Elsevier

Medical Hypotheses

Volume 97, December 2016, Pages 117-130
Medical Hypotheses

Migraine: A disorder of metabolism?

https://doi.org/10.1016/j.mehy.2016.10.029Get rights and content

Highlights

  • Migraine is associated with the development of a metabolic challenge.

  • Migraine triggers can differentially alter energy metabolism and utilization.

  • Common factor linking triggers is an ability to promote insulin resistance.

  • Insulin resistance may underlie the pathogenesis of migraine.

Abstract

The treatment and prevention of migraine within the last decade has become largely pharmacological. While there is little doubt that the advent of drugs (e.g. triptans) has helped many migraine sufferers to lead a normal life, there is still little knowledge with respect to the factors responsible for precipitating a migraine attack. Evidence from biochemical and behavioural studies from a number of disciplines is integrated to put forward the proposal that migraine is part of a cascade of events, which together act to protect the organism when confronted by a metabolic challenge.

Introduction

Migraine is a chronic neurovascular disorder that is characterized by recurring headache of unilateral onset, photophobia, phonophobia and autonomic disturbances [91], [101]. A systematic review of population-based studies reporting migraine prevalence found that the incidence of chronic migraine was estimated to range from 0 to 5.1% [155]. However, sex differences have been noted with women up to four times more likely to be affected than men [136].

Historically, migraine was thought to be a vascular disorder. The association between migraine and vascular diseases such as hypertension and ischemic brain injury and vascular disorders such as coronary heart disease and stroke is well known [226]. However, the advent of new technology has confirmed that migraine pathophysiology is associated with disturbances in many parts of the brain including the hypothalamus, thalamus and brainstem [82].

The recommended treatment and prevention strategies for migraine within the last decade have become largely pharmacological. The discovery of selective 5-hydroxytryptophan agonists has provided many migraine sufferers relief from the severely debilitating symptoms, which often result in the individual being unable to carry out even the most basic of functions during an attack [81], [82]. Prophylactic treatment using a range of drugs (e.g. β-blockers, flunarizine, valproic acid and topiramate), is also not uncommon. However, while drugs are often prescribed for the prevention or management of migraine, pharmacotherapy is often unsuccessful in preventing a recurrence of symptoms in migraine sufferers [65].

The study of migraine is made difficult by the lack of an animal model that translates fully the clinical symptoms of migraine [192], the episodic nature of the attacks [1], and the observation that the migraine ‘trigger’ can be of nutritional, psychological, hormonal or behavioural origin [47], [59], [108], [179], [239], [115], [116]. To date, researchers have been unable to identify a set of triggers common to all migraineurs. Indeed, every case of migraine appears to have its own set of unique triggers making treatment and prevention of the condition difficult. A summary of some of the most common migraine triggers is provided in Table 1.

A significant association between polymorphisms in the insulin receptor gene and migraine pathogenesis has been confirmed [146]. Moreover, there is increasing evidence that altered energy metabolism and utilization may hold the key to understanding the pathogenesis of migraine (e.g. [108], [179]. However, if this is true then it should be possible to establish a link between the known migraine triggers and some alteration in energy metabolism and utilization.

The aim here is to examine the effect (if any) of the most commonly reported migraine triggers on glucoregulation. The review will consist of three sections. The first section will provide a minor review of the biochemical processes usually activated during feeding and fasting in non-migraineurs. This information has been included in order to assist those unfamiliar with the feeding and fasting literature. Then an overview of the most salient pathways of metabolism known to contribute to migraine will be presented. Lastly, data from human and animal studies will be used in order to argue that the common factor linking the known migraine triggers may be an underlying ability, albeit variable, to promote the development of a metabolic challenge.

Section snippets

Section 1: Metabolic effect of feeding and fasting

The human body needs to be able to function when food is not available. Thus, the metabolism of glucose, the main energy source for cells, is a highly regulated mechanism. When food is available, glucose is converted by glycolysis into pyruvate and lactate in the cytosol and any excess glucose is converted to glycogen by glycogenesis and stored. Alternatively, when food intake is low the stored glycogen is converted back to glucose by glycogenolysis [22].

Insulin, a peptide hormone released by

Section 2: Pathways of metabolism in migraine

Early work revealed that an elevation in FFA and ketone bodies often precedes a migraine attack [93]. Similarly, an elevation in FFA, glycerol concentrations, growth hormone, cortisol and ketone bodies can also occur during a migraine attack [207]. Indeed, hypercortisolism is a common finding in migraine patients [246]. The elevation of plasma FFA was noted together with changes in blood glycerol concentrations and insulin was depressed, which when considered together is consistent with a

Section 3: Migraine triggers and glucoregulation

Fukui et al. [72] assessed 200 migraineurs (162 women, 85 men) and found that the most common group of migraine triggers (reported by both genders), could be classed as nutritional triggers. The nutritional triggers in order of frequency were fasting, chocolate, alcohol/red wine and coffee. Other factors such as stress, citrus, cheese, monosodium glutamate, aspartame, menstrual cycle (females), nuts and nitrates were also thought to be able to promote a migraine attack. Space does not permit an

Summary

The aim of this paper was to attempt to stimulate discussion on the relationship between migraine and energy metabolism and utilization by proposing that migraine may be part of a cascade of events, which together act to protect the organism when confronted by a metabolic challenge. From the evidence presented above it would appear that most of the common migraine triggers can be linked to less than optimum energy metabolism and utilization in some way.

More than 95% of migraineurs can identify

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