Abstract 427: Apoliporotein A-I Improves Glucose Tolerance and Enhances Insulin-Dependent and Insulin-Independent Glucose Uptake in the db/db Mouse Model of Type 2 Diabetes

Abstract

Introduction Type 2 diabetes is characterised by decreased high-density lipoprotein (HDL) levels, as well as the level of apolipoprotein A-I (apoA-I), the main apolipoprotein of HDL. Pharmacological elevation of HDL levels is associated with improved glycemic control in patients with type 2 diabetes and HDL also improves glucose uptake into skeletal muscle in vitro. With the current interest in HDL raising therapeutics, understanding how apoA-I/HDL improve glucose tolerance in type 2 diabetes is important. Objective To determine the impact of increasing plasma apoA-I levels on glycemic control and glucose uptake in the db/db mouse model of type 2 diabetes. Methods Fasted 6-7 week old male db/db mice received a single intraperitoneal injection of human apoA-I (40 mg/kg) or PBS. Two hours after the infusion mice were randomly assigned into 3 groups (n=7-8/group) and subjected to a glucose tolerance test (1 g/kg D-glucose), an insulin tolerance test (3 U/kg human insulin) or used to determine glucose uptake into skeletal muscle. For the glucose and insulin tolerance tests blood glucose levels were measured with a glucometer. For the glucose uptake experiments, gastrocnemius muscles were incubated with 1 mM [3H]2-deoxy-glucose and 7 mM D-[14C]mannitol in the presence or absence of insulin, then homogenized. 3H and 14C content of the homogenates was determined by liquid scintillation counting. Results Plasma apoA-I levels reached 65.2±16.6 μg/mL by 2 h post-injection, and remained elevated for >10 h. Mice that received apoA-I had significantly improved glucose tolerance (AUC apoA-I=2574±70; PBS=2927±137, p<0.05) and insulin sensitivity (AUC apoA-I=388.8±23.8; PBS=194.1±19.6, p<0.001). In the absence of insulin, apoA-I increased glucose uptake by 1.8 and 1.7 fold in red and white gastrocnemius muscle, respectively. In the presence of insulin, apoA-I increased glucose uptake 2.5 and 1.8 fold, in red and white gastrocnemius muscle, respectively. Conclusion A single infusion of apoA-I significantly increases glucose tolerance, insulin sensitivity and skeletal muscle glucose uptake in db/db mice. Insulin and apoA-I work synergistically to improve skeletal muscle glucose uptake.