2 CHAPTER 2 38 Discussion Here we investigated metabolites identified by 1H-NMR spectroscopy in serum of migraine patients and controls to assess whether metabolic profiles can distinguish the two groups. We identified 22 metabolites that were predictive for active migraine and estimated that they would remain predictive after correction for age, sex, BMI and smoking status. Active migraine status was linked with metabolic profiles with more (22) metabolites, when compared with lifetime migraine (6), suggesting that active migraine patients may have a more disturbed metabolic profile compared to lifetime migraine patients, at least among the 100 measured metabolites. Although, based on our study, it is not possible to directly interpret the p-values nor to make association on an individual metabolite level among the total 22 compounds associated with active migraine, it is remarkable that the majority of these 22 metabolites have been (indirectly) implicated in migraine before. In our study, we found metabolites involved in lipid metabolism namely; cholesterol, and two types of lipids (CH2 and CH*2CH=CH). A number of studies have previously implicated lipid metabolism in migraine for instance, epidemiologic studies have shown that obesity is a risk factor for migraine and that there is a comorbidity of cerebrovascular and cardiovascular disease and migraine.52, 53 Some studies found an elevated total cholesterol, LDLcholesterol, or triglycerides, and decreased levels of HDL-cholesterol in migraine,54, 55 whereas several other studies found no significant differences in lipid profiles.54, 56 A recent meta-analysis encompassing 2,800 migraine patients and 7,353 controls from eight Dutch cohorts, using a different 1H-NMR metabolomics platform in a systematic approach, also showed alterations in HDL metabolism, in that study defined by a decreased level of lipoprotein A1 and a decreased free cholesterol to total lipid ratio in small HDL subspecies.55 Neurovascular and endothelial dysfunction are believed to be an underlying cause for the increased risk in cerebrovascular and cardiovascular diseases in migraine patients.57, 58 At the basis of this involvement lies a possible higher prevalence of risk factors, such as hypertension and hyperlipidemia, in migraine patients.57 Also the involvement of lipids in migraine pathophysiology has been shown in various studies.54, 55 Regardless, the exact role lipids play is complex and needs further investigation. Glucose is another metabolite we found that has previously been associated with migraine either directly or via metabolically associated pathways. Glucose levels and insulin metabolism, as well as mitochondrial dysfunction have been known to play a role in migraine pathology.59, 60 Still, no association was found between migraine and diabetes type 2.59, 61, 62 It has been suggested that outside attacks, migraine patients have an impaired insulin sensitivity and higher fasting plasma insulin levels compared to controls.63, 64 Recently it was shown that glucose levels were higher during a spontaneous migraine attack compared to outside of an attack.65 Both 1,5-anhydrosorbitol and myoinositol, which were part of our prediction model, are involved in glucose metabolism. 1,5-Anhydrosorbitol is a naturally occurring monosaccharide found in nearly all foods and myoinositol, which is a carbocyclic sugar that is abundant in brain and other mammalian tissues,
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