The brain and glucose
The brain represents more than 20% of the body's energy consumption . Neurons, like all cells, use energy in the form of ATP . The main energy substrate used by the brain to produce ATP is glucose . In the event of a deficiency in glucose intake, proteins and lipids can also be mobilized to meet the energy needs of the brain (Capeau et al. 2020).
Indeed, post-prandial or post-absorptive, glucose reserves are sufficient to supply the brain (glycolysis or glycogenolysis). During a fast , after exhaustion of glycogen reserves, gluconeogenesis is initiated by mobilizing proteins to produce glucose from amino acids. When fasting is prolonged, in order to protect body proteins and therefore muscle mass, fatty acid metabolism is triggered. Unlike muscle, the brain cannot use free fatty acids because they do not pass the blood-brain barrier .
In contrast, ketone bodies produced from lipolysis represent the second energy substrate used by the brain . This phenomenon of ketogenesis also occurs in cases of diabetes secondary to insulin deficiency, not allowing the use of glucose by the brain (Capeau et al. 2020).
Hypoglycemia in migraine
In 1935, PA Gray and his colleagues observed that the diabetic patient presented symptoms similar to the migraine patient (Gray et al. 1935) such as hunger, fatigue, emotional instability, dizziness, mental confusion and headaches. They then bring together several experiences of their colleagues to analyze the results.
First, they observe a higher frequency of migraines in the morning , on an empty stomach or after physical exercise. The blood glucose level of these patients is decreased, suggesting transient hypoglycemia or hyperinsulinism . The administration of 14 g of glucose is then sufficient to gradually reduce the frequency of seizures .
To better understand the link between observed hypoglycemia and migraine , they are interested in the ketogenic diet , a diet low in carbohydrates, but very rich in lipids to induce a state of ketosis. This diet, still used today for weight loss purposes, forces the liver to produce ketone bodies from dietary fat or the body's fat reserves. These ketone bodies then become the main source of energy for the cells . They find in migraine patients following this diet that the frequency of migraines is greatly reduced .
Since then, numerous studies have shown the effectiveness of this diet for treating migraine and a recent meta-analysis from 2017 concluded that it is of definite benefit in preventing attacks (Barbanti et al. 2017).
The administration of glucose to limit the crisis?
In 1971, another team noted that the administration of high doses of glucose (50 g) to migraine patients led to an attack within 8 hours in 60% of cases (Hockaday et al. 1971). This observation, confirmed numerous times since, is independent of the presence of auras or the intensity of the migraine (Zhang et al. 2020). Similarly, insulin administration can lead to a migraine attack within 2-3 hours (Pearce 1971; X. Wang et al. 2017). The latency time between the administration of glucose or insulin and the onset of the migraine attack is the time necessary for the appearance of hypoglycemia.
The injection of glucose causes hyperglycemia , gradually compensated by the secretion of insulin, favoring after a few hours the appearance of hypoglycemia , which triggers the attack. The comparison of the metabolic reaction following the administration of glucose between the migraine group and the control group is surprising. Only the group of migraine sufferers has increased levels of free fatty acids and ketone bodies . These rates increase at the onset of the headache and continue to increase throughout the attack (Di Lorenzo et al. 2015; Gross et al. 2019).
Moreover, the glucose or glycerol levels did not differ between the two groups. Some authors interpret this ketogenesis as a response to the increased energy demand of the migraine patient's neurons . This hypothesis is based on the observation that migraine is linked to a basic hypoglycaemic state against a background of hyperinsulinism ; in this case, the administration of high doses of glucose will, after a few hours, cause much greater functional hypoglycemia, secondary to high insulin production.
During the crisis, the brain's energy demand is such that astrocytes, unable to absorb glucose, use ketone bodies. This hypothesis is all the more credible as the lactate level (an alternative to glucose also used by astrocytes) is found increased during the crisis (Reyngoudt et al. 2011; Watanabe et al. 1996).
Migraine and diabetes, what is the link?
Conversely, it has been shown that migraine patients have a lower risk of developing type 2 diabetes (Fagherazzi et al. 2019). Therefore, the decreased frequency of migraine attacks in patients at high risk of developing diabetes, such as those with obesity, could be a sign of increased blood sugar and early onset diabetes . Thus, the gradual increase in blood sugar could counteract the underlying hypoglycemia of migraine sufferers.
Finally, hyperinsulinism is a condition that has often been reported in migraine patients (Cavestro et al. 2007) and which could be the cause of the underlying hypoglycemia state found in migraineurs. The migraine patient is therefore at the center of a complex system where the stabilization of blood sugar by insulin plays a key role.
Hypoglycaemia and hyperinsulinism have also been correlated with increased NO production (Gruber et al. 2010). This NO is indeed a powerful vasodilator involved in the migraine process ; it is one of the reactive oxygen species (ROS) responsible for oxidative stress, but is also responsible for the apoptosis of pancreatic beta cells and therefore the progression of type 2 diabetes (Kubisch et al. 1997)
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