metabolism in Amyotrophic Lateral Sclerosis, Kirk Siobhan E., Tracey Timothy J., Steyn Frederik J., Ngo Shyuan T., Front. Neurol., 18 March 2019, https://doi.org/10.3389/fneur.2019.00191, https://www.frontiersin.org/articles/10.3389/fneur.2019.00191/full