Effects of HDL and apoA-I on glucose uptake by skeletal muscle: potential role in type 2 diabetes management

Abstract

Emerging evidence from recent studies suggest that HDL and apoA-I have anti-diabetic functions. This thesis aims to determine whether HDL and apoA-I improve glycaemic control by increasing glucose uptake into skeletal muscle, the major site of glucose disposal in the human body. In order to address this question, a series of experiments were carried out in two models: a cell model using cultured primary human skeletal muscle cells (HSKMCs), and an animal model using the leptin receptor knockout (Lepr(db/db)) mouse. The results from this thesis have established that lipid-free apoA-I increases both insulin-dependent- and independent- glucose uptake into HSKMCs in a time- and concentration-dependent manner. The increased glucose uptake was accompanied by enhanced activation of IRS-1/PI3K/Akt/AS160 insulin signaling pathway. Type 2 diabetic db/db mice that were treated with apoA-I had significantly improved glucose and insulin tolerance when treated with a single intraperitoneal infusion of lipid-free apoA-I, accompanied with increased glucose uptake by the gastrocnemius muscle. In conclusion, this thesis establishes that apoA-I increases glucose disposal in skeletal muscle under both normal and type 2 diabetic conditions. These findings suggest that therapeutic agents that increase plasma HDL and apoA-I levels may improve glycemic control in people with type 2 diabetes.