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Topiramate-induced modulation of hepatic molecular mechanisms: an aspect for its anti-insulin resistant effect
Hanan S El-Abhar1, Mona F Schaalan
1Department of Pharmacology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
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.
Insights
Topiramate improves insulin sensitivity by altering liver molecular pathways, increasing beneficial proteins like adiponectin, and reducing fat. This antiepileptic drug offers potential benefits beyond epilepsy treatment.
Area of Science:
- Pharmacology
- Metabolic Diseases
- Hepatology
Background:
- Topiramate, an antiepileptic drug, is known to reduce body weight and improve insulin resistance.
- The liver's role in insulin resistance is critical, but topiramate's hepatic effects remain unclear.
- Understanding topiramate's molecular mechanisms in the liver is essential for its therapeutic application in metabolic disorders.
Purpose of the Study:
- To investigate the hepatic molecular mechanisms underlying topiramate's anti-insulin resistance effects.
- To elucidate how topiramate modulates key proteins and pathways in the liver of obese, insulin-resistant rats.
- To determine the dose-dependent effects of topiramate on hepatic gene and protein expression related to insulin sensitivity.
Main Methods:
- Male Wistar rats were fed a high-fat/high-fructose diet (HFFD) for 10 weeks to induce obesity and insulin resistance.
- Two groups received oral topiramate (40 or 100 mg/kg) for two weeks.
- Hepatic molecular changes, glucose homeostasis, lipid profile, and body composition were analyzed.
Main Results:
- Topiramate significantly increased hepatic adiponectin receptors, GLUT2, and tyrosine kinase activity, while decreasing insulin receptor isoforms.
- It improved glucose homeostasis, lipid profile, reduced liver enzymes (ALT), and decreased pro-inflammatory markers (TNF-α).
- Topiramate administration led to a dose-dependent increase in adiponectin levels and reduced body/fat weights.
Conclusions:
- Topiramate exerts anti-insulin resistance effects partly through modulating hepatic insulin receptor isoforms, activating tyrosine kinase, and upregulating GLUT2 and adiponectin pathways.
- The drug's action involves enhancing adiponectin signaling and improving overall glucose and lipid metabolism.
- These findings highlight topiramate's potential as a therapeutic agent for managing insulin resistance and associated metabolic dysfunction.
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