Valproate-induced insulin resistance and obesity in children.
BACKGROUND
Valproic acid (VPA), a widely used antiepileptic drug, has broad-spectrum activity against both generalized and partial epilepsy. Among the side effects of VPA, weight gain is frequently reported, although the real incidence and magnitude of this problem is unknown. Its pathogenesis is most likely multifactorial, and is controversial.


METHODS
In order to evaluate the role of hyperinsulinemia and related hormonal abnormalities in VPA-induced obesity, data from the existing literature have been analyzed and discussed critically.


RESULTS
Patients suffering from weight gain show various metabolic and endocrinologic abnormalities. The most frequent are hyperinsulinemia and insulin resistance, hyperleptinemia and leptin resistance, and an increase in the availability of long-chain free fatty acids. Significant weight gain is associated with increased levels of insulin and leptin, suggesting a close relationship between obesity-induced hyperinsulinemia and hyperleptinemia. VPA can directly stimulate pancreatic beta-cells and indirectly enhance insulin resistance by suppressing insulin-mediated peripheral glucose uptake. Leptin activation seems to be similar in obese VPA-treated subjects to that seen in otherwise obese subjects.


CONCLUSIONS
The mechanisms of hyperinsulinemia in VPA-induced weight gain remain unclear, although it is likely that obesity is the cause of hyperinsulinemia and all related metabolic changes. However, this heterogeneous metabolic disorder requires further research.
Verrotti
Alberto
A
Department of Pediatrics, University of Chieti, Chieti, Italy.
la Torre
Rosanna
R
Trotta
Daniela
D
Mohn
Angelika
A
Chiarelli
Francesco
F
D000927:Anticonvulsants / Q000009:adverse effects / Q000627:therapeutic use; D002648:Child; D004827:Epilepsy / Q000150:complications / Q000188:drug therapy; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology; D009765:Obesity / Q000139:chemically induced* / Q000150:complications; D014635:Valproic Acid / Q000009:adverse effects* / Q000627:therapeutic use; D015430:Weight Gain / Q000187:drug effects
D000927:Anticonvulsants; D014635:Valproic Acid