title: In vivo PET imaging with [(18)F]FDG to explain improved glucose uptake in an apolipoprotein A-I treated mouse model of diabetes.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  These findings indicate that apoA-I improves glucose disposal in db/db mice by improving insulin sensitivity and enhancing glucose phosphorylation.
authors.affiliation: School of Medical Sciences, Faculty of Medicine, UNSW Australia, Sydney, 2052, NSW, Australia. b.cochran@unsw.edu.au.
authors.forename: Blake J
authors.initials: BJ
authors.lastname: Cochran
authors.affiliation: Faculty of Health Sciences, University of Sydney, Sydney, NSW, Australia.|Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia.
authors.forename: William J
authors.initials: WJ
authors.lastname: Ryder
authors.affiliation: ANSTO LifeSciences, Sydney, NSW, Australia.
authors.forename: Arvind
authors.initials: A
authors.lastname: Parmar
authors.affiliation: School of Medical Sciences, Faculty of Medicine, UNSW Australia, Sydney, 2052, NSW, Australia.
authors.forename: Shudi
authors.initials: S
authors.lastname: Tang
authors.affiliation: Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia.|ANSTO LifeSciences, Sydney, NSW, Australia.
authors.forename: Anthonin
authors.initials: A
authors.lastname: Reilhac
authors.affiliation: ANSTO LifeSciences, Sydney, NSW, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Arthur
authors.affiliation: Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia.|ANSTO LifeSciences, Sydney, NSW, Australia.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Charil
authors.affiliation: ANSTO LifeSciences, Sydney, NSW, Australia.
authors.forename: Hasar
authors.initials: H
authors.lastname: Hamze
authors.affiliation: School of Medical Sciences, Faculty of Medicine, UNSW Australia, Sydney, 2052, NSW, Australia.|Faculty of Medicine, University of Sydney, Sydney, NSW, Australia.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Barter
authors.affiliation: Faculty of Medicine, University of Sydney, Sydney, NSW, Australia.|Department of Cardiology, Concord Repatriation General Hospital, Sydney, NSW, Australia.
authors.forename: Leonard
authors.initials: L
authors.lastname: Kritharides
authors.affiliation: Faculty of Health Sciences, University of Sydney, Sydney, NSW, Australia.|Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Meikle
authors.affiliation: ANSTO LifeSciences, Sydney, NSW, Australia.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Gregoire
authors.affiliation: School of Medical Sciences, Faculty of Medicine, UNSW Australia, Sydney, 2052, NSW, Australia.|Faculty of Medicine, University of Sydney, Sydney, NSW, Australia.
authors.forename: Kerry-Anne
authors.initials: KA
authors.lastname: Rye
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000627:therapeutic use*; D001786:Blood Glucose / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D004195:Disease Models, Animal; D019788:Fluorodeoxyglucose F18 / Q000032:analysis*; D005947:Glucose / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D007700:Kinetics; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D049268:Positron-Emission Tomography / Q000379:methods*
chemical_list: D016632:Apolipoprotein A-I; D001786:Blood Glucose; D019788:Fluorodeoxyglucose F18; D005947:Glucose
keywords: Diabetes; FDG; Glucose uptake; Insulin sensitivity; Kinetic modelling