High-density lipoprotein modulates glucose metabolism in patients with type 2 diabetes mellitus.
BACKGROUND
Low plasma high-density lipoprotein (HDL) is associated with elevated cardiovascular risk and aspects of the metabolic syndrome. We hypothesized that HDL modulates glucose metabolism via elevation of plasma insulin and through activation of the key metabolic regulatory enzyme, AMP-activated protein kinase, in skeletal muscle.


RESULTS
Thirteen patients with type 2 diabetes mellitus received both intravenous reconstituted HDL (rHDL: 80 mg/kg over 4 hours) and placebo on separate days in a double-blind, placebo-controlled crossover study. A greater fall in plasma glucose from baseline occurred during rHDL than during placebo (at 4 hours rHDL=-2.6+/-0.4; placebo=-2.1+/-0.3 mmol/L; P=0.018). rHDL increased plasma insulin (at 4 hours rHDL=3.4+/-10.0; placebo= -19.2+/-7.4 pmol/L; P=0.034) and also the homeostasis model assessment beta-cell function index (at 4 hours rHDL=18.9+/-5.9; placebo=8.6+/-4.4%; P=0.025). Acetyl-CoA carboxylase beta phosphorylation in skeletal muscle biopsies was increased by 1.7+/-0.3-fold after rHDL, indicating activation of the AMP-activated protein kinase pathway. Both HDL and apolipoprotein AI increased glucose uptake (by 177+/-12% and 144+/-18%, respectively; P<0.05 for both) in primary human skeletal muscle cell cultures established from patients with type 2 diabetes mellitus (n=5). The mechanism is demonstrated to include stimulation of the ATP-binding cassette transporter A1 with subsequent activation of the calcium/calmodulin-dependent protein kinase kinase and the AMP-activated protein kinase pathway.


CONCLUSIONS
rHDL reduced plasma glucose in patients with type 2 diabetes mellitus by increasing plasma insulin and activating AMP-activated protein kinase in skeletal muscle. These findings suggest a role for HDL-raising therapies beyond atherosclerosis to address type 2 diabetes mellitus.
Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
Brian G
BG
Drew
Stephen J
SJ
Duffy
Melissa F
MF
Formosa
Alaina K
AK
Natoli
Darren C
DC
Henstridge
Sally A
SA
Penfold
Walter G
WG
Thomas
Nigora
N
Mukhamedova
Barbora
B
de Courten
Josephine M
JM
Forbes
Felicia Y
FY
Yap
David M
DM
Kaye
Gerrit
G
van Hall
Mark A
MA
Febbraio
Bruce E
BE
Kemp
Dmitri
D
Sviridov
Gregory R
GR
Steinberg
Bronwyn A
BA
Kingwell
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000502:physiology; D000818:Animals; D016632:Apolipoprotein A-I / Q000494:pharmacology / Q000627:therapeutic use; D020013:Calcium Signaling / Q000187:drug effects; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D004311:Double-Blind Method; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007262:Infusions, Intravenous; D007328:Insulin / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008297:Male; D051379:Mice; D008875:Middle Aged; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D010629:Phenformin / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D005227:Fatty Acids; D007328:Insulin; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D010629:Phenformin; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose