In vivo PET imaging with [(18)F]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 ([(18)F]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 (k 3) in apoA-I treated mice (3.5 ± 1.1 × 10(-2) min(-1) vs 2.3 ± 0.7 × 10(-2) min(-1), for apoA-I and PBS, respectively; p < 0.05) and an increased influx constant (3.7 ± 0.6 × 10(-3) ml min(-1) g(-1) vs 2.0 ± 0.3 × 10(-3) ml min(-1) g(-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.

• Authors: Blake J Cochran, William J Ryder, Arvind Parmar, Shudi Tang, Anthonin Reilhac, Andrew Arthur, Arnaud Charil, Hasar Hamze, Philip J Barter, Leonard Kritharides, Steven R Meikle, Marie-Claude Gregoire, Kerry-Anne Rye
• Journal: Diabetologia (Diabetologia) Vol. 59 Issue 9 Pg. 1977-84 (09 2016) ISSN: 1432-0428 [Electronic] Germany
• PMID: 27193916 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoprotein A-I
• Blood Glucose
• Fluorodeoxyglucose F18
• Glucose

Topics

• Animals
• Apolipoprotein A-I (therapeutic use)
• Blood Glucose (drug effects)
• Diabetes Mellitus, Type 2 (blood, drug therapy, metabolism)
• Disease Models, Animal
• Fluorodeoxyglucose F18 (analysis)
• Glucose (metabolism)
• Insulin Resistance (physiology)
• Kinetics
• Male
• Mice
• Muscle, Skeletal (drug effects, metabolism)
• Phosphorylation (drug effects)
• Positron-Emission Tomography (methods)