Migraines: The Hypoglycemic Headache?

Photo by Pavel Danilyuk

Migraine and Metabolism: a Mental-Metabolic Match

Migraines are a common, debilitating condition characterized by intense, painful recurring headaches with other various autonomic and sensory symptoms. It’s estimated that over 1 billion individuals worldwide experience a migraine per year. [1] Due to the high occurrence of migraines, much research has been dedicated to understanding the potential causes of them. While studies have primarily focused on the vasculature and neurovasculature aspects of migraines, there’s been a resurgence in interest in their metabolic underpinnings. It is important to note that while numerous specific aspects of the metabolism have been linked to migraines, this article aims to focus on only two of them, namely insulin resistance and mitochondrial dysfunction.

Nicknamed the “hypoglycemic headache,” migraines were first proposed to be linked to blood glucose levels back in 1935. [2] Growing bodies of evidence have since built on this proposal and indicate that impaired energy and brain-glucose metabolisms might actually play a pivotal role in migraines. [3] One of the key players in regulating our blood glucose levels is insulin. Secreted from the beta cells of the pancreas in response to an increase in blood glucose levels, insulin facilitates glucose uptake so that it may be used for energy. Insulin also is able to cross the blood-brain barrier, playing a key role in the gut-brain axis and brain-glucose metabolism. However it seems that the body sensitivity to insulin might differ in people with migraines.[4]

Insulin Resistance and Migraines

Insulin resistance generally refers to when insulin receptors in the liver, skeletal muscle, adipocytes, and/or brain respond less to insulin, resulting in higher amounts of insulin being needed to signal for glucose uptake and prolonged states of increased blood glucose levels following a meal. Insulin resistance is most commonly associated with Type 2 Diabetes and Metabolic Syndrome, however it now seems to also have ties to migraines. Multiple studies have concluded that individuals who experience migraines, especially chronic migraines, are more likely to experience insulin resistance, even when they are non-obese, nondiabetic, and young. [5,6,7] One study even found that the duration of migraine attacks was significantly related to insulin resistance. [8] Additionally, another study found brain mitochondrial dysfunction, impaired brain-glucose metabolism, neuroinflammation, and decreased grey matter concentrations in specific areas are common features in those who experience chronic migraines. [5] This combination of results suggests that migraines might be caused — or at least influenced — by a disruption in energy homeostasis within the brain driven, at least in part, by insulin resistance.

“The novel neuroenergetic hypothesis and altered brain glucose and insulin homeostasis.,” Figure by Wang et al. (2023)

Migraines and the Energy Metabolism Disturbance

Mitochondria, the infamous powerhouse of the cell, unsurprisingly play a critical role in energy homeostasis within the brain, especially through their use of oxidative phosphorylation to produce ATP. However in the case of migraines, the mitochondria are in dysfunction, creating a multitude of negative effects. Mitochondrial dysfunction drives two critical disruptions in the context of migraines. The first is it impacts the calcium homeostasis of these cells, causing deficits in energy and exacerbating neuronal stress. This in turn results in the decrease of the migraine attack threshold. The second is the increase of reactive oxygen species (ROS) production, resulting in pain receptor activation, cellular structure damage, and release of CGRP, which serves as a key migraine mediator. [9] This increase of ROS production as well as the decrease in beta-oxidation and ATP production induced by mitochondrial dysfunction results in insulin resistance. [10] With this established relationship between insulin resistance and mitochondrial dysfunction, it makes sense why studies have also found a connection between migraines and mitochondrial dysfunction. [3]

Photo by Jane Trang Doan

Going Forward

While further research into this relationship between migraines and the metabolism is necessary, there are still findings that provide actionable strategies to combat this. One of these strategies is through diet, more specifically the Keto diet. In an analysis of seven studies, researchers found that the Keto Diet — a low-carbohydrate high-protein high-fat diet that causes the body to enter a state of ketosis — is effective in helping manage migraines. The Keto Diet has multiple positive effects, such as protecting against inflammation, enhancing brain metabolism, and decreasing potential oxidative injury and mitochondrial permeability transition. [11] These benefits seem to extend to helping with migraines, as the study found that within just a few days of starting the Keto Diet, results ranged from a decreased frequency in migraines to total disappearance of them. [11]

Another strategy is incorporating more exercise into daily life, as it increases the release of myokines, which combat inflammation, and improves mitochondrial function and insulin sensitivity. This ultimately assists in addressing both the metabolic and the neurovascular components of migraines. Through targeting various aspects comprising the brain-glucose metabolism, these strategies hold promise for reducing the frequency and severity of migraines​.

Sources:

[1] Amiri, P., Kazeminasab, S., Nejadghaderi, S. A., Mohammadinasab, R., Pourfathi, H., Araj-Khodaei, M., Sullman, M. J. M., Kolahi, A., & Safiri, S. (2022). Migraine: A review on its history, global epidemiology, risk factors, and comorbidities. Frontiers in Neurology, 12. https://doi.org/10.3389/fneur.2021.800605

[2] Gray, P. A., & Burtness, H. I. (1935). HYPOGLYCEMIC HEADACHE. Endocrinology, 19*(5), 549–560. https://doi.org/10.1210/endo-19-5-549

[3] Gross, E. C., Lisicki, M., Fischer, D., Sándor, P. S., & Schoenen, J. (2019). The metabolic face of migraine — from pathophysiology to treatment. Nature Reviews Neurology, 15(11), 627–643. https://doi.org/10.1038/s41582-019-0255-4

[4] Rainero, I., Limone, P., Ferrero, M., Valfrè, W., Pelissetto, C., Rubino, E., Gentile, S., Lo Giudice, R., & Pinessi, L. (2005). Insulin Sensitivity is Impaired in Patients with Migraine. Cephalalgia, 25(8), 593–597. https://doi.org/10.1111/j.1468-2982.2005.00928.x

[5] Del Moro, L., Rota, E., Pirovano, E., & Rainero, I. (2022). Migraine, brain glucose metabolism and the “Neuroenergetic” hypothesis: A scoping review. Journal of Pain, 23(8), 1294–1317. https://doi.org/10.1016/j.jpain.2022.02.006

[6] Rainero, I., Govone, F., Gai, A., Vacca, A., & Rubino, E. (2018). Is migraine primarily a metaboloendocrine disorder? Current Pain and Headache Reports, 22(5). https://doi.org/10.1007/s11916-018-0691-7

[7] Cavestro, C., Rosatello, A., Micca, G., Ravotto, M., Marino, M. P., Asteggiano, G., & Beghi, E. (2007). Insulin Metabolism is Altered in Migraineurs: A New Pathogenic Mechanism for Migraine? Headache the Journal of Head and Face Pain, 47(10), 1436–1442. https://doi.org/10.1111/j.1526-4610.2007.00719.x

[8] Bhoi, S. K., Kalita, J., & Misra, U. K. (2012). Metabolic syndrome and insulin resistance in migraine. The Journal of Headache and Pain, 13(4), 321–326. https://doi.org/10.1007/s10194-012-0416-y

[9] Wang, Y., Wang, Y., Yue, G., & Zhao, Y. (2023). Energy metabolism disturbance in migraine: From a mitochondrial point of view. Frontiers in Physiology, 14. https://doi.org/10.3389/fphys.2023.1133528

[10] Kim, J., Wei, Y., & Sowers, J. R. (2008). Role of mitochondrial dysfunction in insulin resistance. Circulation Research, 102(4), 401–414. https://doi.org/10.1161/circresaha.107.165472

[11] Barbanti, P., Fofi, L., Aurilia, C., Egeo, G., & Caprio, M. (2017). Ketogenic diet in migraine: rationale, findings and perspectives. Neurological Sciences, 38(S1), 111–115. https://doi.org/10.1007/s10072-017-2889-6

Images:

Pavel Danilyuk. (2021, February 8). Woman Sitting On A Sofa · Free Stock Photo. Pexels. https://www.pexels.com/photo/woman-sitting-on-a-sofa-6753167/

‌Del Moro, L., Rota, E., Pirovano, E., & Rainero, I. (2022). Migraine, Brain Glucose Metabolism and the “Neuroenergetic” Hypothesis: A Scoping Review. The Journal of Pain. https://doi.org/10.1016/j.jpain.2022.02.006

Jane Trang Doan. (2017, July 4). Variety of Food on Wooden Coaster· Free Stock Photo. Pexels. https://www.pexels.com/photo/variety-of-food-on-wooden-coaster-793759/