Topiramate-Induced Modulation of Hepatic Molecular Mechanisms: An Aspect for Its Anti-Insulin Resistant Effect

Abstract

Topiramate is an antiepileptic drug known to ameliorate insulin resistance besides reducing body weight. Albeit liver plays a fundamental role in regulation of overall insulin resistance, yet the effect of topiramate on this organ is controversial and is not fully investigated. The current work aimed to study the potential hepatic molecular mechanistic cassette of the anti-insulin resistance effect of topiramate. To this end, male Wistar rats were fed high fat/high fructose diet (HFFD) for 10 weeks to induce obese, insulin resistant, hyperglycemic animals, but with no overt diabetes. Two HFFD-groups received oral topiramate, 40 or 100 mg/kg, for two weeks. Topiramate, on the hepatic molecular level, has opposed the high fat/high fructose diet effect, where it significantly increased adiponectin receptors, GLUT2, and tyrosine kinase activity, while decreased insulin receptor isoforms. Besides, it improved the altered glucose homeostasis and lipid profile, lowered the ALT level, caused subtle, yet significant decrease in TNF-α, and boosted adiponectin in a dose dependent manner. Moreover, topiramate decreased liver weight/, visceral fat weight/, and epididymal fat weight/body weight ratios. The study proved that insulin-resistance has an effect on hepatic molecular level and that the topiramate-mediated insulin sensitivity is ensued partly by modulation of hepatic insulin receptor isoforms, activation of tyrosine kinase, induction of GLUT2 and elevation of adiponectin receptors, as well as their ligand, adiponectin, besides its known improving effect on glucose tolerance and lipid homeostasis.

Novel CoQ10 Antidiabetic Mechanisms Underlie Its Positive Effect: Modulation of Insulin and Adiponectine Receptors, Tyrosine Kinase, PI3K, Glucose Transporters, sRAGE and Visfatin in Insulin Resistant/Diabetic Rats

“…Aminotransferases are indicators of hepatic health that is compromised in case of obesity, IR and diabetes [75]. Moreover, fatty changes are associated with the increased level of TNF-α, proven to increase in this model [19], which has a great influence on ALT elevation. Therefore, activated aminotransferases may reflect the role of hepatic gluconeogenesis and/or inflammation in the type 2 diabetes pathophysiology.…”

“…These aliquots were used for the estimation of adiponectin receptor 1 and 2 (Adipo R1 & R2) [19], glucose transporter 2 and 4 (GLUT 2 & 4) and myeloperoxidase (MPO) activity, using the corresponding ELISA rat kit (Uscn, Wuhan, China; EIAab, Wuhan, China and Hycult biotech, Uden, Netherlands, respectively).…”

Topiramate has protective effect on renal injury

“…Topiramate (TPM), which is a sulfamate-substituted monosaccharide, is used in neurotherapy for the management of epilepsy and migraine (9). It is documented to possess weight-reducing properties in addition to insulin resistance-improving effects (10,11). It has been demonstrated that TPM decreases TNF-α and oxidative stress in addition to being an effective antioxidant (11,12,13).…”

“…It is documented to possess weight-reducing properties in addition to insulin resistance-improving effects (10,11). It has been demonstrated that TPM decreases TNF-α and oxidative stress in addition to being an effective antioxidant (11,12,13). The inhibition of TNF-α release or its neutralization with anti-TNF-α antibodies decreases the number of neutrophils infi ltrating the kidney and reduces I/R injury (14).…”

Beneficial effects of Spirogyra Neglecta Extract on antioxidant and anti-inflammatory factors in streptozotocin-induced diabetic rats

“…Oxidative stress causes production of abnormal cytokine production (TNF- and IL-6) 25 . TNF- not only increases adipocyte lipolysis but also has adverse effects on the insulin signaling pathway through changing the tyrosine/serine phosphorylation of insulin receptor substrate 26 . CRP is a key inflammatory factor that is regulated by IL-6, IL-1, and TNF-α, and produced by the liver in response to inflammation 27 .…”