Metabolic disorders are associated with the progression of amyotrophic lateral sclerosis. This new study by Tanya S McDonald and colleagues from the University of Queensland is very interesting because it focuses on physiology and not on molecular phenomenas.
Throughout the progression of ALS disease in laboratory mice, researchers have identified increased glucose uptake, possibly due to insulin-independent mechanisms. This glucose was then stored as glycogen in tissues such as the liver, rather than being used as an energy source. This might explain ALS' hypermetabolism.
Normally, in a healthy human, the postprandial state (after-meal) elevates glucose levels and triggers the release of insulin from the pancreas. As insulin levels rise, there is an increase in glucose uptake and then storage of excess glucose in peripheral tissues.
Glycogen is one of two forms of energy storage, with glycogen being short-term storage and the other being triglyceride stores in adipose tissue (i.e. body fat) for long term storage.
Patients with ALS cannot maintain their weight, and experience rapid muscle loss. Curiously, this muscle loss is not the subject of much attention from scientists who are interested only in motor neurons. They often deplore a lack of biomarkers, while the loss of muscle mass is an obvious biomarker. This article suggests that ALS is a form of diabetes, although this is not formally expressed in the article.
Rapid weight loss in patients with ALS is associated with rapid disease progression, while conversely, a higher body mass index (~ 27) tends to increase the survival rate. Studies also suggest that insulin resistance plays a role in disease progression in patients and animal models of ALS.
Glucose homeostasis is fundamental for the human body and is mainly regulated by the levels of 4 major hormones:
The ratios of these circulating hormones will dictate the activity of specific metabolic pathways that control glucose homeostasis. There are many other hormones (thyroid hormone, growth hormone, etc.) and adipokines (adiponectin, leptin, etc.) that can influence glucose homeostasis, as well as neural mechanisms that control higher level functions such as hunger and satiety.
Insulin secretion depends on oxidative metabolism. In humans, glycogen is made and stored primarily in liver cells and skeletal muscle cells.
SOD1G93A mice exhibit loss of body weight and lean body mass with reduced activity and increased oxygen uptake in the mid-symptomatic stage of disease.
McDonald and his colleagues first investigated whether the weight loss frequently observed in SOD1G93A mice was due to reduced food intake or increased energy expenditure.
At the onset of the disease, the mice showed no difference in body weight, but still had a 10% loss of their lean body mass (body mass other than fat, including bones, muscles, blood, skin, etc.). That is, fat was substituted for muscle mass.
At the mid-symptomatic stage, the SOD1G93A mice weighed significantly less than their normal counterparts, with a loss of 8 and 10% of total body weight and lean body mass, respectively.
However, the total food intake was similar between normal mice and SOD1G93A mice at these two stages of the disease.
While at the initial stage there was no difference in oxygen uptake between mutated and normal mice, at the mid symptomatic stage the mean oxygen uptake in SOD1G93A mice was significantly higher than in normal mice.
This increase in oxygen uptake in the mid-symptomatic stage was not, however, due to an increase in average locomotor activity, as the reduction in locomotor activity was only measured during the dark cycle in the dying stages. onset and semi-symptomatic. Indeed, during the light phase, the mid-symptom SOD1G93A mice were 126% more active than their normal counterparts.
No correlation was found between the decrease in lean body mass and the average oxygen uptake over a 24-hour period.This increase in oxygen uptake at the mid-symptomatic stage is therefore unexplained.
Exogenous glucose uptake is increased in SOD1G93A mice at the mid-symptomatic stage of the disease
The scientists then set out to determine whether glucose management was impaired in SOD1G93A mice.
At the onset of symptoms, SOD1G93A mice and their normal counterparts responded similarly to glucose.
However, in the mid-symptomatic stage of the disease, SOD1G93A mice showed a faster rate of blood glucose clearance.
The authors then confirmed that the loss of body weight in SOD1G93A mice was not responsible for the decrease in blood glucose concentration.
Although the baseline insulin concentration remained unchanged, the response of plasma insulin to exogenous glucose was significantly lower in SOD1G93A mice, with a 44% reduction in insulin concentrations.
At the onset of the disease and at its mid-symptomatic stage there was no difference in the immunoreactive zone of the glucagon-positive cells.
But at the mid-symptomatic stage McDonald and his colleagues found in the pancreas of SOD1G93A mice, a 22% reduction in insulin-positive β cells compared to the pancreas of normal mice.
Despite this difference in baseline blood glucose concentrations, normal and SOD1G93A mice responded similarly to insulin. This is a major difference between diabetes and ALS.
Although the SOD1G93A mice weighed less at onset and during the middle of symptoms, the amount of insulin did not correlate with the inverse of blood sugar levels. This indicates that the detection of oxidative metabolism was inoperative, which is one of the characteristics of diabetes.
In addition to insulin and glucagon levels, the authors also demonstrated that glycogen concentrations were 210 and 480% higher in the liver of SOD1G93A mice at onset and mid-symptom stages, respectively.
Insulin tolerance is not affected in SOD1G93A mice, despite decreased fasting blood sugar
After an overnight fast, the accumulation of glycogen in the liver was still 400-500% higher in SOD1G93A mice amid symptoms compared to their normal counterparts.
These changes are insulin independent because there was no difference in the elimination of glucose in response to exogenous insulin. In addition, SOD1G93A mice exhibit reduced insulin-expressing cell surface area and impaired insulin release in response to exogenous glucose. SOD1G93A mice also showed an accumulation of glycogen in the liver, despite increased circulating glucagon concentrations and gene expression data, suggesting a decrease in both glycogen synthesis and degradation.
This indicates that glucagon signaling may be altered in the liver of SOD1G93A mice. Finally, the gene expression profile of several metabolic enzymes suggested that the liver switches from using glucose to fatty acids as an energy source, which has already been found in skeletal muscle and CNS tissues in the body. SLA.
This confirms the results in other affected tissues which show a shift from the use of glucose to lipids as the primary fuel source for the TCA cycle. Although the exact trigger that leads to this change is unknown, it has been proposed that an increase in fatty acid metabolism occurs to compensate for the inability of tissues to use glucose and glycogen as energy substrates. Although this is a beneficial short-term compensatory mechanism, chronic dependence on fatty acid metabolism via β-oxidation can lead to the accumulation of toxic byproducts, especially reactive oxygen species. (ROS).
What is described in this article is a reminder of the evolution of diabetes. When diabetes begins, the pancreas normally produces insulin. Muscle cells preferably use fatty acids as an energy source. Gradually the cells of the body responsible for collecting and using glucose become insensitive to insulin. Since glucose cannot enter the cells, the beta cells of the islets of Langerhans in the pancreas will produce more insulin to force the cells to take up glucose. In this article the mechanism is a little different, instead of making more insulin, the body stores glucose in the form of glycogen. The more diabetes progresses, the more beta cells are depleted, until they disappear. This disappearance was also noted in the article.
However, this does not explain the local appearance of the onset of ALS and the geographical progression of the disease, and it is a work on model mice for ALS. It is known that work on mice is rarely transferable to humans, particularly for neurodegenerative diseases.
Yet, this article is unique. This is an article that talks about physiology, it does not appeal to obscure molecules that are arbitrarily assigned biological roles, it suggests a mechanism for ALS that is down to earth.
Of course there are still many unknowns as to why ALS often starts with a specific muscle and then progresses. We don't know how to treat diabetes any more than we do with ALS, but I believe that an important step has been accomplished.
This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.