Background and Aim:
Inflammation underlies the pathogenesis of insulin resistance and type 2 diabetes. We recently demonstrated that in a mouse model of insulin resistance, lipid-free apolipoprotein A-I (apoA-I), effective in suppressing hepatic inflammation and improved insulin resistance. However, was apoA-I is not suitable as a therapy option as it is a large molecule that is difficult to synthesise. In the current study we have tested whether treatment with apoA-I mimetics, L-5F and D-4F, could emulate the protective effects of apoA-I because these mimetics have been used successfully in animal models of atherosclerosis, ovarian cancer, renal disease and arthritis.
Method and Results: Insulin resistance was induced in C57BL/6 mice by dietary intervention whereby mice were fed a high-fat diet (HFD) for 10 weeks before commencing treatment. The HFD mice were subgrouped to receive either (i) saline; (ii) lipid-free apoAI (8mg/kg by injections bi-weekly); (iii) L-5F (10mg/kg by injections bi-weekly ) or; (iv) D-4F (300µg/ml via drinking water) for 4 weeks. All groups were compared to control mice fed a standard chow diet. Findings show mice treated with either lipid-free apoAI, L-5F or D-4F when compared to HFD, resulted in (i) improved glucose tolerance and insulin sensitivity that was associated with decreased hepatic inflammation (TNFα, IL6, IL-1b and IFN-g); (ii) suppression of hepatic mRNA expression for the rate-limiting enzymes in gluconeogenesis (PEPCK and G6Pase) and lipogenic genes (SREBP1c and ChREBP) and; (iii) reduced hepatic macrophage infiltration.
Conclusions: We conclude that the L5-F and D4-F apoA-I mimetics were just as effective as lipid-free apoAI in reversing insulin resistance in the HFD C57BL/6 mouse model. All treatments were shown to mediate their effects by suppression of inflammation in the liver, suppression of hepatic gluconeogenesis and reduction of de novo lipid synthesis. These findings may open new therapeutic options for a HDL-based treatment to prevent the inflammation underlying insulin resistance and subsequently reduce the risk for type 2 diabetes.