Characterization of insulin secretion in Valproate-treated patients with epilepsy.
OBJECTIVE
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.
Pylvänen
Virpi
V
Department of Neurology, University of Oulu, Oulu, Finland. virpi.pylvanen@oulu.fi
Pakarinen
Arto
A
Knip
Mikael
M
Isojärvi
Jouko
J
D000328:Adult; D000927:Anticonvulsants / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D001786:Blood Glucose / Q000032:analysis / Q000378:metabolism; D002096:C-Peptide / Q000097:blood / Q000378:metabolism; D004827:Epilepsy / Q000097:blood* / Q000188:drug therapy*; D005215:Fasting / Q000097:blood / Q000378:metabolism; D005260:Female; D006801:Humans; D006946:Hyperinsulinism / Q000097:blood / Q000139:chemically induced / Q000150:complications; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009765:Obesity / Q000139:chemically induced / Q000209:etiology; D011384:Proinsulin / Q000097:blood / Q000378:metabolism; D012636:Secretory Rate / Q000187:drug effects / Q000502:physiology; D014635:Valproic Acid / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D015430:Weight Gain / Q000187:drug effects
D000927:Anticonvulsants; D001786:Blood Glucose; D002096:C-Peptide; D007328:Insulin; D014635:Valproic Acid; D011384:Proinsulin