Reduced urinary glutamate levels are associated with the frequency of migraine attacks in females.

BACKGROUND AND PURPOSE: Recent evidences indicate that glutamatergic homeostasis disorders are implicated in the pathogenesis of migraine. In particular, plasma and cerebrospinal fluid glutamate levels seem to be altered in migraine patients. However, the impacts of glutamate on migraine and especially on aura symptoms, alterations in the frequency of migraine attacks as well as investigations on glutamate on migraine-related metabolic dysfunctions, like hyperinsulinaemia, and an atherogenic lipid profile remain elusive to date. The aim of the present study was to investigate the impact of glutamate on migraine and related metabolic dysfunctions. METHODS: We investigated the urinary glutamate levels of female migraineurs (n = 48) in the interictal phase and healthy controls (n = 48). Parameters of the insulin- and lipid metabolism, inflammatory parameters and anthropometric parameters were additionally determined. RESULTS: Urinary glutamate levels of female migraineurs were significantly decreased with respect to the control group. Logistic regression revealed an odds ratio of 4.04 for migraine. We found a significant correlation with the time-period of patients' last attack and a significant inverse correlation with the annual frequency of migraine attacks. Other parameters of the insulin- and lipid metabolism, anthropometric and inflammatory parameters showed no significant correlation with glutamate levels. CONCLUSION: We show here that female migraineurs exhibit decreased urinary glutamate levels which are associated with a 4.04-fold higher risk for migraine and correlated with patients' frequency of migraine attacks.

Oxidative stress is associated with migraine and migraine-related metabolic risk in females.

BACKGROUND AND PURPOSE: Oxidative stress is discussed to be implicated in the pathophysiology of migraine. However, data are in part controversial and the possible underlying mechanisms remain elusive to date. The aim of this study was to investigate the oxidative stress status of female patients with migraine and its implications on migraine-related metabolic alterations. METHODS: Oxidative stress markers malondialdehyde (MDA), 4-hydroxy-2-nonenal (HNE), carbonylated proteins, parameters of associated nitric oxide stress, inflammation, lipid- and glucose-metabolism were determined in the interictal phase in female patients with migraine and controls. RESULTS: We found significantly increased HNE levels in female migraineurs compared with controls. Logistic regression analyses of HNE revealed an odds ratio for migraine of 4.55. HNE showed significant correlations with the nitric oxide pathway, the insulin- and the lipid-metabolism. CONCLUSIONS: We show here that increased oxidative stress is associated with migraine and contributes to migraine-related metabolic risk like nitrosative stress, an atherogenic lipid profile and hyperinsulinemia. Our data suggest that oxidative stress may represent a key event in the pathophysiology of migraine and a suitable therapeutic target.

Increased matrix metalloproteinase activity is associated with migraine and migraine-related metabolic dysfunctions.

OBJECTIVE: Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) are discussed to be involved in the pathophysiology of migraine. Moreover, MMPs may also be involved in migraine-related metabolic alterations like an atherogenic lipid profile and hyperinsulinemia. The aim of this study was to investigate the impact of MMPs and TIMPs on migraine with and without aura and related metabolic dysfunctions. METHODS: MMP activity, six MMPs and three TIMPs, parameters of the insulin and lipid metabolism as well as anthropometric parameters were determined in 124 non-obese subjects. RESULTS: We found highly significant increased MMP activity in migraine patients independent of aura symptoms, which was associated with migraine with an odds ratio of 7.57. Interestingly, none of the determined MMPs and TIMPs showed significant different serum levels between migraine patients and healthy controls. We found significant correlations between MMP activity and parameters of the insulin and lipid metabolism, like Homeostasis Model Assessment index (HOMA index), cholesterol, triglycerides, and oxidized LDL. CONCLUSION: We show here that increased MMP activity is tightly associated with migraine and migraine-related hyperinsulinemia and atherogenic lipid alterations. Our findings represent a new pathophysiological mechanism, which may be of clinical relevance, especially in regard to therapeutic approaches using MMP inhibitors.

Increased nitric oxide stress is associated with migraine.

Nitric oxide (NO) has been implicated in migraine attacks, but the role of NO in migraine remains unclear. We here hypothesize that increased NO in the headache-free period is associated with migraine. One hundred and thirty probands participated in this study. Various parameters of the NO pathway, such as nitrate, nitrite, arginine, citrulline, nitrosylated proteins, asymmetric dimethylarginine, symmetrical dimethylarginine, expression of endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase and two polymorphisms of eNOS were investigated. We found significant increased nitrate and decreased nitrite levels in migraineurs in the headache-free period. Nitrate and nitrite levels showed a significant inverse correlation. Logistic regression revealed an odds ratio of 3.6 for migraine. Other parameters of the NO pathway were neither altered in migraineurs nor correlated with nitrate. We show here that migraine patients suffer under sustained increased nitrosative stress in the headache-free period, which is associated with a 3.6-fold higher risk for migraine.

Hyperinsulinaemia in migraineurs is associated with nitric oxide stress.

There is growing evidence that alterations in the insulin and glucose metabolism may be involved in the pathogenesis of migraine. Nitric oxide (NO) stress has been associated with migraine. However, the role of NO on the insulin and glucose metabolism in migraineurs has remained elusive to date. The aim of the present study was to investigate the insulin and glucose metabolism in migraineurs and to determine possible interactions with the NO pathway. One hundred and twenty non-obese probands participated in this study, including 48 migraineurs and 72 healthy volunteers. Various parameters of the NO pathway, glucose metabolism as well as body measurement parameters were determined. We found a highly significantly increased insulin and Homeostasis Model Assessment (HOMA)-index in migraine patients, whereas fasting glucose was decreased. Logistic regression revealed an odds ratio of 5.67 for migraine, when comparing the lowest with the highest quartile of HOMA. Multivariate analysis showed that HOMA, waist-to-length ratio and nitrite as parameters of NO stress were highly significantly correlated. We show here that hyperinsulinaemia is associated with migraine and, furthermore, is correlated with increased NO stress. These findings represent a new pathophysiological mechanism that may be of clinical relevance.

Lipid profile in normal weight migraineurs - evidence for cardiovascular risk.

BACKGROUND: Recent studies suggest that migraine is associated with metabolic disorders. In particular, migraine may be associated with cardiovascular risk; however, an association of migraine with cardiovascular risk factors like hypercholesterolemia has been proposed, but previous studies have yielded in part conflicting results. The aim of the present study is to evaluate the lipid profile in normal weight migraine patients. METHODS: One hundred thirty-six probands participated in this study. The study group was divided into normal weight migraineurs and control groups, including normal weight controls, obese and overweight controls and migraineurs. Various parameters of the lipid metabolism and inflammatory parameters were investigated. RESULTS: We found significant increased cholesterol, low density lipoprotein cholesterol (LDL-C) and oxidized LDL-C in normal weight migraineurs. Increased oxidized LDL-C was associated with a 7.93-fold increased risk for migraine. Alterations in the lipid profile were not accompanied by increased inflammatory parameters. CONCLUSIONS: We show here that normal weight migraineurs exhibit independent of aura symptoms an atherogenic lipid profile, which shares common features with obesity-related lipid alterations. Our data suggest that migraine is associated with a higher risk for cardiovascular disease and its clinical consequences.

Asymmetric dimethylarginine (ADMA) is tightly correlated with growth in juveniles without correlations to obesity related disorders.

BACKGROUND: Asymmetrical dimethylarginine (ADMA) was found to be increased in conditions associated with atherosclerosis and metabolic disorders. We investigated ADMA in obese juveniles with pre-atherosclerotic symptoms and in normal weight juveniles. DESIGN: To elucidate correlations of ADMA in juveniles with obesity related disorders such as insulin resistance, low grade inflammation, hypertension and pre-atherosclerosis, we analysed ADMA by high performance liquid chromatography (HPLC) in 68 obese and 68 healthy, age and gender matched juveniles. RESULTS: ADMA levels are slightly, but significantly increased (p=0.04) in obese (0.78+/-0.01 micromol/l), compared to normal weight juveniles (0.74+/-0.01 micromol/l). There are no robust correlations of ADMA with obesity related disorders, like dyslipidemia, hypertension, low-grade inflammation and pre-atherosclerosis. Age, body length and alkaline phosphatase, as markers of growth are correlated with ADMA. Multiple testing revealed that, alkaline phosphatase turned out as highly significant positively correlated with ADMA in normal weight (r=0.45/p<0.0001) and obese (r=0.59/p<0.0001) children. CONCLUSIONS: We show here, that ADMA is slightly increased in obese juveniles without any robust correlations to obesity related disorders. ADMA is tightly correlated with alkaline phosphatase as a marker of growth in obese and normal weight, healthy juveniles.

Body fat distribution of overweight females with a history of weight cycling.

Weight cycling may cause a redistribution of body fat to the upper body fat compartments. We investigated the distribution of subcutaneous adipose tissue (SAT) in 30 overweight women with a history of weight-cycling and age-matched controls (167 normal weight and 97 overweight subjects). Measurements of SAT were performed using an optical device, the Lipometer. The SAT topography describes the thicknesses of SAT layers at 15 anatomically well-defined body sites from neck to calf. The overweight women with a history of weight cycling had significantly thicker SAT layers on the upper body compared to the overweight controls, but even thinner SAT layers on their legs than the normal weight women. An android fat pattern was attributed to overweight females and, even more pronounced, to the weight cyclers. The majority of normal weight women showed a gynoid fat pattern. Using stepwise discriminant analysis, 89.0% of all weight cyclers and overweight controls could be classified correctly into the two groups. These findings show the importance of normal weight maintenance as a health-promoting factor.

Android subcutaneous adipose tissue topography in lean and obese women suffering from PCOS: comparison with type 2 diabetic women.

The new optical device, the lipometer, enables the noninvasive, quick, safe, and precise determination of the thickness of subcutaneous adipose tissue (SAT) layers at any given site of the human body. Fifteen anatomically well-defined body sites from neck to calf describe a SAT topography (SAT-Top) like an individual "fingerprint" of a subject. This SAT-Top was examined in 16 women with polycystic ovary syndrome (PCOS) and compared to the body fat distribution of 87 age-matched healthy controls and 20 type-2 diabetic women. SAT-Top differences of these three groups were described and, to render the possibility of visual comparison, the 15-dimensional body fat information was condensed to a two-dimensional factor plot by factor analysis. All PCOS patients had an android body fat distribution with significantly thinner SAT layers on the legs as compared to healthy controls. Moreover, a hierarchical cluster analysis resulted in two distinctly different groups of PCOS women, a lean (PCOSL) and an obese (PCOSO) cluster: compared to healthy women, lean PCOS patients had significantly lower total SAT development, even though height, weight, and body mass index did not deviate significantly. Especially on the legs, their SAT layers were significantly lowered, indicating a more "apple-like" fat distribution type. Obese PCOS women showed a SAT-Top pattern very similar to that of women with type-2 diabetes, although the mean age difference between these groups was more than 30 years. Compared to healthy controls, the SAT-Top of these obese PCOS patients was strongly shifted into the android direction, appearing as "super-apples" with a significantly increased upper trunk obesity to 237.8% and a significantly decreased leg SAT development to 79.8%.

Subcutaneous adipose tissue pattern in lean and obese women with polycystic ovary syndrome.

The new optical device, Lipometer, permits the noninvasive, quick, safe, and precise measurement of the thickness of subcutaneous adipose tissue (SAT) layers at any given site of the human body. Fifteen anatomically well-defined body sites from neck to calf describe the SAT topography (SAT-Top) like an individual "fingerprint." SAT-Top was examined in 33 women with polycystic ovary syndrome (PCOS), in 87 age-matched healthy controls and in 20 Type-II diabetic women. SAT-Top differences of these three groups were described, and, based on a hierarchical cluster analysis, two distinctly different groups of PCOS women, a lean (PCOS(L)) and an obese (PCOS(O)) cluster, were found. For visual comparison of the different types of body fat distribution, the 15-dimensional body fat information was condensed to a two-dimensional factor plot by factor analysis. For comparison of the PCOS like body fat distribution with the "healthy" fat pattern, the (previously published) SAT-Top results of 590 healthy women and men (20-70 years old) and 162 healthy girls and boys (7-11 years old) were added to the factor plot. PCOS(O) women showed a SAT-Top pattern very similar to that of women with Type-II diabetes, even though the diabetic women were on average 30 years older. Compared with their healthy controls, SAT-Top of these PCOS(O) patients was strongly skewed into the android direction, providing significantly decreased leg SAT development and significantly higher upper body obesity. Compared with healthy women, PCOS(L) patients had significantly lower total SAT development (even though height, weight, and body mass index did not deviate significantly), showing a slightly lowered amount of body fat in the upper region and a highly significant leg SAT reduction. This type of fat pattern is the same as found in girls and boys before developing their sex specific body fat distribution. We conclude that women with PCOS develop an android SAT-Top, but compared in more detail, we found two typical types of body fat distribution: the "childlike" SAT pattern in lean PCOS patients, and the "diabetic" body fat distribution in obese PCOS women.