Valproate-Induced Insulin Resistance and Obesity in Children

Abstract

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 β-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.

Inhibition of hepatic carnitine palmitoyl-transferase I (CPT IA) by valproyl-CoA as a possible mechanism of valproate-induced steatosis

“…It regulates glucose and fatty acid metabolism in response to different physiological and hormonal states. In several clinical studies involving patients subjected to VPA treatment, a significant weight gain is often described [25][26][27] as an unwanted side effect. Valproic acid-related weight gain was originally reported to be associated with hyperinsulinemia, probably explained by the fact 5 that VPA might inhibit the metabolism of insulin in the liver.…”

Avaliação do ciclo estral, tecido ovariano e uterino e parâmetros fetais de ratas Wistar tratadas com Topiramato

“…phenobarbital, phenytoin and carbamezepine) may promote abnormalities of baseline endocrine status and lower fertility (HERZOG et al, 2004(HERZOG et al, , 2005. According to Verroti et al (2011a) it is difficult to determine whether hormonal abnormalities are due to epilepsy-related hypothalamic-pituitary axis dysfunction or to side effects of antiepileptic drugs. However, treatment with certain AEDs, such as phenobarbital, phenytoin, carbamezepine and valproate may increase the risk of reproductive endocrine disorders in women with epilepsy (VERROTI et al, 2009(VERROTI et al, , 2011a.…”

“…According to Verroti et al (2011a) it is difficult to determine whether hormonal abnormalities are due to epilepsy-related hypothalamic-pituitary axis dysfunction or to side effects of antiepileptic drugs. However, treatment with certain AEDs, such as phenobarbital, phenytoin, carbamezepine and valproate may increase the risk of reproductive endocrine disorders in women with epilepsy (VERROTI et al, 2009(VERROTI et al, , 2011a. According to authors, the effects of the new AEDs, including Topiramate, have not been widely studied.…”

The Impact of Cardiometabolic Risk in Patients with Severe Mental Illness: From Evidence to Clinical Management

“…Brown et al, 2008), the long-term use of both tricyclic antidepressants (incidence rate ratio, IRR=1.77) and SSRIs (IRR=2.06) in at least moderate daily doses (Andersohn et al, 2009), as well as the use of antidepressant medication in high-risk patients (Rubi net al, 2008). Furthermore, although understudied, certain mood stabilizers, especially valproate, have been associated with an elevated risk for the development of insulin resistance (Verrotti et al, 2009;Pylvänen et al, 2006), conferring a risk for diabetes mellitus, which is possibly related to weight gain (Masuccio et al, 2010), and/or fatty liver infiltration (Luef et al, 2004), but also to valproate itself (Pylvänen et al, 2002). Additionally to weight gain and diabetes, some SGAs cause hypertriglyceridaemia, which is an independent risk factor of coronary arteriosclerosis (Tschoner et al, 2007).…”