Brain Glucose and Glycogen in Autism: Speech, Seizures, Sleep & Beyond

The following article is written by an autism parent and researcher, who has an interest in both autism and sports sciences. It lays out possible underlying reasons for some of the struggles and symptoms associated with autism. It is not possible to say who might benefit from understanding the possible issues outlined in this writing; however, it may be particularly significant for someone who also suffers from seizures and/or has limited speech.

The information on this page should in no way be taken as a medical advice. As always, our charity endorses your right to information and encourages people to work with trusted health care professionals.

Glucose, Energy and the Brain — a Missing Piece of the Autism Puzzle?

Glucose, a form of sugar, is the primary source of energy for every cell in the body. Much of the food we eat gets broken down into glucose, which is then transported through the blood to our cells.

Our cells use glucose to make ATP, the energy molecule. Without ATP, as without oxygen, we could not live.

Glucose keeps our body — our muscles — moving, but it is also necessary for all brain functions. The brain is the most energy-demanding organ, using one-half of all the sugar energy in the body.

In addition to oxygen, the brain also relies on a continuous supply of glucose. Similar to oxygen deprivation, severe and sudden reduction (or increases) in the levels of brain glucose can result in cognitive decline, autonomic failure, seizures, loss of consciousness, lasting brain damage, and even death.

We do not know what would happen in the case of mild, but on-going, energy shortages in the brain during development, and later. What would be the symptoms? Would a young brain in chronic state of energy deficiency be able to perform highest level functions, such as speech and social interaction?

“Glucose is the main cerebral fuel throughout life. Inadequate cerebral glucose supply…during the neonatal period or infancy, when the brain is still developing, lead to long-term neurological impairments, ranging from cognitive dysfunction to…epilepsy, or even aphasia (lack of speech).” (Flykanaka-Gantenbein 2004)

Glycogen: Storing Glucose for ‘Rainy Days’

Glycogen is the ‘warehouse’ form of glucose. This is how our cells store unused glucose to serve as energy later on, in case of emergency and shortage of supply of glucose from blood. This glycogen gets stored in our muscle cells to be used during prolonged physical activity. Glycogen is also stored in our liver and in the brain.

Muscle glycogen is the predominant fuel source used during long bouts of exercise. In fact, aerobic performance, for example long distance running, is directly related to initial glycogen stores.

Once glycogen is depleted, the athlete will feel fatigued and performance will suffer.

Until recently, glucose that enters the brain from the blood was considered the only available glucose for the brain.

However recently it has been revealed that cells in our brains, especially astrocytes, do store glucose as glycogen. They later release this energy to be used by neurons (via lactate conversion). Glycogen is also involved in many other processes in the brain.

Glycogen is emerging as a key part of brain energy metabolism. Perturbed glycogen states are observed in many brain disorders, including aphasia (lack of speech) and epilepsy.

Most children with glycogen-related genetic disorders suffer seizures, intellectual disability and/or autism.

Disturbed levels of glycogen and glucose in the brain can lead to: 

• Aphasia (lack of speech!)
• Seizures
• Reduced social interaction
• Anxiety
• Sleep disturbances
• Aggressive behaviours
• Depression
• Memory problems
• Fatigue /brain fog
• Migraines

The Invisible (Biological) Consequences of Disturbed Glycogen and Glucose Metabolism in the Brain – Glutamate & Beyond

Brain glycogen plays a key role in maintaining a balance between excitatory and inhibitory neurotransmitters (brain signalling molecules).

Glutamate is the major excitatory molecule in the brain. It is necessary for brain function but has to be tightly regulated in order to maintain balance and prevent over-excitability of neurons and formation of seizures.

“Glycogen metabolism in the brain is emerging as a fundamental process for maintenance of…neuronal excitability and synaptic plasticity…Manipulations inducing dysfunctional brain glycogen metabolism have been shown to impair memory formation as well as to increase susceptibility to epileptic seizures.” (DiNuzzo 2019)

When brain glucose/glycogen metabolism is disturbed, this increases the risk of glutamate imbalance (glutamate toxicity) and increases the risk of seizures.

Glycogen also has important roles in control of brain potassium and oxidative stress management. Potassium levels and oxidative stress in the brain are involved in formation of seizures and in the overall functioning of the brain.

What can Cause Disturbed Glycogen or Glucose Metabolism in the Brain?

Some of the possible reasons:

1. Genetic factors – many known (and how many unknown?) glycogen-related genetic disorders have autism or intellectual disability as a consequence, also seizures are present in many cases.
2. Early life infection/inflammation – if there are inflammatory molecules present in the brain in early life this can throw brain energy metabolism off balance, and cause long term problems in glycogen/glucose metabolism even after the primary inflammatory trigger is long gone.
3. Disturbances in levels of glucose in the blood, so that not enough glucose (or too much of it) reaches the brain — for example it is known that in diabetes there is increased risk of seizures, or even coma and death, if blood glucose levels fluctuate suddenly.
4. Problems with glucose transport — in this scenario there would be normal levels of glucose in the blood but not enough of it reaches the brain via the blood brain barrier. An alternative scenario would be that the optimal level of glucose reaches the brain but there are problems in how it moves around the brain and reaches different brain areas. Disturbances in ‘glucose transporters’ can also be caused by genetic or external factors such as infections (see 1. above)

Could we make a case that in some autism cases the brain (and possibly the body?) are in a state of suboptimal energy supply?

If This Is the Case, What can be Done?

1. Alternative Energy for the Brain: ‘Bypassing’ Glucose

While the brain is mostly dependent on glucose as a primary energy source, it is also capable of utilising ketones as an alternative form of energy. Ketones (ketone bodies) are produced by the body when fasting or on a ketogenic diet. Some ketones are available as supplements (BHB and others).

These ketones play a neuroprotective role likely through an improvement in metabolic efficiency, by sparing glucose, or in other words increasing brain energy reserves.

“Ketone bodies are thought to stabilize the lactate/pyruvate ratio and bypass the metabolic blocks associated with…impairment of glucose metabolism.” (LaManna 2009)

“A defect of the glucose-transporter protein of brain capillaries should interfere with cerebral energy metabolism and brain function. We have studied two children with persistent low concentrations of glucose in cerebrospinal fluid, seizures, and delayed development who seemed to have a genetic defect involving the type 1 glucose transporter. Both responded dramatically to treatment with a ketogenic diet.” (De Vivo 1991)

2. Supplements to Improve Glucose and Glycogen Metabolism: What can we Learn from Athletes?

Glycogen and glucose are BIG topics in energy sports nutrition, especially in endurance athletes such as long distance cyclists, runners etc, but also in muscle building/strength exercises.

Much of the science of sports nutrition and supplementation revolves around managing & supporting glycogen stores and glucose metabolism.

Common sports supplements include the following:

• Creatine
• Arginine (precursor to creatine, works well in combination with creatine) and its metabolite agmatine
• HMB and its precursor leucine, also work well in combination with creatine
• Taurine (present in Red Bull, also available as cheap powder or pills)
• Ornithine, glutamine, beta alanine, glycine, carnitine, Branched Chain Amino Acids (BCAA*)

Many of the above have been researched for potential benefits in brain function and/or seizure management, in addition to muscle strength and athletic endurance.

* (BCAAs may be effective for seizure prevention if used short term, so might be best if ‘pulsed’? Similarly, taurine in animal studies appears to prevent and reduce seizures, but there is a potential risk that very large dose can have the opposite effects.)

In our bodies creatine seems to be closely involved in glucose regulation and energy management in the muscles and the brain.

“Creatine itself may…improve muscle glycogen stores…Creatine supplementation has the potential to promote changes in glucose metabolism that may favor a healthier metabolic profile.” (Solis 2021)

Creatine is extremely important for brain energy and function. Children with genetic disorders that impair creatine metabolism often suffer seizures, autism, impairments in speech and communication, intellectual disability, among others. (These disorders are potentially treatable with either high doses of creatine, or with l-arginine and glycine and/or betaine, which are biological precursors to creatine).

Creatine is the most popular sports/muscle supplement in the world (approx 1 to 1.2 million tubs are sold each month in the UK).

The monohydrate form of creatine is the most researched one by far, and the most popular. It doesn’t have a strong taste, which makes it relatively easy to hide in foods/drinks, although it has a rather ‘gritty’ texture. It also comes in pill form.

Dosages (adults): as a sports supplement at least 20g per day creatine is advised for the ‘loading phase’ for the first week or two, then reduced to 3-5g per day.

Creatine monohydrate has a very good safety profile but can be taxing for the kidneys if taken in large doses over long periods.

Creatine has been shown to be neuroprotective in epilepsy, ageing, and brain injury — by preventing glutamate toxicity (again via its regulation of glucose/glycogen in the brain).

“Creatine effectively (prevented) excitotoxic cascade. Even excessive concentrations of creatine had no neurotoxic effects, so that high-dose creatine supplementation as a health-promoting agent in specific pathological situations or as a primary prophylactic compound in risk populations seems feasible. In conclusion, we were able to demonstrate that the protective potential of creatine was primarily mediated by its impact on cellular energy metabolism and NMDA receptor function, along with reduced glutamate.” (Genius 2012)

Creatine also has well known neuroprotective benefits, and has been proposed as a treatment for a wide range of disorders, from depression to inflammatory bowel disease.

“Fully in line with these pioneering data is a first single case study with a 33-year-old patient with a two-year history of Crohn’s ileitis, who responded very well to creatine supplementation (1.5 g per day, given as monotherapy for a time period of 6 months) with both symptomatic and endoscopic improvement in disease activity.” (Wallimann 2021)

Beta-Hydroxy-beta-Methylbutyrate — or HMB — is a metabolite of the amino acid leucine (we get leucine from food protein and a small amount of it is converted into HMB).

It has been researched in sports science and used by athletes for decades, but is still relatively unknown.

HMB has positive effects in mitochondria energy production, but also inflammation and oxidative stress. It also seems to be involved closely in glucose utilisation by muscle and probably other types of tissue and the brain.

In ANIMAL studies HMB:

• protects the gut from inflammation
• crosses the blood-brain barrier and reverses age-related cognitive decline
• reverses metabolic disease

Additional Things that may Be Helpful for Balancing Glucose/Glycogen Metabolism, Brain Function and Seizures

Intranasal Insulin

Insulin has neuroprotective action. Mechanisms include the regulation of neurotransmitters, promoting glycogen synthesis. Insulin‘s role in neuroprotection might derive from its stabilising effect on levels of glucose in the brain..

Intranasal insulin (INI)  has been trialled for improving cognition in mild cognitive impairment or dementia. INI was also shown to be beneficial for cognitive function for people with and without diabetes in one study.

“After 24 weeks of treatment participants with diabetes who received INI had faster walking speeds…increased cerebral blood flow…improved decision making and verbal memory. Combined, the INI-treated participants both with and without type 2 diabetes demonstrated faster walking and better executive functioning and memory.” (Novak 2022)

“In this study we show that low-dose intranasal insulin inhibited…seizures and reduced epileptic discharge activities in mice, potentially by alleviating the increase in seizure-induced glutamate in the hippocampus. Meanwhile, intranasal insulin increased GABA levels… In chronic KA-induced epilepsy, low-dose intranasal insulin reduces the frequency of spontaneous recurrent seizures and epileptic discharges.” (Peng, 2020)

Taking a Deeper Dive into Science of Glucose Metabolism in the Brain – Implications for Autism Research and Treatments

Impairments in brain energy glucose metabolism, particularly in astrocytes, can account for the emergence of all autism symptoms, regardless of the upstream causes and pathologies.

The presentation ‘Astrocyte Glucose Metabolism in Autism – Implications for future research and treatments‘, and supporting references, can be viewed below or downloaded here.