Endocrine Abstracts

Probucol is a traditional anti-hyperlipidemic agent harboring marked antioxidant activity. While probucol is highly hydrophobic, its succinic acid ester, succinobucol, was reported as a water-soluble derivative and was in clinical trials. Succinobucol was shown to be more potent in lipid-lowering, anti-inflammatory and anti-atherogenic effects than probucol in animal models. In addition, succinobucol reduced HbA1c in diabetic patients. Although the clinical trials finally ended in failure, it appears a promising strategy for drug discovery to modulate water-solubility of established active compounds. Meanwhile, we have reported chemical modification of lipophilic agents with branched origo-glycerol as a suitable approach to intensify hydrophilicity. Thus we synthesized highly hydrophilic derivative of probucol, ProBGL₂ and evaluated its effects on glucose and lipid metabolism in HFD-fed mice. 1 g/kg/day of probucol or ProBGL₂ were orally administered for a week to male ddY mice fed HFD (24 wk), and then ipGTT was performed. Plasma insulin and lipid parameters were also determined. While body weight and food intake were not affected, glucose tolerance was much improved in probucol and ProBGL₂ groups (AUC; -50%). Fasting plasma insulin levels and HOMA-IR in the both groups were 70% decreased, suggesting increase in insulin sensitivity. However, ProBGL₂ did not change plasma total cholesterol concentration though probucol lowered it more than 50%. Furthermore, TBARS assay revealed ProBGL₂ did not possess antioxidant activities in contrast to probucol. Plasma TG and NEFA levels were not altered. Our data demonstrate that probucol and its hydrophilic derivative, ProBGL₂ ameliorate glucose intolerance and insulin resistance in HFD-fed mice and those are independent of the canonical potency of probucol such as lipid-lowering or antioxidant activities. ProBGL₂ should be a novel potent anti-diabetic agent.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This work was supported, however funding details unavailable.