In vivo PET imaging with [18F]FDG to explain improved glucose uptake in an apolipoprotein A-I treated mouse model of diabetes

Abstract

Aims/hypothesis: Type 2 diabetes is characterised by decreased HDL levels, as well as the level of apolipoprotein A-I (apoA-I), the main apolipoprotein of HDLs. Pharmacological elevation of HDL and apoA-I levels is associated with improved glycaemic control in patients with type 2 diabetes. This is partly due to improved glucose uptake in skeletal muscle. Methods: This study used kinetic modelling to investigate the impact of increasing plasma apoA-I levels on the metabolism of glucose in the db/db mouse model. Results: Treatment of db/db mice with apoA-I for 2 h significantly improved both glucose tolerance (AUC 2574 ± 70 mmol/l × min vs 2927 ± 137 mmol/l × min, for apoA-I and PBS, respectively; p < 0.05) and insulin sensitivity (AUC 388.8 ± 23.8 mmol/l × min vs 194.1 ± 19.6 mmol/l × min, for apoA-I and PBS, respectively; p < 0.001). ApoA-I treatment also increased glucose uptake by skeletal muscle in both an insulin-dependent and insulin-independent manner as evidenced by increased uptake of fludeoxyglucose ([18F]FDG) from plasma into gastrocnemius muscle in apoA-I treated mice, both in the absence and presence of insulin. Kinetic modelling revealed an enhanced rate of insulin-mediated glucose phosphorylation (k3) in apoA-I treated mice (3.5 ± 1.1 × 10−2min−1vs 2.3 ± 0.7 × 10−2min−1, for apoA-I and PBS, respectively; p < 0.05) and an increased influx constant (3.7 ± 0.6 × 10−3ml min−1g−1vs 2.0 ± 0.3 × 10−3ml min−1g−1, for apoA-I and PBS, respectively; p < 0.05). Treatment of L6 rat skeletal muscle cells with apoA-I for 2 h indicated that increased hexokinase activity mediated the increased rate of glucose phosphorylation. Conclusions/interpretation: These findings indicate that apoA-I improves glucose disposal in db/db mice by improving insulin sensitivity and enhancing glucose phosphorylation.