Endothelial-vasoprotective effects of high-density lipoprotein are impaired in patients with type 2 diabetes mellitus but are improved after extended-release niacin therapy.
BACKGROUND
High-density lipoprotein (HDL)-raising therapies are currently under intense evaluation, but the effects of HDL may be highly heterogeneous. We therefore compared the endothelial effects of HDL from healthy subjects and from patients with type 2 diabetes mellitus and low HDL (meeting the criteria for metabolic syndrome), who are frequently considered for HDL-raising therapies. Moreover, in diabetic patients, we examined the impact of extended-release (ER) niacin therapy on the endothelial effects of HDL.


RESULTS
HDL was isolated from healthy subjects (n=10) and patients with type 2 diabetes (n=33) by sequential ultracentrifugation. Effects of HDL on endothelial nitric oxide and superoxide production were characterized by electron spin resonance spectroscopy analysis. Effects of HDL on endothelium-dependent vasodilation and early endothelial progenitor cell-mediated endothelial repair were examined. Patients with diabetes were randomized to a 3-month therapy with ER niacin (1500 mg/d) or placebo, and endothelial effects of HDL were characterized. HDL from healthy subjects stimulated endothelial nitric oxide production, reduced endothelial oxidant stress, and improved endothelium-dependent vasodilation and early endothelial progenitor cell-mediated endothelial repair. In contrast, these beneficial endothelial effects of HDL were not observed in HDL from diabetic patients, which suggests markedly impaired endothelial-protective properties of HDL. ER niacin therapy improved the capacity of HDL to stimulate endothelial nitric oxide, to reduce superoxide production, and to promote endothelial progenitor cell-mediated endothelial repair. Further measurements suggested increased lipid oxidation of HDL in diabetic patients, and a reduction after ER niacin therapy.


CONCLUSIONS
HDL from patients with type 2 diabetes mellitus and metabolic syndrome has substantially impaired endothelial-protective effects compared with HDL from healthy subjects. ER niacin therapy not only increases HDL plasma levels but markedly improves endothelial-protective functions of HDL in these patients, which is potentially more important.


BACKGROUND
clinicaltrials.gov. Identifier: NCT00346970.
Sorrentino
Sajoscha A
SA
Klinik für Kardiologie und Angiologie, Medizinische Hochschule Hannover, Hannover, Germany.
Besler
Christian
C
Rohrer
Lucia
L
Meyer
Martin
M
Heinrich
Kathrin
K
Bahlmann
Ferdinand H
FH
Mueller
Maja
M
Horváth
Tibor
T
Doerries
Carola
C
Heinemann
Mariko
M
Flemmer
Stella
S
Markowski
Andrea
A
Manes
Costantina
C
Bahr
Matthias J
MJ
Haller
Hermann
H
von Eckardstein
Arnold
A
Drexler
Helmut
H
Landmesser
Ulf
U
D000368:Aged; D000818:Animals; D002478:Cells, Cultured; D003692:Delayed-Action Preparations; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D003925:Diabetic Angiopathies / Q000188:drug therapy / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D000960:Hypolipidemic Agents / Q000008:administration & dosage*; D015227:Lipid Peroxidation / Q000187:drug effects; D008075:Lipoproteins, HDL / Q000097:blood*; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008819:Mice, Nude; D008875:Middle Aged; D019255:NADPH Oxidases / Q000378:metabolism; D009525:Niacin / Q000008:administration & dosage*; D009569:Nitric Oxide / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D003692:Delayed-Action Preparations; D005609:Free Radicals; D000960:Hypolipidemic Agents; D008075:Lipoproteins, HDL; D013481:Superoxides; D009525:Niacin; D009569:Nitric Oxide; D009195:Peroxidase; D019255:NADPH Oxidases