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Keywords:

  • Valproate;
  • Insulin;
  • Weight gain

Abstract

  1. Top of page
  2. Abstract
  3. SUBJECTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Summary: Purpose: Valproate (VPA) treatment has been reported to be associated with obesity and high fasting serum insulin concentrations in parallel with an unfavorable serum lipid profile and hyperandrogenism and polycystic ovaries in women. The pathogenetic mechanism underlying these changes has remained unknown, although several mechanisms have been implicated.

Methods: Fifty-one patients receiving monotherapy (31 male and 20 female patients) were included in this study, with 45 (23 male and 22 female) healthy control subjects. These participants were interviewed, clinically examined, and blood samples for fasting plasma glucose, serum insulin, proinsulin, and C-peptide concentrations were taken after an overnight fast.

Results: The valproate-treated patients had fasting hyperinsulinemia (11.30 ± 6.23 pM vs. 6.28 ± 4.66 pM in the control subjects; p < 0.001), although the fasting serum proinsulin and C-peptide concentrations were not significantly higher in the patients than in the control subjects. In addition, proinsulin/insulin (0.30 ± 0.14) and C-peptide/insulin ratios (35.48 ± 24.09) were lower (p < 0.001) in the VPA-treated patients when compared with the control subjects (0.53 ± 0.36 and 94.27 ± 61.85, respectively), and they also had lower fasting plasma glucose concentrations (4.72 ± 0.35 mM) than the control subjects (5.12 ± 0.58 mM; p < 0.01).

Conclusions: This study suggests that valproate does not induce insulin secretion but might interfere with the insulin metabolism in the liver, resulting in higher insulin concentrations in the peripheral circulation. These changes are seen irrespective of concomitant weight gain, suggesting that increased insulin concentrations induce weight gain and not vice versa.

Valproate (VPA) is an extensively used broad-spectrum antiepileptic drug (1). It is currently widely applied in other indications as well, such as bipolar disorders (2) and migraine prophylaxis (3). In many cases of epilepsy and bipolar disorder, the duration of treatment may be long, which emphasizes the importance of the long-term safety of the drug.

It is well established that VPA treatment is associated with weight gain in about half of the patients, both among male and female patients (4–7). The mechanism behind VPA-related weight gain is unknown, although several mechanisms have been implicated (8–12).

Increased serum insulin concentrations have been reported in both male and female patients taking VPA (5,7). In one study, male epilepsy patients receiving VPA monotherapy were observed to have higher serum insulin concentrations than the control subjects or the oxcarbazepine (OXC)- or carbamazepine (CBZ)-treated men with epilepsy. The VPA-treated men were also observed to have serum triglyceride concentrations above the normal range more often than were obese OXC- or CBZ-treated men with epilepsy or the control subjects (13). Furthermore, obesity in VPA-treated female patients was associated with a high prevalence of polycystic ovaries, hyperandrogenism, and other features of the insulin-resistance syndrome (e.g., visceral obesity and adverse changes in the serum lipid concentrations) (4–6). Hyperinsulinemia and the associated unfavorable serum lipid profile are regarded as independent risk factors for coronary heart disease (14–16), and obese women with VPA-related metabolic and endocrine disorders appear to cluster risk factors for cardiovascular disease (17). The purpose of this study was to evaluate possible changes in insulin secretion and metabolism during VPA treatment and their role in VPA-related weight gain.

SUBJECTS AND METHODS

  1. Top of page
  2. Abstract
  3. SUBJECTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The study was carried out in the Outpatient Department of Neurology, Oulu University Hospital, with the approval of the local Ethics Committee according to the principles of the Declaration of Helsinki. Epilepsy type was classified according to the recommendations of the International League Against Epilepsy (18).

Subjects

Oulu University Hospital in Finland is the primary referral center for all adult patients with epilepsy from a source adult population of ∼260,000. During the years 1996–1997, 1,386 patients were seen in the Department of Neurology for epilepsy (19). One hundred twenty-four patients with epilepsy were receiving VPA monotherapy. The hospital records of these patients were reviewed, and those who had no diseases other than epilepsy or regular medication other than VPA for epilepsy were invited to take part in the study. Of these 74 patients, 51 (69%) eventually agreed to participate in the study. The clinical characteristics of the patients are given in Table 1.

Table 1. Clinical characteristics of the patients studied
 No.of patientsAge (yr)Seizure frequencyType of epilepsyDuration of VPA medication (yr)Daily VPA dose (mg/d)Serum VPA concentration (mM)
>1/mo<1/moGL
  1. Values are expressed as mean ± SD, except for the number of patients and type of epilepsy.

  2. No, number; G, primarily generalized seizure type; L, localization-related seizure type; VPA, valproate.

Male3130.4 ± 11.422923 85.8 ± 3.91,098 ± 353389 ± 130
Female2032.8 ± 12.811917 37.4 ± 6.2  997 ± 359423 ± 178
All5131.4 ± 11.932840116.4 ± 5.01,059 ± 355403 ± 151

The control group comprised 45 (23 male, 22 female) healthy subjects recruited at the Outpatient Clinic, Department of Neurology, including outpatients with neurologic symptoms but no neurologic diagnosis, members of the staff of Oulu University Hospital, and other healthy volunteers. Their mean age was 30.9 ± 8.5 years. Informed consent was obtained from all participating subjects.

Methods

All patients and control subjects were clinically examined and interviewed by the first author. The hospital records of the patients were carefully reviewed, and any information about weight and height before VPA treatment was collected. Weight and height were measured, and body mass index (BMI, the weight in kilograms divided by the square of height in meters) was calculated. Waist and hip circumferences were measured, and WHR [waist circumference (in cm) divided by the hip circumference (in cm)] was calculated. Obesity was defined as a BMI >25 kg/m2.

Blood samples were obtained at 8 a.m. after an overnight fast for the analysis of serum insulin, proinsulin, C-peptide, and VPA concentrations. Plasma glucose concentrations also were measured.

Assays

Serum samples were frozen at −20°C until analyzed. Serum VPA concentrations were assayed with a fluorescence polarization immunoassay system (AxSym analyzer; Abbott Diagnostic Division, Irving, TX, U.S.A.). The sensitivity of the VPA assay was 0.58 mg/L, the intraassay coefficient of variation was 1.8%, and the interassay coefficient of variation was 2.7%.

The concentrations of insulin were analyzed with a method based on immunologic chemiluminescence by using the Bayer ADVIA Centaur analyzer (Tarrytown, NY, U.S.A.). The sensitivity of the insulin assay was 2.0 pM, the intraassay coefficient of variation (CV) was 3.9%, and the interassay variation 8.8%. C-peptide concentrations were analyzed with a radioimmunoassay by using reagent kits from Diagnostic Products Co. (Los Angeles, CA, U.S.A.). The sensitivity of the C-peptide assay was 70 pM, and the intraassay and interassay variations were 3.4% and 7.2%, respectively. The proinsulin concentrations were analyzed with an enzyme immunoassay method by using reagent kits from Dako Ltd. (Ely, U.K.). The concentrations of plasma glucose were measured with an enzymatic colorimetric method by using Cobas Integra 700 analyzer (F. Hoffman-La Roche, Ltd., Basel, Switzerland).

Indices and ratios

The homeostasis model assessment (HOMA) index was calculating according to the following equation: insulin (μU/m ×[glucose (mM)/22.5]. The C-peptide (pM)-to-insulin (pM, CP/I) and proinsulin (pM)-to-insulin (pM, PI/I) ratios also were calculated.

Statistical analysis

The Mann–Whitney U test was used for the statistical analyses, as the data showed a skewed distribution.

RESULTS

  1. Top of page
  2. Abstract
  3. SUBJECTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The main results are shown in Table 2.

Table 2. Anthropometric and laboratory data in the patients and the control subjects
 BMI (kg/m2)WHRGlucose (mM)Insulin (pM)Proinsulin (pM)C-peptide (pM)Proinsulin/insulinC-peptide/insulinHOMA
  1. Values are expressed as mean ± SD.

  2. BMI, body mass index; WHR, waist–hip ratio; HOMA, homeostasis model assessment; N, number; Pat, patients; Ctrl, control subjects.

  3. ap < 0.01 when compared with the obese control subjects.

  4. bp < 0.001 when compared with the obese control subjects.

  5. cp < 0.05 when compared with the normal-weight control subjects.

  6. dp < 0.01 when compared with the normal-weight control subjects.

  7. ep < 0.001 when compared with the normal-weight control subjects.

  8. fp < 0.01 when compared with all control subjects.

  9. gp < 0.001 when compared with all control subjects.

Obese pat (27)27.9 ± 1.70.97 ± 0.08 4.84 ± 0.27a12.19 ± 6.04b3.34 ± 1.93460 ± 320 0.30 ± 0.11a 37.88 ± 24.90b2.61 ± 1.4b
Normal-weight pat (24)22.5 ± 1.2 0.86 ± 0.08c 4.58 ± 0.40c10.30 ± 6.42e2.64 ± 1.55304 ± 220 0.31 ± 0.18d 32.79 ± 23.33e2.11 ± 1.4e
All pat. (51)25.3 ± 3.10.90 ± 0.08 4.72 ± 0.35f11.30 ± 6.23g3.01 ± 1.78390 ± 290 0.30 ± 0.14g 35.48 ± 24.09g2.37 ± 1.4g
Obese ctrl. (24)28.0 ± 3.00.92 ± 0.085.28 ± 0.636.43 ± 3.662.67 ± 0.86579 ± 3000.55 ± 0.39107.06 ± 70.631.55 ± 1.0
Normal-weight ctrl (21)21.3 ± 2.10.81 ± 0.074.92 ± 0.456.20 ± 6.172.02 ± 0.75365 ± 2000.50 ± 0.33 78.98 ± 48.661.40 ± 1.4
All ctrl (45)24.8 ± 4.20.87 ± 0.095.12 ± 0.586.28 ± 4.862.35 ± 0.87480 ± 2700.53 ± 0.36 94.27 ± 61.851.45 ± 1.18

The VPA-treated patients with epilepsy had significantly lower fasting plasma glucose concentrations (p < 0.001) and significantly higher fasting serum insulin (p < 0.001) levels than the control subjects. Serum proinsulin and C-peptide levels were similar in the patients and the control subjects, but the patients had lower PI/I (p < 0.05) and CP/I (p < 0.001) ratios than the control subjects. In addition, the HOMA index (p < 0.001) was higher in the patients than in the control subjects.

Additional analyses were performed based on the BMI of the study subjects. These analyses showed that the obese VPA-treated patients had significantly lower fasting plasma glucose levels (p < 0.01) and higher serum insulin concentrations (p < 0.001) than the obese control subjects. In addition, they had lower PI/I (p < 0.01) and CP/I ratios (p < 0.001) than the obese control subjects. The obese VPA-treated patients also had a higher HOMA index (p < 0.001) than the obese control subjects. Proinsulin levels tended to be higher in the obese patients (p = 0.06) than in the obese control subjects. Similarly, the normal-weight VPA-treated patients had higher serum insulin concentrations (p < 0.001) and lower PI/I (p < 0.05) and CP/I ratios (p < 0.01) than the normal-weight control subjects. They also had lower fasting plasma glucose concentrations (p < 0.05) than the normal-weight control subjects. Moreover, the HOMA index was higher (p < 0.001) in the VPA-treated normal-weight patients than in the normal-weight control subjects.

Among the 51 patients were 42 patients with VPA monotherapy who had weight and height documented in their hospital records before the VPA medication. Twenty (48%) of these patients had had an increase in their BMI of ≥10% during the VPA treatment and were considered to have experienced indisputable weight gain. The mean BMI increase during VPA treatment was 21.1 ± 14.1% in these subjects. In the 22 patients with no weight gain during treatment, the mean change is BMI was 4.5 ± 4.2%. The patients with indisputable weight gain during VPA treatment had lower BMI (19.9 ± 3.9 kg/m2) before the treatment than did those who had not gained weight (23.5 ± 2.7 kg/m2). No differences were found in any of the laboratory parameters measured between these two groups. The patients with indisputable weight gain had significantly longer duration of medication (7.3 ± 3.9 years) than did those patients with no weight gain (4.6 ± 4.9 years). No correlation was noted between the metabolic data and daily VPA dosage or serum drug concentration.

DISCUSSION

  1. Top of page
  2. Abstract
  3. SUBJECTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

This study shows that patients taking VPA monotherapy have fasting hyperinsulinemia in their peripheral circulation, although the fasting serum proinsulin and C-peptide levels did not differ significantly between the patients receiving VPA treatment and the control subjects. In addition, the PI/I and CP/I ratios were reduced in the VPA-treated patients, and they had also lower fasting plasma glucose concentrations than did the control subjects. These findings were similar regardless of sex or seizure type or whether the patients had gained weight or not during VPA treatment or whether they were obese or of normal weight at the time of the clinical examination, which suggests that the observed metabolic changes seen are not due to weight gain or obesity.

The mechanism behind VPA-related weight gain has remained open. Several mechanisms have been implicated, such as stimulation of appetite (8), distorted regulation of energy expenditure (9), inhibition of β-oxidation (10), and competitive binding with palmitate to albumin (11), which all can lead to weight gain. A direct stimulation of insulin secretion from the pancreatic beta cells has been suggested (20), but according to the present results, this seems unlikely. Moreover, the increased insulin concentrations in the peripheral circulation seen in all VPA-treated patients can secondarily induce weight gain by increasing the uptake of glucose into the adipose cell and by activating lipogenic and glycolytic enzymes, thus stimulating lipogenesis (21), leading to obesity (22).

VPA-related hyperinsulinemia may increase the health risks of patients taking the drug. Previously, hyperinsulinemia in patients taking VPA for epilepsy has been shown to be associated with weight gain, polycystic ovary syndrome–like findings, hyperandrogenism, and unfavorable lipid changes in women with epilepsy (4,5,17). An association between hyperinsulinemia, obesity, and an unfavorable lipid profile has also been observed in men taking VPA for epilepsy (13). In addition, hyperinsulinemia is known to be an independent risk factor for cardiovascular diseases (14,15). Interestingly, in a prospective study, the increased serum insulin concentrations as well as unfavorable serum lipid profile returned to normal within 2 months after VPA was replaced with lamotrigine in women with epilepsy, although weight reduction occurred more gradually and progressively during the 12-month follow-up (5).

Serum proinsulin and C-peptide concentrations have been measured in a limited number of patients taking VPA in a few previous studies. In a 1-month prospective study in eight VPA-treated patients, Breum et al. (23) did not find any changes in fasting serum insulin, C-peptide, or fasting plasma glucose concentrations. Luef et al. (7,12,20,24) reported results from three studies, none of them detecting any increase in the fasting serum concentrations of insulin, C-peptide, or proinsulin in VPA-treated patients, but they showed higher concentrations of these hormones in the postprandial state than those in patients treated with CBZ, LTG, or both.

Insulin and C-peptide are released in equimolar amounts from the pancreatic islets, whereas only a small proportion of proinsulin and related intermediate-cleavage forms are secreted into the portal vein (25). The liver is the primary organ for the degradation of insulin. About half of the secreted insulin is removed from the circulation on its initial passage through the liver (25), insulin-specific protease and glutathione-insulin transhydrogenase being the enzymes involved (26). In contrast, the hepatic extraction of C-peptide is low, as the kidneys play a major role in the removal of C-peptide (27).

The low PI/I and CP/I ratios in the VPA-treated patients seen in the present study appear to be due to the disproportionately increased serum insulin concentrations, because serum C-peptide and proinsulin levels were not elevated in the VPA-treated patients. Serum insulin concentrations are considered to reflect the posthepatic amount of insulin, whereas the C-peptide and proinsulin levels reflect the amount of insulin initially secreted from the pancreatic beta cells (25). In general, an increased PI/I ratio is associated with type 2 diabetes as well as development of type 2 diabetes within the next 2–5 years (28). The reduced CP/I ratio merely reflects a decreased hepatic extraction of insulin (29). A low CP/I ratio is usually associated with hyperinsulinemia, impaired glucose tolerance, or overt type 2 diabetes (30).

The present findings of low PI/I and CP/I ratios in VPA-treated patients suggest that insulin secretion from the beta cells is not increased during VPA treatment. Instead, the hepatic extraction of insulin seems to be reduced, which is often the case in obese subjects (31). However, we observed decreased PI/I and CP/I ratios both in normal-weight and obese patients treated with VPA, and these ratios were lower in the VPA-treated obese subjects than in the obese control subjects. VPA, which is a known inhibitor of liver metabolism (1), could inhibit the hepatic degradation of insulin, leading to high fasting serum insulin concentrations in the VPA-treated patients, whereas serum C-peptide and proinsulin levels would remain normal.

Hyperinsulinemia during VPA treatment has previously been suggested to be due to the development of insulin resistance (5,13,32). The present observations do not support that concept, although the VPA-treated patients had a higher HOMA index than did the control subjects. The HOMA index was developed to assess insulin resistance with a simpler procedure than the glucose clamp method (33). In normal conditions, an increased HOMA value does reflect a reduced sensitivity to insulin. It is questionable whether the HOMA index is a useful marker of insulin resistance in abnormal situations associated with, for example, reduced hepatic insulin extraction combined with unchanged insulin secretion from the pancreatic islets. The increased HOMA index in VPA-treated patients most likely reflects primarily decreased hepatic insulin degradation, in particular because both obese and normal-weight patients did have a higher HOMA index than their respective control groups. One cannot, however, exclude the possibility that the increased HOMA index in patients receiving VPA treatment might also reflect insulin resistance. The observation that the VPA-treated patients had lower fasting plasma glucose concentrations than the control subjects argues against reduced insulin sensitivity among these patients.

In conclusion, the findings of this study suggest that VPA itself does not induce increased insulin secretion but may interfere with insulin metabolism in the liver, resulting in higher insulin concentrations in the peripheral circulation and subsequently reduced plasma glucose concentrations. The metabolic changes seen in VPA-treated patients appear irrespective of concomitant weight gain, suggesting that the hyperinsulinemia develops first, resulting in the metabolic changes. The host-related factors might determine whether peripheral hyperinsulinemia will contribute to the development of obesity in these patients.

REFERENCES

  1. Top of page
  2. Abstract
  3. SUBJECTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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