- Email: [email protected]
The effects of topiramate and valproate therapy on insulin, c-peptide, leptin, neuropeptide Y, adiponectin, visfatin, and resistin levels in children with epilepsy
G Model
YSEIZ-2192; No. of Pages 6 Seizure xxx (2013) xxx–xxx
Contents lists available at ScienceDirect
Seizure journal homepage: www.elsevier.com/locate/yseiz
The effects of topiramate and valproate therapy on insulin, c-peptide, leptin, neuropeptide Y, adiponectin, visfatin, and resistin levels in children with epilepsy Fatma Mujgan Sonmez a,*, Dilek Zaman b, Ayse Aksoy c, Orhan Deger d, Rezzan Aliyazicioglu d, Gu¨lay Karaguzel e, Kerim Fazlioglu f a
Turgut Ozal University, Faculty of Medicine, Department of Child Neurology, Ankara, Turkey Giresun University, Faculty of Medicine, Department of Pediatrics, Giresun, Turkey c Sami Ulus Hospital, Department of Child Neurology, Ankara, Turkey d Karadeniz Technical University, Faculty of Medicine, Department of Biochemistry, Trabzon, Turkey e Karadeniz Technical University, Faculty of Medicine, Department of Pediatric Endocrinology, Trabzon, Turkey f Karadeniz Technical University, Faculty of Medicine, Department of Child Neurology, Trabzon, Turkey b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 11 March 2013 Received in revised form 9 July 2013 Accepted 11 July 2013
Purpose: Antiepileptic drugs may affect the endocrine system. We investigated the effects of valproic acid and topiramate on the levels of insulin, c-peptide and adipocytokines in pre-pubertal patients with idiopathic partial and generalized epilepsy. Methods: Forty-one children with epilepsy were included. The patients were divided into two groups (valproic acid; n = 21, topiramate; n = 20). The weight, height, body mass index and homeostasis model assessment of insulin resistance (HOMA-IR) were recorded and insulin, c-peptide, leptin, neuropeptide Y, adiponectin, visfatin and resistin levels were determined at 0, 6 and 12 months of therapy. Results: In the valproate group, weight and height increased significantly. Seven of 21 patients were overweight at the end of one year. Leptin was higher in the overweight subgroup. Although insulin and HOMA-IR increased (p < 0.05), none of the patients showed hyperinsulinism or IR. Resistin had decreased at the 6th and 12th months (p < 0.05). In the topiramate group, some statistically nonsignificant changes were demonstrated. Conclusion: The mechanisms behind valproate and topiramate-related weight control are still unclear, especially in children. Valproate and topiramate affect the weight, BMI, and insulin, leptin and adipocytokine levels in prepubertal children. We suggest that further studies including more patients with a long follow-up period are necessary to draw a firm conclusion regarding an association between the treatment with these drugs and the levels of leptin, insulin and adipocytokines. ß 2013 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Keywords: Valproate Topiramate Weight Adipocytokines Insulin C-peptide
1. Introduction Epilepsy is among the common chronic illnesses of childhood. Anticonvulsant drugs are used for its long-term treatment. This therapy may be associated with several metabolic abnormalities.1 Valproate is a broad-spectrum antiepileptic drug used effectively in both partial and generalized seizures.2 Topiramate is a new generation antiepileptic drug. In mid 2005 it was approved as monotherapy in adults and children over 2 years.3,4 Although
* Corresponding author. Current address: Turgut Ozal University, Faculty of Medicine, Department of Child Neurology, Alparslan Turkes Caddesi, No: 57 Emek, Ankara, Turkey. Tel.: +90 312 2035151; mobile: +90 533 654 8654. E-mail addresses: [email protected], [email protected] (F.M. Sonmez).
many endocrinologic side effects have been reported with valproate such as polycystic ovaries and hyperadrogenism the most striking seem to be weight gain for valproate and weight loss for topiramate.5 It was demonstrated in several studies that valproate is associated with weight gain in approximately half of the patients among both males and females.5–7 Although several mechanisms have been implicated, those underlying valproate-related weight gain remain unknown.8,9 The roles of hyperinsulinemia and insulin resistance (IR) as well as of leptin, ghrelin and neuropeptide Y levels have been investigated in patients with epilepsy who gained weight, primarily in adults. However, studies including children with epilepsy have been limited and the results appear controversial.10,11 It was shown that topiramate is effective in the treatment of eating disorders and may cause energy expenditure in rats, but the
1059-1311/$ – see front matter ß 2013 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.seizure.2013.07.007
Please cite this article in press as: Sonmez FM, et al. The effects of topiramate and valproate therapy on insulin, c-peptide, leptin, neuropeptide Y, adiponectin, visfatin, and resistin levels in children with epilepsy. Seizure: Eur J Epilepsy (2013), http://dx.doi.org/ 10.1016/j.seizure.2013.07.007
G Model
YSEIZ-2192; No. of Pages 6 2
F.M. Sonmez et al. / Seizure xxx (2013) xxx–xxx
latter could not be demonstrated in humans.12,13 Human studies investigating the mechanisms of topiramate in weight control are limited. Although some of the study results have shown the role of decreased leptin levels, increased adiponectin levels and increased insulin sensitivity, the mechanisms behind the topiramate-related weight loss are still unknown.14,15 The purpose of this study was to evaluate possible changes in insulin, c-peptide, leptin, neuropeptide Y, adiponectin, visfatin and resistin levels during valproate or topiramate therapies and their role in the weight status of children with epilepsy. 2. Methods and materials This study was carried out in the Department of Pediatric Neurology with the approval of the Hospital Ethics Committee, and was supported by the University Scientific Research Found. Epilepsy type was classified according to the recommendations of the International League Against Epilepsy. Written informed parental consent was obtained from all participating subjects.16 2.1. Subjects During the period July 2007–July 2008, 46 prepubertal patients (ages range between 6 and 12 years; mean age: 8.3 1.7 years) with a history of new-onset seizure and who were diagnosed as idiopathic generalized or partial epilepsy were included in this study. The study was completed with 41 of the 46 enrolled patients aged between 6 and 12 years. The study group consisted of 17 females (mean age: 8.7 0.5 years) and 24 males (mean age: 8.0 0.3 years). The epilepsy diagnosis was based on history, neurologic examination, electroencephalography (EEG), and magnetic resonance imaging (MRI). Patients with symptoms and signs of illnesses other than epilepsy (e.g. endocrine, metabolic, hepatic, or renal diseases), a history of status epilepticus, previous use of any antiepileptic drugs, or previous use of drugs affecting calorie intake were not included in the study. All patients had a normal neurologic examination and normal cranial MRI findings. The patients were divided into two groups according to their drug therapy. Group 1 consisted of 24 patients, mean age 8.0 1.6 years, who received sodium valproate, 20 mg/kg/day, twice Daily, and group 2 consisted of 22 patients, mean age 8.6 1.7 years, who received topiramate 3 mg/kg/day, twice daily. 2.2. Methods All patients were clinically examined and interviewed by the first author. Weight and height were measured and weight z score and body mass index (BMI; as weight [in kilograms] divided by height [in meters] squared) were calculated before the initiation of the therapy and at the 6th and 12th months of therapy. All patients with a BMI between the 85th and 95th percentiles for age and gender were classified as overweight and those above the 95th percentile for age and gender as obese. Pubertal development was assessed according to Tanner stages and Tanner I patients were included in the study.17 Blood samples were obtained at 8 a.m. after an overnight fast for the analysis of serum insulin, c-peptide, leptin, neuropeptide Y, adiponectin, visfatin, resistin and valproate concentrations. The analyses were done before the initiation of therapy and at the 6th and 12th months of the therapy. Topiramate concentrations could not be measured. Plasma glucose concentrations were also measured and the fasting serum glucose to insulin (G0/I0) ratio was calculated. IR was estimated using the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR, fasting insulin x fasting glucose/22.5).18 IR is defined as HOMA-IR levels 3.16 according to the following equation: insulin (uIU/ml) [glucose (mg/dl) 0.055/22.5].
2.3. Assays Serum samples were frozen at 70 8C until analyzed. Serum glucose concentrations were measured by Roche Modular Autoanalyzer using commercial Roche diagnostic kits by enzymatic calorimetric method. The concentrations of insulin and c-peptide were analyzed with chemiluminescence immunometric assay using a DPC-Immulite 2000 autoanalyzer. Leptin concentrations were analyzed with an enzyme-amplified sensitivity immunoassay using kits from BioSource Co. Neuropeptide Y and visfatin concentrations were analyzed with a competitive enzyme immunoassay by using kits from Phoenix Pharmaceuticals Co. Adiponectin and resistin concentrations were analyzed with an enzyme-linked immunosorbent assay using kits from Linco Research Co. 2.4. Statistical analysis Statistical analyses were performed using the Statistical Package for The Social Sciences software (SPSS 13.0.1 serial number: 9069728). The chi-square test was used to compare qualitative datas. In each group, the conformity of the measured values to normal distribution was analyzed using Kolmogorov– Smirnov test. Variation during the period for the data that conformed to normal distribution was analyzed by repeated measures ANOVA (post hoc by paired t test), and the data showing skewed distribution were analyzed using Friedman test (post hoc by Wilcoxon test) in each group. When comparing the two groups, the data conforming to normal distribution were analyzed using Student t test and data showing skewed distribution by Mann– Whitney-U test, and correlations were analyzed by Pearson’s test. A value of p < 0.05 was determined as statistically significant. 3. Results The study was completed with 41 of the 46 enrolled patients. Five patients (3 from group 1 and 2 from group 2) dropped out of the study because of uncontrolled seizures with monotherapy and were treated at another center. Thus, evaluations were made based on the results of 41 patients (17 females, 24 males) aged between 6 and 12 years. The mean age of the patients was 8.3 1.7 years. Patients were divided into two groups according to their drug therapy. Group 1 (sodium valproate) consisted of 21 patients (10 females, 11 males; mean age 8.0 1.6 years), and group 2 (topiramate) consisted of 20 patients (7 females, 13 males; mean age: 8.5 1.8 years). There was no statistically significant difference between the two patient groups with respect to the mean age. Epilepsy types were generalized in 9 patients (7 in group 1, 2 in group 2) and partial seizures in 32 patients (14 in group 1, 18 in group 2). The most common seizure types were complex partial in 21 patients (51.5%) and simple partial in 11 patients (27%) (Table 1). The most common EEG finding was focal epileptiform activity (58.5%) (Table 1). The rate of seizure control was similar between the two groups. In the valproate-treated group weight and height increased significantly both at the 6th and 12th months (p < 0.0005). BMI increased significantly at the 12th month compared with the values at the 6th month of the therapy (p < 0.05) (Table 2). None of the patients had become obese during the one-year-follow-up. Although only 1 patient (4.7%) was overweight at the initiation of the therapy, 4 patients at the 6th month (19%) and 7 patients at the 12th month (33%) had become overweight. When overweight and non-overweight patients were compared, leptin levels were found to be higher in the overweight group (p = 0.03). There were no differences in the other laboratory parameters between the overweight and non-overweight groups (Table 3).
Please cite this article in press as: Sonmez FM, et al. The effects of topiramate and valproate therapy on insulin, c-peptide, leptin, neuropeptide Y, adiponectin, visfatin, and resistin levels in children with epilepsy. Seizure: Eur J Epilepsy (2013), http://dx.doi.org/ 10.1016/j.seizure.2013.07.007
G Model
YSEIZ-2192; No. of Pages 6 F.M. Sonmez et al. / Seizure xxx (2013) xxx–xxx Table 1 Seizure type and EEG findings of the patients. Seizure type
n
Simple partial Complex partial GTC Tonic Clonic Absance
11 21 3 1 3 2
Total
41
% 27 51.5 7 2.5 7 5
100
EEG findings
n
%
Epileptiform activity Focal 24 Generalized 6 Paroxysmal abnormality Focal 6 Generalized 3 Normal 2 Total
41
Table 3 The comparison of BMI and laboratory data among overweight and non overweight patients in VPA treated group.
58.5 14.6 14.6 7.3 5 100
GTC, generalized tonic-clonic.
In the valproate treated group, fasting glucose concentrations and the G0/I0 ratio did not differ at 0, 6 and 12 months of therapy. Although insulin levels and HOMA-IR increased during the followup (p = 0.038 and p = 0.036), none of the patients showed hyperinsulinism or IR. Resistin levels decreased significantly at the 6th and 12th months of therapy when compared to the levels at the initiation of the therapy (p = 0.001), but there was no correlation between resistin levels and BMI. There was no significant difference in c-peptide, visfatin and neuropeptide Y levels during the follow-up (Table 4). In the topiramate-treated group there was no difference in weight, height, BMI, fasting glucose concentrations, HOMA-IR, cpeptide, visfatin, and neuropeptide Y levels. Although the participating children did not lose weight during topiramate therapy, they also did not gain weight. It can thus be speculated that the absence of a weight gain despite their being in a period of growth may be the result of the anorectic effect of topiramate. Insulin levels tended to increase at the 6th month of the therapy, but this increase was not significant. Resistin levels increased at the 6th month but decreased at the 12th month, leptin showed a decrease and adiponectin showed an increase at the 6th and 12th months of therapy, but none of these results was statistically significant (Table 4). There were no statistically significant differences in insulin, cpeptide, leptin, or other adipocytokines between male and female patients in either group (Table 5).
3
BMI (kg/m2) G0/I0 HOMA-IR Glucose (mg/dl) I˙nsulin (uIU/ml) C-peptide (ng/ml) Leptin (ng/ml) Resistin (ng/ml) Visfatin (ng/ml) Neuropeptide Y (ng/ml) Adiponectin (ng/ml)
Overweight (n = 7)
Non-overweight (n = 14)
Mean SD
Mean SD
33.7 8.2 21.4 9.7 1.1 0.6 78.3 5.1 5.6 3.2 1.1 0.5 2.9 1.6 8.3 4.3 11.1 6.1 0.5 0.2 15,151.4 4457.9
16.8 1.4 29.6 13.4 0.7 0.6 80.2 6.0 3.8 2.9 0.9 0.6 1.8 0.7 7.2 2.0 8.1 0.9 0.7 0.3 13,719.4 5656.8
p
0.001a 0.16 0.28 0.48 0.20 0.81 0.03b 0.56 0.24 0.23 0.57
BMI: body mass index, G0/I0: Fasting glucose/fasting insulin ratio, HOMA-IR: Homeostasis model assessment of insulin resistance. a p < 0.001. b p < 0.05. Table 4 Anthropometric and laboratory data in patients treated with topiramate. Parameters
Initiation Mean SD
6th month Mean SD
12th month Mean SD
Weight (kg) Height (cm) BMI (kg/m2) Glucose (mg/dl) G0/I0 HOMA-IR Insulin (uIU/ml) C-peptide (ng/ml) Leptin (ng/ml) Resistin (ng/ml) Visfatin (ng/ml) Neuropeptide Y (ng/ml) Adiponectin (ng/ml)
29.6 8.6 127.8 12.5 17.8 2.5 84.3 6.6 25.5 13.7 0.9 0.5 4.7 2.6 1.1 0.5 3.4 3.0 9.7 3.6 9.5 8.3 0.9 0.8 13,687.8 7028.4
30.5 8.9 128.4 11.9a 17.4 2.5 84.7 5.2 23.9 13.4 1.1 0.8 5.3 4.0 1.2 0.6 2.6 2.6 10.3 3.4 7.8 1.1 0.6 0.4 14,417.2 5991.8
31.5 8.4 130.7 11.9 17.4 2.3 82.1 8.6 26.3 12.6 0.8 0.7 4.4 3.2 0.9 0.5 2.4 2.1 8.9 3.6 8.8 5.6 0.7 0.5 16,594.1 8963.4
BMI: body mass index, G0/I0: fasting glucose/fasting insulin ratio. HOMA-IR: homeostasis model assessment of insulin resistance. a Comparison of 0 and 6 months: p < 0.001.
4. Discussion Table 2 Anthropometric and laboratory data in patients treated with valproate. Parameters
Initiation Mean SD
6th month Mean SD
12th month Mean SD
Weight (kg) Height (cm) BMI (kg/m2) Glucose (mg/dl) G0/I0 HOMA-IR Insulin (uIU/ml) C-peptide (ng/ml) Leptin (ng/ml) Resistin (ng/ml) Visfatin (ng/ml) Neuropeptide Y (ng/ml) Adiponectin (ng/ml)
26.3 6.8 125.0 8.7 16.6 2.5 80.8 5.2 30.9 12.4 0.6 0.3 3.3 1.8 1.1 0.5 2.1 1.6 12.9 8.1 8.1 2.1 0.8 0.3 13,086.6 3680.9
29.0 6.7a 128.6 9.9a 17.4 1.8d 81.1 7.9 31.8 12.5 0.6 0.4 3.3 2.0 1.0 0.5 2.3 1.7 8.5 3.0 8.6 3.0 0.6 0.3 13,451.7 6015.3
30.7 6.7b,c 131.3 9.9b,c 17.6 1.7e 79.6 5.7 26.9 12.7 0.8 0.6f 4.4 3.1f 1.0 0.6 2.2 1.2 7.6 2.9c 9.1 3.7 0.6 0.3 14,196.7 5219.2
BMI, body mass index. G0/I0: fasting glucose/fasting insulin ratio. HOMA-IR: homeostasis model assesment of insulin resistance. a Comparison of 0 and 6 month: p < 0.001. b Comparison of 0 and 12 months: p < 0.001. c Comparison of 6 and 12 months: p < 0.001. d Comparison of 0 and 6 months: p < 0.05. e Comparison of 0 and 12 month: p < 0.05. f Comparison of 6 and 12 months: p < 0.05.
Weight gain is one of the most common adverse effects of valproate. Although several mechanisms have been suggested, the precise mechanisms underlying the valproate-related weight gain remains unclear. Conceivable pathophyssiological mechanisms are (1) dysregulation of the hypothalamic system with valproate therapy; (2) valproate-induced hyperinsulinemia leading to IR, (3) valproate-induced hyperleptinemia leading to leptin resistance; and (4) possible interaction between valproate and adiponectin and influence of genetic factors on body weight during valproic acid therapy.8,9,20 Excessive weight gain can lead to worsened treatment compliance. Several studies reported that valproate treatment was related with excessive weight gain in children.21,22 In a oneyear prospective study, Verrotti et al.23 reported the obesity rates as 35% in 20 prepubertal girls with epilepsy. In the same study the participants were divided into two subgroups as overweight and not overweight, and hyperinsulinemia and IR were shown in the overweight group. In our study none of the valproate-treated patients gained excessive weight or became obese, but 7 of the 21 patients (33%) had become overweight after one year of follow-up. Because the patients in our study were prepubertal children, the increase in weight and height can be accepted as usual. As BMI reflects body fat, the increase in the BMI could be accepted as an indicator of valproate-related weight gain.
Please cite this article in press as: Sonmez FM, et al. The effects of topiramate and valproate therapy on insulin, c-peptide, leptin, neuropeptide Y, adiponectin, visfatin, and resistin levels in children with epilepsy. Seizure: Eur J Epilepsy (2013), http://dx.doi.org/ 10.1016/j.seizure.2013.07.007
G Model
YSEIZ-2192; No. of Pages 6
5.6 4.8 1.2 0.7 2.9 2.7 9.8 2.5 7.8 1.3 0.6 0.5 14946.0 6594.4
NPY*: Neuropeptide Y.
6 0
4.9 2.4 1.0 0.4 3.6 2.9 9.2 2.5 10.5 10.3 1.1 1.0 14375.1 7755.9 4.4 2.3 1.1 0.5 1.8 0.6 9.0 2.3 7.6 0.3 0.7 0.6 15706.9 8457.5 4.6 2.1 1.1 0.4 2.4 1.7 11.2 4.7 7.7 0.5 0.6 0.2 13435.1 4998.5 4.2 3.1 1.1 0.6 3.3 3.0 10.7 5.1 7.7 0.4 0.6 0.3 12441.3 5761.5 3.8 2.1 0.9 0.4 2.2 1.2 7.7 3.5 9.3 4.2 0.7 0.3 14466.4 3933.5 3.0 1.8 0.9 0.4 2.3 1.7 8.2 1.6 8.4 2.2 0.7 0.4 14412.5 7061.2 Insulin (uIU/ml) C-peptide (ng/ml) Leptin (ng/ml) Resistin (ng/ml) Visfatin (ng/ml) NPY* (ng/ml) Adiponectin (ng/ml)
5.0 3.9 1.1 0.8 2.2 1.2 7.5 2.3 8.9 3.4 0.6 0.3 1300.0 6569.3 3.5 2.4 1.0 0.6 2.3 1.7 8.8 4.2 8.7 3.8 0.6 0.2 12394.8 4757.9 3.9 2.0 1.2 0.3 2.4 2.2 14.8 9.0 8.7 2.9 1.1 0.9 12289.8 4725.5
2.6 1.3 0.9 0.6 1.8 0.7 11.3 7.3 7.6 0.3 0.7 0.4 13810.9 2406.1
Male (n = 13)
12 6 0
Female (n = 7)
0 6 0
6
12
Topiramate group Valproate group
12
Male (n = 11) Female (n = 10) Adipocytokines
Table 5 Gender-specific results of the insulin, c-peptide and adypocytocines.
4.4 3.7 0.9 0.6 2.7 2.6 8.8 4.2 9.4 7.0 0.7 0.5 17071.8 9825.6
F.M. Sonmez et al. / Seizure xxx (2013) xxx–xxx
12
4
The main findings in the studies about valproate-related weight gain are differences in the serum fasting glucose and insulin levels. The tendency of glucose levels to decrease is one such difference.24 Valproate itself is a derivative of fatty acids. The increase in the long-chain fatty acids increases insulin production, and decreases serum glucose concentrations.25 On the other hand valproate inhibits b-oxidation of fatty acids. In our study, valproate-treated patients showed neither a decrease in glucose levels nor a correlation between insulin and glucose levels. These findings indicate that there are additional factors. While serum insulin levels reflects the hepatic metabolism,19 the increase in insulin found in our study is thought to be due to the inhibition of hepatic insulin metabolism by valproate. Leptin is a product of the obese gene and is considered to be a signal factor that regulates body weight and energy expenditure. Obesity is associated with higher leptin levels.26 Several studies have shown an increase in leptin levels in obese compared with the nonobese patients.19,27 In our study, the reason for the lack of an increase in leptin levels might be attributed to the lack of obesity. However, when we divided the patients into groups of overweight and not overweight, the overweight group showed a significant increase in leptin levels. While these results suggested that valproate was not interacting only with leptin in appetite and energy control, they did not show that its effects were independent of leptin. Leptin regulates body weight through neuropeptide Y, which stimulates food intake and decreases energy expenditure. Neuropeptide regulates appetite via both central and peripheral mechanisms.28 In a six-month follow-up study, Aydin et al.10 showed an increase in BMI, insulin, and neuropeptide Y levels at the 3rd month of the valproate treatment. This increase was thought to also be due to the serum insulin and leptin levels or valproate-induced central and peripheral mechanisms. In our study, there was no difference in neuropeptide Y levels during the follow-up, and the lack of obesity could be a reason. Cansu et al.,11 suggested that increased serum leptin, neuropeptid Y and galanin levels play an important role in valproate associated weight gain in children.Adiponectin is an adipocyte-derived protein that plays a major role in insulin sensitivity and regulation of glucose homeostasis. Adiponectin levels are negatively correlated with BMI, IR and cardiac events.29,30 In a study in children, Rauchenzauner et al.,31 demonstrated a similar result. It was known that valproate-related weight gain is associated not only with elevated insulin and leptin levels but also decreased adiponectin levels; however, the underlying mechanisms remain unknown. In our study, no difference in adiponectin levels was demonstrated during the follow-up. When the negative correlation between adiponectin levels and visceral fat is considered, the reason for the lack of a difference in adiponectin levels may be the fact that none of our patients developed obesity. Visfatin is defined as a protein that mimics insulin action and activates intracellular signaling cascade for insulin. Haider et al.,32 suggested that high serum visfatin concentrations could be an independent factor in the development of metabolic syndrome and cause impaired glucose tolerance in obese children. However, Rauchenzauner et al.,31 did not show a difference in visfatin concentrations among obese and non-obese valproate-treated children.30 The results of the prior study are thought to be acceptable because none of the patients had visceral fat accumulation and no difference in glucose concentrations was seen. In our study, there was no difference in visfatin concentrations, and the underlying reasons may be the same. Resistin impaires insulin-stimulated glucose uptake, increases hepatic glucose production, impairs glucose tolerance, and leads to IR. Serum resistin levels increase in obesity but are positively correlated with visceral fat instead of BMI.33 The results of resistin and energy balance-associated human studies are controversial
Please cite this article in press as: Sonmez FM, et al. The effects of topiramate and valproate therapy on insulin, c-peptide, leptin, neuropeptide Y, adiponectin, visfatin, and resistin levels in children with epilepsy. Seizure: Eur J Epilepsy (2013), http://dx.doi.org/ 10.1016/j.seizure.2013.07.007
G Model
YSEIZ-2192; No. of Pages 6 F.M. Sonmez et al. / Seizure xxx (2013) xxx–xxx
and the number of studies done with children using antiepileptic drugs to clarify the mechanisms behind weight gain remains limited. Tomoum et al.,34 found no difference between resistin levels in valproate-treated children and reported that none of the patients developed obesity. In our study, resistin showed an increase at the 12th month when compared to levels at the initiation of therapy. We could not explain this contradictory result. As there are only a limited number of studies evaluating the interaction of valproate treatment, weight gain and resistin levels, more studies are needed to clarify the underlying mechanisms. Topiramate is a new-generation antiepileptic drug that affects body weight negatively.1,13,35 It was shown in some animal studies that topiramate administration causes weight loss.36,37 Topiramate inhibits white adipose tissue depots and enhances regulatory thermogenesis through its effect on lipoprotein lipase (LPL) activity in brown adipose tissue. It stimulates LPL activity in skeletal muscles and hence promotes substrate oxidation.35 LPL activity in white fat tissue leads to a decrease in fat accumulation and decreases blood glucose and triglyceride levels.38 Wilding et al.39 showed weight loss and improved blood pressure and glucose tolerance in obese patients after one year of follow-up in a clinical series of 1289 patients with epilepsy. Ben-Menachem et al.,40 reported body fat and weight loss within the 3rd month of the topiramate therapy, and they suggested that decreased calorie intake was effective in weight loss in the early stages of therapy. As weight loss increased, a decrease in leptin levels and an improvement in glucose, insulin and total cholesterol levels were seen in the same study. York et al.,41 showed that topiramate suddenly decreased food intake and increased the metabolic rate. In the same study hypothalamic neuropeptide Y was shown to be increased, leptin remained unaffected and leptin increased in the adipose tissue. However, Theisen et al.,42 could not show a relationship between topiramate-associated weight loss and leptin levels in their prospective study. Li et al.,14 conducted a study including 18 topiramate-treated children with epilepsy aged 6.8 years, and showed a decrease in BMI (the first study in childhood with topiramate). In that study, there was no difference between leptin levels before and after the treatment, but adiponectin levels were found to be increased, and the leptin/adiponectin ratio was found to be decreased. These results suggested that the increase in adiponectin levels during topiramate therapy might be an important factor in topiramate-related weight loss. The underlying mechanisms of topiramate-related weight loss remain unknown. In our study, the decrease in leptin and increase in adiponectin levels seen at the 6th and 12th months of the topiramate treatment (though failing to reach a statistical significance) and the stability in BMI of the growing children (although no significant decrease in BMI was seen) might suggest that these changes could be related to topiramate-associated weight loss. There was no difference in the other parameters. We also were unable to describe any difference in the leptin/adiponectin-ratio between the two groups. In conclusion, the mechanisms behind valproate, and topiramate-related weight control are still unclear, especially in children. Valproate and topiramate affect the weight, BMI, and insulin and leptin levels in prepubertal children. We suggest that further studies including more patients with a long follow-up period are necessary to draw a firm conclusion regarding an association between the treatment with these antiepileptic drugs and the levels of leptin, insulin, adiponectin, visfatin, neuropeptide-Y, and resistin. Ethical approval We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
5
Conflict of interest None of the authors has any conflict of interest to disclose. Acknowledgement This study was supported by the Karadeniz Technical University Research Foundation (Project number: 2006-114031). References 1. Matsuda I, Higashi A, Inotsume N. Physiologic and metabolic aspects of anticonvulsants. Pediatric Clinics of North America 1989;36:1099–109. 2. Shneker BF, Fountain NB. Epilepsy. Disease-a-Month 2003;49:426–76. 3. Chung AM, Eiland LS. Use of second-generation antiepileptic drugs in the pediatric population. Paediatric Drugs 2008;10:217–54. 4. Ben-Menachem E, Sander JW, Stefan H, Schwalen S, Scha¨uble B. Topiramate monotherapy in the treatment of newly or recently diagnosed epilepsy. Clinical Therapeutics 2008;30:1180–95. 5. Isoja¨rvi JI, Laatikainen TJ, Pakarinen AJ, Juntunen KT, Myllyla¨ VV. Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. New England Journal of Medicine 1993;329:1383–8. 6. Isojarvi JI, Laatikainen TJ, Knip M, Pakarinen AJ, Juntunen KT, Myllyla¨ VV. Obesity and endocrine disorders in women taking valproate for epilepsy. Annals of Neurology 1996;39:579–84. 7. Isoja¨rvi JI, Ra¨ttya¨ J, Myllyla¨ VV, Knip M, Koivunen R, Pakarinen AJ, et al. Valproate, lamotrigine, and insulin-mediated risks in women with epilepsy. Annals of Neurology 1998;43:446–51. 8. Verrotti A, La Torre R, Trotta R, Mohn A, Chiarelli F. Valproate-induced insulin resistance and obesity in children. Hormone Research 2009;75:125–31. 9. Luef GJ, Lechleitner M, Bauer G, Trinka E, Hengster P. Valproic acid modulates islet cell insulin secretion: a possible mechanism of weight gain in epilepsy patients. Epilepsy Research 2003;55:53–8. 10. Aydin K, Serdaroglu A, Okuyaz C, Bideci A, Gucuyener K. Serum insulin, leptin, and neuropeptide y levels in epileptic children treated with valproate. Journal of Child Neurology 2005;20:848–51. 11. Cansu A, Serdaroglu A, Camurdan O, Hirfanoglu T, Cinaz P. Serum insu¨lin, cortisol, leptin, neuropeptide Y, galanin and ghrelin levels in epileptic children receiving valproate. Hormone Research in Paediatrics 2011;76:65–71. 12. McElroy SL, Arnold LM, Shapira NA, Keck Jr PE, Rosenthal NR, Karim MR, et al. Topiramate in the treatment of binge eating disorder associated with obesity: a randomized, placebo-controlled trial. American Journal of Psychiatry 2003; 160:255–61. 13. Picard F, Deshaies Y, Lalonde J, Samson P, Richard D. Topiramate reduces energy and fat gains in lean (Fa/?) and obese (fa/fa) Zucker rats. Obesity Research 2000;8:656–63. 14. Li HF, Zou Y, Xia ZZ, Gao F, Feng JH, Yang CW. Effects of topiramate on weight and metabolism in children with epilepsy. Acta Paediatrica 2009;98:1521–5. 15. Wilkes JJ, Nelson E, Osborne M, Demarest KT, Olefsky JM. Topiramate is an insulin-sensitizing compound in vivo with direct effects on adipocytes in female ZDF rats. American Journal of Physiology – Endocrinology and Metabolism 2005;288:617–24. 16. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. From the Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia 1981;22:489-501. 17. Tanner JM, Whitehouse RH. Clinical longutidinal studies for height, weight, height velocity, and stages of puberty. Archives of Disease in Childhood 1976;51:170–9. 18. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Tumer RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in men. Diabetologia 1985;28:412–9. 19. Verrotti A, Basciani F, Morresi S, de Martino M, Morgese G, Chiarelli F. Serum leptin changes in epileptic patients who gain weight after therapy with valproic acid. Neurology 1999;53:230–2. ˜ ete RR, Gil A. Adiponectin, the missing link in 20. Gil-Campos M, Canete R, Can insulin resistance and obesity. Clinical Nutrition 2004;23:963–74. 21. Egger J, Brett EM. Effects of sodium valproate in 100 children with special reference to weight. British Medical Journal 1981;283:577–81. 22. Novak GP, Maytal J, Alshansky A, Eviatar L, Sy-Kho R, Siddique Q. Risk of excessive weight gain in epileptic children treated with valproate. Journal of Child Neurology 1999;14:490–5. 23. Verrotti A, Basciani F, De Simone M, Trotta D, Morgese G, Chiarelli F. Insulin resistance in epileptic girls who gain weight after therapy with valproic acid. Journal of Child Neurology 2002;17:265–88. 24. Demir E, Aysun S. Weight gain associated with valproate in childhood. Pediatric Neurology 2000;22:361–4. 25. Brodersen R, Jorgensen N, Vorum H, Krukow N. Valproate and palmitate binding to human serum albumin: an hypothesis on obesity. Molecular Pharmacology 1990;37:706–9. 26. Rauchenzauner M, Haberlandt E, Scholl-Bu¨rgi S, Schoenherr E, Tatarczyk T, Engl J, et al. Effect of valproic acid treatment on body composition, leptin and the soluble leptin receptor in epileptic children. Epilepsy Research 2008;80:142–9.
Please cite this article in press as: Sonmez FM, et al. The effects of topiramate and valproate therapy on insulin, c-peptide, leptin, neuropeptide Y, adiponectin, visfatin, and resistin levels in children with epilepsy. Seizure: Eur J Epilepsy (2013), http://dx.doi.org/ 10.1016/j.seizure.2013.07.007
G Model
YSEIZ-2192; No. of Pages 6 6
F.M. Sonmez et al. / Seizure xxx (2013) xxx–xxx
27. Pylva¨nen V, Knip M, Pakarinen A, Kotila M, Turkka J, Isoja¨rvi JI. Serum insulin and leptin levels in valproate-associated obesity. Epilepsia 2002;43:514–7. 28. Gehlert DR. Role of hypothalamic neuropeptide Y in feeding and obesity. Neuropeptides 1999;33:329–38. 29. Chandran M, Phillips SA, Ciaraldi T, Henry RR. Adiponectin: more than just another fat cell hormone? Diabetes Care 2003;26:2442–50. 30. Korner A, Kratzsch J, Gausche R, Schaab M, Erbs S, Kiess W. New predictors of the metabolic syndrome in children-role of adipocytokines. Pediatric Research 2007;61:640–5. 31. Rauchenzauner M, Haberlandt E, Scholl-Bu¨rgi S, Ernst B, Hoppichler F, Karall D, et al. Adiponectin and visfatin concentrations in children treated with valproic acid. Epilepsia 2008;49:353–7. 32. Haider DG, Holzer G, Schaller G, Weghuber D, Widhalm K, Wagner O, et al. The adipokine visfatin is markedly elevated in obese children. Journal of Pediatric Gastroenterology and Nutrition 2006;43:548–9. 33. Rajala MW, Obici S, Scherer PE, Rossetti L. Adipose-derived resistin and gutderived resistin-like molecule-beta selectively impair insulin action on glucose production. Journal of Clinical Investigation 2003;111:225–30. 34. Tomoum HY, El-Hadidi ES. Ghrelin and resistin levels in children with epilepsy on valproic acid. Journal of Pediatric Neurology 2009;7:223–9. 35. Richard D, Ferland J, Lalonde J, Samson P, Deshaies Y. Influence of topiramate in the regulation of energy balance. Nutrition 2000;16:961–6. 36. Liang Y, Chen X, Osborne M, DeCarlo SO, Jetton TL, Demarest K. Topiramate ameliorates hyperglycaemia and improves glucose-stimulated insulin
37.
38.
39.
40.
41.
42.
release in ZDF rats and db/db mice. Diabetes Obesity and Metabolism 2005;7: 360–9. Lalonde J, Samson P, Poulin S, Deshaies Y, Richard D. Additive effects of leptin and topiramate in reducing fat deposition in lean and obese ob/ob mice. Physiology and Behavior 2004;80:415–20. Frigerio F, Chaffard G, Berwaer M, Maechler P. The antiepileptic drug topiramate preserves metabolism-secretion coupling in insulin secreting cells chronically exposed to the fatty acid oleate. Biochemical Pharmacology 2006;72:965–73. Wilding J, Van Gaal L, Rissanen A, Vercruysse F, Fitchet M, OBES-002 Study Group. A randomized double-blind placebo-controlled study of the longterm efficacy and safety of topiramate in the treatment of obese subjects. International Journal of Obesity and Related Metabolic Disorders 2004;28: 1399–410. Ben-Menachem E, Axelsen M, Axelsen M, Johanson EH, Stagge A, Smith U. Predictors of weight loss in adults with topiramate-treated epilepsy. Obesity Research 2003;11:556–62. York DA, Singer L, Thomas S, Bray GA. Effect of topiramate on body weight and body composition of osborne-mendel rats fed a high-fat diet: alterations in hormones, neuropeptide, and uncoupling-protein mRNAs. Nutrition 2000;16: 967–75. Theisen FM, Beyenburg S, Gebhardt S, Kluge M, Blum WF, Remschmidt H, et al. A prospective study of body weight and serum leptin levels in patients treated with topiramate. Clinical Neuropharmacology 2008;31:226–30.
Please cite this article in press as: Sonmez FM, et al. The effects of topiramate and valproate therapy on insulin, c-peptide, leptin, neuropeptide Y, adiponectin, visfatin, and resistin levels in children with epilepsy. Seizure: Eur J Epilepsy (2013), http://dx.doi.org/ 10.1016/j.seizure.2013.07.007
YSEIZ-2192; No. of Pages 6 Seizure xxx (2013) xxx–xxx
Contents lists available at ScienceDirect
Seizure journal homepage: www.elsevier.com/locate/yseiz
The effects of topiramate and valproate therapy on insulin, c-peptide, leptin, neuropeptide Y, adiponectin, visfatin, and resistin levels in children with epilepsy Fatma Mujgan Sonmez a,*, Dilek Zaman b, Ayse Aksoy c, Orhan Deger d, Rezzan Aliyazicioglu d, Gu¨lay Karaguzel e, Kerim Fazlioglu f a
Turgut Ozal University, Faculty of Medicine, Department of Child Neurology, Ankara, Turkey Giresun University, Faculty of Medicine, Department of Pediatrics, Giresun, Turkey c Sami Ulus Hospital, Department of Child Neurology, Ankara, Turkey d Karadeniz Technical University, Faculty of Medicine, Department of Biochemistry, Trabzon, Turkey e Karadeniz Technical University, Faculty of Medicine, Department of Pediatric Endocrinology, Trabzon, Turkey f Karadeniz Technical University, Faculty of Medicine, Department of Child Neurology, Trabzon, Turkey b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 11 March 2013 Received in revised form 9 July 2013 Accepted 11 July 2013
Purpose: Antiepileptic drugs may affect the endocrine system. We investigated the effects of valproic acid and topiramate on the levels of insulin, c-peptide and adipocytokines in pre-pubertal patients with idiopathic partial and generalized epilepsy. Methods: Forty-one children with epilepsy were included. The patients were divided into two groups (valproic acid; n = 21, topiramate; n = 20). The weight, height, body mass index and homeostasis model assessment of insulin resistance (HOMA-IR) were recorded and insulin, c-peptide, leptin, neuropeptide Y, adiponectin, visfatin and resistin levels were determined at 0, 6 and 12 months of therapy. Results: In the valproate group, weight and height increased significantly. Seven of 21 patients were overweight at the end of one year. Leptin was higher in the overweight subgroup. Although insulin and HOMA-IR increased (p < 0.05), none of the patients showed hyperinsulinism or IR. Resistin had decreased at the 6th and 12th months (p < 0.05). In the topiramate group, some statistically nonsignificant changes were demonstrated. Conclusion: The mechanisms behind valproate and topiramate-related weight control are still unclear, especially in children. Valproate and topiramate affect the weight, BMI, and insulin, leptin and adipocytokine levels in prepubertal children. We suggest that further studies including more patients with a long follow-up period are necessary to draw a firm conclusion regarding an association between the treatment with these drugs and the levels of leptin, insulin and adipocytokines. ß 2013 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Keywords: Valproate Topiramate Weight Adipocytokines Insulin C-peptide
1. Introduction Epilepsy is among the common chronic illnesses of childhood. Anticonvulsant drugs are used for its long-term treatment. This therapy may be associated with several metabolic abnormalities.1 Valproate is a broad-spectrum antiepileptic drug used effectively in both partial and generalized seizures.2 Topiramate is a new generation antiepileptic drug. In mid 2005 it was approved as monotherapy in adults and children over 2 years.3,4 Although
* Corresponding author. Current address: Turgut Ozal University, Faculty of Medicine, Department of Child Neurology, Alparslan Turkes Caddesi, No: 57 Emek, Ankara, Turkey. Tel.: +90 312 2035151; mobile: +90 533 654 8654. E-mail addresses: [email protected], [email protected] (F.M. Sonmez).
many endocrinologic side effects have been reported with valproate such as polycystic ovaries and hyperadrogenism the most striking seem to be weight gain for valproate and weight loss for topiramate.5 It was demonstrated in several studies that valproate is associated with weight gain in approximately half of the patients among both males and females.5–7 Although several mechanisms have been implicated, those underlying valproate-related weight gain remain unknown.8,9 The roles of hyperinsulinemia and insulin resistance (IR) as well as of leptin, ghrelin and neuropeptide Y levels have been investigated in patients with epilepsy who gained weight, primarily in adults. However, studies including children with epilepsy have been limited and the results appear controversial.10,11 It was shown that topiramate is effective in the treatment of eating disorders and may cause energy expenditure in rats, but the
1059-1311/$ – see front matter ß 2013 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.seizure.2013.07.007
Please cite this article in press as: Sonmez FM, et al. The effects of topiramate and valproate therapy on insulin, c-peptide, leptin, neuropeptide Y, adiponectin, visfatin, and resistin levels in children with epilepsy. Seizure: Eur J Epilepsy (2013), http://dx.doi.org/ 10.1016/j.seizure.2013.07.007
G Model
YSEIZ-2192; No. of Pages 6 2
F.M. Sonmez et al. / Seizure xxx (2013) xxx–xxx
latter could not be demonstrated in humans.12,13 Human studies investigating the mechanisms of topiramate in weight control are limited. Although some of the study results have shown the role of decreased leptin levels, increased adiponectin levels and increased insulin sensitivity, the mechanisms behind the topiramate-related weight loss are still unknown.14,15 The purpose of this study was to evaluate possible changes in insulin, c-peptide, leptin, neuropeptide Y, adiponectin, visfatin and resistin levels during valproate or topiramate therapies and their role in the weight status of children with epilepsy. 2. Methods and materials This study was carried out in the Department of Pediatric Neurology with the approval of the Hospital Ethics Committee, and was supported by the University Scientific Research Found. Epilepsy type was classified according to the recommendations of the International League Against Epilepsy. Written informed parental consent was obtained from all participating subjects.16 2.1. Subjects During the period July 2007–July 2008, 46 prepubertal patients (ages range between 6 and 12 years; mean age: 8.3 1.7 years) with a history of new-onset seizure and who were diagnosed as idiopathic generalized or partial epilepsy were included in this study. The study was completed with 41 of the 46 enrolled patients aged between 6 and 12 years. The study group consisted of 17 females (mean age: 8.7 0.5 years) and 24 males (mean age: 8.0 0.3 years). The epilepsy diagnosis was based on history, neurologic examination, electroencephalography (EEG), and magnetic resonance imaging (MRI). Patients with symptoms and signs of illnesses other than epilepsy (e.g. endocrine, metabolic, hepatic, or renal diseases), a history of status epilepticus, previous use of any antiepileptic drugs, or previous use of drugs affecting calorie intake were not included in the study. All patients had a normal neurologic examination and normal cranial MRI findings. The patients were divided into two groups according to their drug therapy. Group 1 consisted of 24 patients, mean age 8.0 1.6 years, who received sodium valproate, 20 mg/kg/day, twice Daily, and group 2 consisted of 22 patients, mean age 8.6 1.7 years, who received topiramate 3 mg/kg/day, twice daily. 2.2. Methods All patients were clinically examined and interviewed by the first author. Weight and height were measured and weight z score and body mass index (BMI; as weight [in kilograms] divided by height [in meters] squared) were calculated before the initiation of the therapy and at the 6th and 12th months of therapy. All patients with a BMI between the 85th and 95th percentiles for age and gender were classified as overweight and those above the 95th percentile for age and gender as obese. Pubertal development was assessed according to Tanner stages and Tanner I patients were included in the study.17 Blood samples were obtained at 8 a.m. after an overnight fast for the analysis of serum insulin, c-peptide, leptin, neuropeptide Y, adiponectin, visfatin, resistin and valproate concentrations. The analyses were done before the initiation of therapy and at the 6th and 12th months of the therapy. Topiramate concentrations could not be measured. Plasma glucose concentrations were also measured and the fasting serum glucose to insulin (G0/I0) ratio was calculated. IR was estimated using the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR, fasting insulin x fasting glucose/22.5).18 IR is defined as HOMA-IR levels 3.16 according to the following equation: insulin (uIU/ml) [glucose (mg/dl) 0.055/22.5].
2.3. Assays Serum samples were frozen at 70 8C until analyzed. Serum glucose concentrations were measured by Roche Modular Autoanalyzer using commercial Roche diagnostic kits by enzymatic calorimetric method. The concentrations of insulin and c-peptide were analyzed with chemiluminescence immunometric assay using a DPC-Immulite 2000 autoanalyzer. Leptin concentrations were analyzed with an enzyme-amplified sensitivity immunoassay using kits from BioSource Co. Neuropeptide Y and visfatin concentrations were analyzed with a competitive enzyme immunoassay by using kits from Phoenix Pharmaceuticals Co. Adiponectin and resistin concentrations were analyzed with an enzyme-linked immunosorbent assay using kits from Linco Research Co. 2.4. Statistical analysis Statistical analyses were performed using the Statistical Package for The Social Sciences software (SPSS 13.0.1 serial number: 9069728). The chi-square test was used to compare qualitative datas. In each group, the conformity of the measured values to normal distribution was analyzed using Kolmogorov– Smirnov test. Variation during the period for the data that conformed to normal distribution was analyzed by repeated measures ANOVA (post hoc by paired t test), and the data showing skewed distribution were analyzed using Friedman test (post hoc by Wilcoxon test) in each group. When comparing the two groups, the data conforming to normal distribution were analyzed using Student t test and data showing skewed distribution by Mann– Whitney-U test, and correlations were analyzed by Pearson’s test. A value of p < 0.05 was determined as statistically significant. 3. Results The study was completed with 41 of the 46 enrolled patients. Five patients (3 from group 1 and 2 from group 2) dropped out of the study because of uncontrolled seizures with monotherapy and were treated at another center. Thus, evaluations were made based on the results of 41 patients (17 females, 24 males) aged between 6 and 12 years. The mean age of the patients was 8.3 1.7 years. Patients were divided into two groups according to their drug therapy. Group 1 (sodium valproate) consisted of 21 patients (10 females, 11 males; mean age 8.0 1.6 years), and group 2 (topiramate) consisted of 20 patients (7 females, 13 males; mean age: 8.5 1.8 years). There was no statistically significant difference between the two patient groups with respect to the mean age. Epilepsy types were generalized in 9 patients (7 in group 1, 2 in group 2) and partial seizures in 32 patients (14 in group 1, 18 in group 2). The most common seizure types were complex partial in 21 patients (51.5%) and simple partial in 11 patients (27%) (Table 1). The most common EEG finding was focal epileptiform activity (58.5%) (Table 1). The rate of seizure control was similar between the two groups. In the valproate-treated group weight and height increased significantly both at the 6th and 12th months (p < 0.0005). BMI increased significantly at the 12th month compared with the values at the 6th month of the therapy (p < 0.05) (Table 2). None of the patients had become obese during the one-year-follow-up. Although only 1 patient (4.7%) was overweight at the initiation of the therapy, 4 patients at the 6th month (19%) and 7 patients at the 12th month (33%) had become overweight. When overweight and non-overweight patients were compared, leptin levels were found to be higher in the overweight group (p = 0.03). There were no differences in the other laboratory parameters between the overweight and non-overweight groups (Table 3).
Please cite this article in press as: Sonmez FM, et al. The effects of topiramate and valproate therapy on insulin, c-peptide, leptin, neuropeptide Y, adiponectin, visfatin, and resistin levels in children with epilepsy. Seizure: Eur J Epilepsy (2013), http://dx.doi.org/ 10.1016/j.seizure.2013.07.007
G Model
YSEIZ-2192; No. of Pages 6 F.M. Sonmez et al. / Seizure xxx (2013) xxx–xxx Table 1 Seizure type and EEG findings of the patients. Seizure type
n
Simple partial Complex partial GTC Tonic Clonic Absance
11 21 3 1 3 2
Total
41
% 27 51.5 7 2.5 7 5
100
EEG findings
n
%
Epileptiform activity Focal 24 Generalized 6 Paroxysmal abnormality Focal 6 Generalized 3 Normal 2 Total
41
Table 3 The comparison of BMI and laboratory data among overweight and non overweight patients in VPA treated group.
58.5 14.6 14.6 7.3 5 100
GTC, generalized tonic-clonic.
In the valproate treated group, fasting glucose concentrations and the G0/I0 ratio did not differ at 0, 6 and 12 months of therapy. Although insulin levels and HOMA-IR increased during the followup (p = 0.038 and p = 0.036), none of the patients showed hyperinsulinism or IR. Resistin levels decreased significantly at the 6th and 12th months of therapy when compared to the levels at the initiation of the therapy (p = 0.001), but there was no correlation between resistin levels and BMI. There was no significant difference in c-peptide, visfatin and neuropeptide Y levels during the follow-up (Table 4). In the topiramate-treated group there was no difference in weight, height, BMI, fasting glucose concentrations, HOMA-IR, cpeptide, visfatin, and neuropeptide Y levels. Although the participating children did not lose weight during topiramate therapy, they also did not gain weight. It can thus be speculated that the absence of a weight gain despite their being in a period of growth may be the result of the anorectic effect of topiramate. Insulin levels tended to increase at the 6th month of the therapy, but this increase was not significant. Resistin levels increased at the 6th month but decreased at the 12th month, leptin showed a decrease and adiponectin showed an increase at the 6th and 12th months of therapy, but none of these results was statistically significant (Table 4). There were no statistically significant differences in insulin, cpeptide, leptin, or other adipocytokines between male and female patients in either group (Table 5).
3
BMI (kg/m2) G0/I0 HOMA-IR Glucose (mg/dl) I˙nsulin (uIU/ml) C-peptide (ng/ml) Leptin (ng/ml) Resistin (ng/ml) Visfatin (ng/ml) Neuropeptide Y (ng/ml) Adiponectin (ng/ml)
Overweight (n = 7)
Non-overweight (n = 14)
Mean SD
Mean SD
33.7 8.2 21.4 9.7 1.1 0.6 78.3 5.1 5.6 3.2 1.1 0.5 2.9 1.6 8.3 4.3 11.1 6.1 0.5 0.2 15,151.4 4457.9
16.8 1.4 29.6 13.4 0.7 0.6 80.2 6.0 3.8 2.9 0.9 0.6 1.8 0.7 7.2 2.0 8.1 0.9 0.7 0.3 13,719.4 5656.8
p
0.001a 0.16 0.28 0.48 0.20 0.81 0.03b 0.56 0.24 0.23 0.57
BMI: body mass index, G0/I0: Fasting glucose/fasting insulin ratio, HOMA-IR: Homeostasis model assessment of insulin resistance. a p < 0.001. b p < 0.05. Table 4 Anthropometric and laboratory data in patients treated with topiramate. Parameters
Initiation Mean SD
6th month Mean SD
12th month Mean SD
Weight (kg) Height (cm) BMI (kg/m2) Glucose (mg/dl) G0/I0 HOMA-IR Insulin (uIU/ml) C-peptide (ng/ml) Leptin (ng/ml) Resistin (ng/ml) Visfatin (ng/ml) Neuropeptide Y (ng/ml) Adiponectin (ng/ml)
29.6 8.6 127.8 12.5 17.8 2.5 84.3 6.6 25.5 13.7 0.9 0.5 4.7 2.6 1.1 0.5 3.4 3.0 9.7 3.6 9.5 8.3 0.9 0.8 13,687.8 7028.4
30.5 8.9 128.4 11.9a 17.4 2.5 84.7 5.2 23.9 13.4 1.1 0.8 5.3 4.0 1.2 0.6 2.6 2.6 10.3 3.4 7.8 1.1 0.6 0.4 14,417.2 5991.8
31.5 8.4 130.7 11.9 17.4 2.3 82.1 8.6 26.3 12.6 0.8 0.7 4.4 3.2 0.9 0.5 2.4 2.1 8.9 3.6 8.8 5.6 0.7 0.5 16,594.1 8963.4
BMI: body mass index, G0/I0: fasting glucose/fasting insulin ratio. HOMA-IR: homeostasis model assessment of insulin resistance. a Comparison of 0 and 6 months: p < 0.001.
4. Discussion Table 2 Anthropometric and laboratory data in patients treated with valproate. Parameters
Initiation Mean SD
6th month Mean SD
12th month Mean SD
Weight (kg) Height (cm) BMI (kg/m2) Glucose (mg/dl) G0/I0 HOMA-IR Insulin (uIU/ml) C-peptide (ng/ml) Leptin (ng/ml) Resistin (ng/ml) Visfatin (ng/ml) Neuropeptide Y (ng/ml) Adiponectin (ng/ml)
26.3 6.8 125.0 8.7 16.6 2.5 80.8 5.2 30.9 12.4 0.6 0.3 3.3 1.8 1.1 0.5 2.1 1.6 12.9 8.1 8.1 2.1 0.8 0.3 13,086.6 3680.9
29.0 6.7a 128.6 9.9a 17.4 1.8d 81.1 7.9 31.8 12.5 0.6 0.4 3.3 2.0 1.0 0.5 2.3 1.7 8.5 3.0 8.6 3.0 0.6 0.3 13,451.7 6015.3
30.7 6.7b,c 131.3 9.9b,c 17.6 1.7e 79.6 5.7 26.9 12.7 0.8 0.6f 4.4 3.1f 1.0 0.6 2.2 1.2 7.6 2.9c 9.1 3.7 0.6 0.3 14,196.7 5219.2
BMI, body mass index. G0/I0: fasting glucose/fasting insulin ratio. HOMA-IR: homeostasis model assesment of insulin resistance. a Comparison of 0 and 6 month: p < 0.001. b Comparison of 0 and 12 months: p < 0.001. c Comparison of 6 and 12 months: p < 0.001. d Comparison of 0 and 6 months: p < 0.05. e Comparison of 0 and 12 month: p < 0.05. f Comparison of 6 and 12 months: p < 0.05.
Weight gain is one of the most common adverse effects of valproate. Although several mechanisms have been suggested, the precise mechanisms underlying the valproate-related weight gain remains unclear. Conceivable pathophyssiological mechanisms are (1) dysregulation of the hypothalamic system with valproate therapy; (2) valproate-induced hyperinsulinemia leading to IR, (3) valproate-induced hyperleptinemia leading to leptin resistance; and (4) possible interaction between valproate and adiponectin and influence of genetic factors on body weight during valproic acid therapy.8,9,20 Excessive weight gain can lead to worsened treatment compliance. Several studies reported that valproate treatment was related with excessive weight gain in children.21,22 In a oneyear prospective study, Verrotti et al.23 reported the obesity rates as 35% in 20 prepubertal girls with epilepsy. In the same study the participants were divided into two subgroups as overweight and not overweight, and hyperinsulinemia and IR were shown in the overweight group. In our study none of the valproate-treated patients gained excessive weight or became obese, but 7 of the 21 patients (33%) had become overweight after one year of follow-up. Because the patients in our study were prepubertal children, the increase in weight and height can be accepted as usual. As BMI reflects body fat, the increase in the BMI could be accepted as an indicator of valproate-related weight gain.
Please cite this article in press as: Sonmez FM, et al. The effects of topiramate and valproate therapy on insulin, c-peptide, leptin, neuropeptide Y, adiponectin, visfatin, and resistin levels in children with epilepsy. Seizure: Eur J Epilepsy (2013), http://dx.doi.org/ 10.1016/j.seizure.2013.07.007
G Model
YSEIZ-2192; No. of Pages 6
5.6 4.8 1.2 0.7 2.9 2.7 9.8 2.5 7.8 1.3 0.6 0.5 14946.0 6594.4
NPY*: Neuropeptide Y.
6 0
4.9 2.4 1.0 0.4 3.6 2.9 9.2 2.5 10.5 10.3 1.1 1.0 14375.1 7755.9 4.4 2.3 1.1 0.5 1.8 0.6 9.0 2.3 7.6 0.3 0.7 0.6 15706.9 8457.5 4.6 2.1 1.1 0.4 2.4 1.7 11.2 4.7 7.7 0.5 0.6 0.2 13435.1 4998.5 4.2 3.1 1.1 0.6 3.3 3.0 10.7 5.1 7.7 0.4 0.6 0.3 12441.3 5761.5 3.8 2.1 0.9 0.4 2.2 1.2 7.7 3.5 9.3 4.2 0.7 0.3 14466.4 3933.5 3.0 1.8 0.9 0.4 2.3 1.7 8.2 1.6 8.4 2.2 0.7 0.4 14412.5 7061.2 Insulin (uIU/ml) C-peptide (ng/ml) Leptin (ng/ml) Resistin (ng/ml) Visfatin (ng/ml) NPY* (ng/ml) Adiponectin (ng/ml)
5.0 3.9 1.1 0.8 2.2 1.2 7.5 2.3 8.9 3.4 0.6 0.3 1300.0 6569.3 3.5 2.4 1.0 0.6 2.3 1.7 8.8 4.2 8.7 3.8 0.6 0.2 12394.8 4757.9 3.9 2.0 1.2 0.3 2.4 2.2 14.8 9.0 8.7 2.9 1.1 0.9 12289.8 4725.5
2.6 1.3 0.9 0.6 1.8 0.7 11.3 7.3 7.6 0.3 0.7 0.4 13810.9 2406.1
Male (n = 13)
12 6 0
Female (n = 7)
0 6 0
6
12
Topiramate group Valproate group
12
Male (n = 11) Female (n = 10) Adipocytokines
Table 5 Gender-specific results of the insulin, c-peptide and adypocytocines.
4.4 3.7 0.9 0.6 2.7 2.6 8.8 4.2 9.4 7.0 0.7 0.5 17071.8 9825.6
F.M. Sonmez et al. / Seizure xxx (2013) xxx–xxx
12
4
The main findings in the studies about valproate-related weight gain are differences in the serum fasting glucose and insulin levels. The tendency of glucose levels to decrease is one such difference.24 Valproate itself is a derivative of fatty acids. The increase in the long-chain fatty acids increases insulin production, and decreases serum glucose concentrations.25 On the other hand valproate inhibits b-oxidation of fatty acids. In our study, valproate-treated patients showed neither a decrease in glucose levels nor a correlation between insulin and glucose levels. These findings indicate that there are additional factors. While serum insulin levels reflects the hepatic metabolism,19 the increase in insulin found in our study is thought to be due to the inhibition of hepatic insulin metabolism by valproate. Leptin is a product of the obese gene and is considered to be a signal factor that regulates body weight and energy expenditure. Obesity is associated with higher leptin levels.26 Several studies have shown an increase in leptin levels in obese compared with the nonobese patients.19,27 In our study, the reason for the lack of an increase in leptin levels might be attributed to the lack of obesity. However, when we divided the patients into groups of overweight and not overweight, the overweight group showed a significant increase in leptin levels. While these results suggested that valproate was not interacting only with leptin in appetite and energy control, they did not show that its effects were independent of leptin. Leptin regulates body weight through neuropeptide Y, which stimulates food intake and decreases energy expenditure. Neuropeptide regulates appetite via both central and peripheral mechanisms.28 In a six-month follow-up study, Aydin et al.10 showed an increase in BMI, insulin, and neuropeptide Y levels at the 3rd month of the valproate treatment. This increase was thought to also be due to the serum insulin and leptin levels or valproate-induced central and peripheral mechanisms. In our study, there was no difference in neuropeptide Y levels during the follow-up, and the lack of obesity could be a reason. Cansu et al.,11 suggested that increased serum leptin, neuropeptid Y and galanin levels play an important role in valproate associated weight gain in children.Adiponectin is an adipocyte-derived protein that plays a major role in insulin sensitivity and regulation of glucose homeostasis. Adiponectin levels are negatively correlated with BMI, IR and cardiac events.29,30 In a study in children, Rauchenzauner et al.,31 demonstrated a similar result. It was known that valproate-related weight gain is associated not only with elevated insulin and leptin levels but also decreased adiponectin levels; however, the underlying mechanisms remain unknown. In our study, no difference in adiponectin levels was demonstrated during the follow-up. When the negative correlation between adiponectin levels and visceral fat is considered, the reason for the lack of a difference in adiponectin levels may be the fact that none of our patients developed obesity. Visfatin is defined as a protein that mimics insulin action and activates intracellular signaling cascade for insulin. Haider et al.,32 suggested that high serum visfatin concentrations could be an independent factor in the development of metabolic syndrome and cause impaired glucose tolerance in obese children. However, Rauchenzauner et al.,31 did not show a difference in visfatin concentrations among obese and non-obese valproate-treated children.30 The results of the prior study are thought to be acceptable because none of the patients had visceral fat accumulation and no difference in glucose concentrations was seen. In our study, there was no difference in visfatin concentrations, and the underlying reasons may be the same. Resistin impaires insulin-stimulated glucose uptake, increases hepatic glucose production, impairs glucose tolerance, and leads to IR. Serum resistin levels increase in obesity but are positively correlated with visceral fat instead of BMI.33 The results of resistin and energy balance-associated human studies are controversial
Please cite this article in press as: Sonmez FM, et al. The effects of topiramate and valproate therapy on insulin, c-peptide, leptin, neuropeptide Y, adiponectin, visfatin, and resistin levels in children with epilepsy. Seizure: Eur J Epilepsy (2013), http://dx.doi.org/ 10.1016/j.seizure.2013.07.007
G Model
YSEIZ-2192; No. of Pages 6 F.M. Sonmez et al. / Seizure xxx (2013) xxx–xxx
and the number of studies done with children using antiepileptic drugs to clarify the mechanisms behind weight gain remains limited. Tomoum et al.,34 found no difference between resistin levels in valproate-treated children and reported that none of the patients developed obesity. In our study, resistin showed an increase at the 12th month when compared to levels at the initiation of therapy. We could not explain this contradictory result. As there are only a limited number of studies evaluating the interaction of valproate treatment, weight gain and resistin levels, more studies are needed to clarify the underlying mechanisms. Topiramate is a new-generation antiepileptic drug that affects body weight negatively.1,13,35 It was shown in some animal studies that topiramate administration causes weight loss.36,37 Topiramate inhibits white adipose tissue depots and enhances regulatory thermogenesis through its effect on lipoprotein lipase (LPL) activity in brown adipose tissue. It stimulates LPL activity in skeletal muscles and hence promotes substrate oxidation.35 LPL activity in white fat tissue leads to a decrease in fat accumulation and decreases blood glucose and triglyceride levels.38 Wilding et al.39 showed weight loss and improved blood pressure and glucose tolerance in obese patients after one year of follow-up in a clinical series of 1289 patients with epilepsy. Ben-Menachem et al.,40 reported body fat and weight loss within the 3rd month of the topiramate therapy, and they suggested that decreased calorie intake was effective in weight loss in the early stages of therapy. As weight loss increased, a decrease in leptin levels and an improvement in glucose, insulin and total cholesterol levels were seen in the same study. York et al.,41 showed that topiramate suddenly decreased food intake and increased the metabolic rate. In the same study hypothalamic neuropeptide Y was shown to be increased, leptin remained unaffected and leptin increased in the adipose tissue. However, Theisen et al.,42 could not show a relationship between topiramate-associated weight loss and leptin levels in their prospective study. Li et al.,14 conducted a study including 18 topiramate-treated children with epilepsy aged 6.8 years, and showed a decrease in BMI (the first study in childhood with topiramate). In that study, there was no difference between leptin levels before and after the treatment, but adiponectin levels were found to be increased, and the leptin/adiponectin ratio was found to be decreased. These results suggested that the increase in adiponectin levels during topiramate therapy might be an important factor in topiramate-related weight loss. The underlying mechanisms of topiramate-related weight loss remain unknown. In our study, the decrease in leptin and increase in adiponectin levels seen at the 6th and 12th months of the topiramate treatment (though failing to reach a statistical significance) and the stability in BMI of the growing children (although no significant decrease in BMI was seen) might suggest that these changes could be related to topiramate-associated weight loss. There was no difference in the other parameters. We also were unable to describe any difference in the leptin/adiponectin-ratio between the two groups. In conclusion, the mechanisms behind valproate, and topiramate-related weight control are still unclear, especially in children. Valproate and topiramate affect the weight, BMI, and insulin and leptin levels in prepubertal children. We suggest that further studies including more patients with a long follow-up period are necessary to draw a firm conclusion regarding an association between the treatment with these antiepileptic drugs and the levels of leptin, insulin, adiponectin, visfatin, neuropeptide-Y, and resistin. Ethical approval We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
5
Conflict of interest None of the authors has any conflict of interest to disclose. Acknowledgement This study was supported by the Karadeniz Technical University Research Foundation (Project number: 2006-114031). References 1. Matsuda I, Higashi A, Inotsume N. Physiologic and metabolic aspects of anticonvulsants. Pediatric Clinics of North America 1989;36:1099–109. 2. Shneker BF, Fountain NB. Epilepsy. Disease-a-Month 2003;49:426–76. 3. Chung AM, Eiland LS. Use of second-generation antiepileptic drugs in the pediatric population. Paediatric Drugs 2008;10:217–54. 4. Ben-Menachem E, Sander JW, Stefan H, Schwalen S, Scha¨uble B. Topiramate monotherapy in the treatment of newly or recently diagnosed epilepsy. Clinical Therapeutics 2008;30:1180–95. 5. Isoja¨rvi JI, Laatikainen TJ, Pakarinen AJ, Juntunen KT, Myllyla¨ VV. Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. New England Journal of Medicine 1993;329:1383–8. 6. Isojarvi JI, Laatikainen TJ, Knip M, Pakarinen AJ, Juntunen KT, Myllyla¨ VV. Obesity and endocrine disorders in women taking valproate for epilepsy. Annals of Neurology 1996;39:579–84. 7. Isoja¨rvi JI, Ra¨ttya¨ J, Myllyla¨ VV, Knip M, Koivunen R, Pakarinen AJ, et al. Valproate, lamotrigine, and insulin-mediated risks in women with epilepsy. Annals of Neurology 1998;43:446–51. 8. Verrotti A, La Torre R, Trotta R, Mohn A, Chiarelli F. Valproate-induced insulin resistance and obesity in children. Hormone Research 2009;75:125–31. 9. Luef GJ, Lechleitner M, Bauer G, Trinka E, Hengster P. Valproic acid modulates islet cell insulin secretion: a possible mechanism of weight gain in epilepsy patients. Epilepsy Research 2003;55:53–8. 10. Aydin K, Serdaroglu A, Okuyaz C, Bideci A, Gucuyener K. Serum insulin, leptin, and neuropeptide y levels in epileptic children treated with valproate. Journal of Child Neurology 2005;20:848–51. 11. Cansu A, Serdaroglu A, Camurdan O, Hirfanoglu T, Cinaz P. Serum insu¨lin, cortisol, leptin, neuropeptide Y, galanin and ghrelin levels in epileptic children receiving valproate. Hormone Research in Paediatrics 2011;76:65–71. 12. McElroy SL, Arnold LM, Shapira NA, Keck Jr PE, Rosenthal NR, Karim MR, et al. Topiramate in the treatment of binge eating disorder associated with obesity: a randomized, placebo-controlled trial. American Journal of Psychiatry 2003; 160:255–61. 13. Picard F, Deshaies Y, Lalonde J, Samson P, Richard D. Topiramate reduces energy and fat gains in lean (Fa/?) and obese (fa/fa) Zucker rats. Obesity Research 2000;8:656–63. 14. Li HF, Zou Y, Xia ZZ, Gao F, Feng JH, Yang CW. Effects of topiramate on weight and metabolism in children with epilepsy. Acta Paediatrica 2009;98:1521–5. 15. Wilkes JJ, Nelson E, Osborne M, Demarest KT, Olefsky JM. Topiramate is an insulin-sensitizing compound in vivo with direct effects on adipocytes in female ZDF rats. American Journal of Physiology – Endocrinology and Metabolism 2005;288:617–24. 16. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. From the Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia 1981;22:489-501. 17. Tanner JM, Whitehouse RH. Clinical longutidinal studies for height, weight, height velocity, and stages of puberty. Archives of Disease in Childhood 1976;51:170–9. 18. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Tumer RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in men. Diabetologia 1985;28:412–9. 19. Verrotti A, Basciani F, Morresi S, de Martino M, Morgese G, Chiarelli F. Serum leptin changes in epileptic patients who gain weight after therapy with valproic acid. Neurology 1999;53:230–2. ˜ ete RR, Gil A. Adiponectin, the missing link in 20. Gil-Campos M, Canete R, Can insulin resistance and obesity. Clinical Nutrition 2004;23:963–74. 21. Egger J, Brett EM. Effects of sodium valproate in 100 children with special reference to weight. British Medical Journal 1981;283:577–81. 22. Novak GP, Maytal J, Alshansky A, Eviatar L, Sy-Kho R, Siddique Q. Risk of excessive weight gain in epileptic children treated with valproate. Journal of Child Neurology 1999;14:490–5. 23. Verrotti A, Basciani F, De Simone M, Trotta D, Morgese G, Chiarelli F. Insulin resistance in epileptic girls who gain weight after therapy with valproic acid. Journal of Child Neurology 2002;17:265–88. 24. Demir E, Aysun S. Weight gain associated with valproate in childhood. Pediatric Neurology 2000;22:361–4. 25. Brodersen R, Jorgensen N, Vorum H, Krukow N. Valproate and palmitate binding to human serum albumin: an hypothesis on obesity. Molecular Pharmacology 1990;37:706–9. 26. Rauchenzauner M, Haberlandt E, Scholl-Bu¨rgi S, Schoenherr E, Tatarczyk T, Engl J, et al. Effect of valproic acid treatment on body composition, leptin and the soluble leptin receptor in epileptic children. Epilepsy Research 2008;80:142–9.
Please cite this article in press as: Sonmez FM, et al. The effects of topiramate and valproate therapy on insulin, c-peptide, leptin, neuropeptide Y, adiponectin, visfatin, and resistin levels in children with epilepsy. Seizure: Eur J Epilepsy (2013), http://dx.doi.org/ 10.1016/j.seizure.2013.07.007
G Model
YSEIZ-2192; No. of Pages 6 6
F.M. Sonmez et al. / Seizure xxx (2013) xxx–xxx
27. Pylva¨nen V, Knip M, Pakarinen A, Kotila M, Turkka J, Isoja¨rvi JI. Serum insulin and leptin levels in valproate-associated obesity. Epilepsia 2002;43:514–7. 28. Gehlert DR. Role of hypothalamic neuropeptide Y in feeding and obesity. Neuropeptides 1999;33:329–38. 29. Chandran M, Phillips SA, Ciaraldi T, Henry RR. Adiponectin: more than just another fat cell hormone? Diabetes Care 2003;26:2442–50. 30. Korner A, Kratzsch J, Gausche R, Schaab M, Erbs S, Kiess W. New predictors of the metabolic syndrome in children-role of adipocytokines. Pediatric Research 2007;61:640–5. 31. Rauchenzauner M, Haberlandt E, Scholl-Bu¨rgi S, Ernst B, Hoppichler F, Karall D, et al. Adiponectin and visfatin concentrations in children treated with valproic acid. Epilepsia 2008;49:353–7. 32. Haider DG, Holzer G, Schaller G, Weghuber D, Widhalm K, Wagner O, et al. The adipokine visfatin is markedly elevated in obese children. Journal of Pediatric Gastroenterology and Nutrition 2006;43:548–9. 33. Rajala MW, Obici S, Scherer PE, Rossetti L. Adipose-derived resistin and gutderived resistin-like molecule-beta selectively impair insulin action on glucose production. Journal of Clinical Investigation 2003;111:225–30. 34. Tomoum HY, El-Hadidi ES. Ghrelin and resistin levels in children with epilepsy on valproic acid. Journal of Pediatric Neurology 2009;7:223–9. 35. Richard D, Ferland J, Lalonde J, Samson P, Deshaies Y. Influence of topiramate in the regulation of energy balance. Nutrition 2000;16:961–6. 36. Liang Y, Chen X, Osborne M, DeCarlo SO, Jetton TL, Demarest K. Topiramate ameliorates hyperglycaemia and improves glucose-stimulated insulin
37.
38.
39.
40.
41.
42.
release in ZDF rats and db/db mice. Diabetes Obesity and Metabolism 2005;7: 360–9. Lalonde J, Samson P, Poulin S, Deshaies Y, Richard D. Additive effects of leptin and topiramate in reducing fat deposition in lean and obese ob/ob mice. Physiology and Behavior 2004;80:415–20. Frigerio F, Chaffard G, Berwaer M, Maechler P. The antiepileptic drug topiramate preserves metabolism-secretion coupling in insulin secreting cells chronically exposed to the fatty acid oleate. Biochemical Pharmacology 2006;72:965–73. Wilding J, Van Gaal L, Rissanen A, Vercruysse F, Fitchet M, OBES-002 Study Group. A randomized double-blind placebo-controlled study of the longterm efficacy and safety of topiramate in the treatment of obese subjects. International Journal of Obesity and Related Metabolic Disorders 2004;28: 1399–410. Ben-Menachem E, Axelsen M, Axelsen M, Johanson EH, Stagge A, Smith U. Predictors of weight loss in adults with topiramate-treated epilepsy. Obesity Research 2003;11:556–62. York DA, Singer L, Thomas S, Bray GA. Effect of topiramate on body weight and body composition of osborne-mendel rats fed a high-fat diet: alterations in hormones, neuropeptide, and uncoupling-protein mRNAs. Nutrition 2000;16: 967–75. Theisen FM, Beyenburg S, Gebhardt S, Kluge M, Blum WF, Remschmidt H, et al. A prospective study of body weight and serum leptin levels in patients treated with topiramate. Clinical Neuropharmacology 2008;31:226–30.
Please cite this article in press as: Sonmez FM, et al. The effects of topiramate and valproate therapy on insulin, c-peptide, leptin, neuropeptide Y, adiponectin, visfatin, and resistin levels in children with epilepsy. Seizure: Eur J Epilepsy (2013), http://dx.doi.org/ 10.1016/j.seizure.2013.07.007