Poor glycemic control in type 2 diabetes enhances functional and compositional alterations of small, dense HDL3c.
High-density lipoprotein (HDL) possesses multiple biological activities; small, dense HDL3c particles displaying distinct lipidomic composition exert potent antiatherogenic activities which can be compromised in dyslipidemic, hyperglycemic insulin-resistant states. However, it remains indeterminate (i) whether such functional HDL deficiency is related to altered HDL composition, and (ii) whether it originates from atherogenic dyslipidemia, dysglycemia, or both. In the present work we analyzed compositional characteristics of HDL subpopulations and functional activity of small, dense HDL3c particles in treatment-naïve patients with well-controlled (n=10) and poorly-controlled (n=8) type 2 diabetes (T2D) and in normolipidemic age- and sex-matched controls (n=11). Our data reveal that patients with both well- and poorly-controlled T2D displayed dyslipidemia and low-grade inflammation associated with altered HDL composition. Such compositional alterations in small, dense HDL subfractions were specifically correlated with plasma HbA1c levels. Further analysis using a lipidomic approach revealed that small, dense HDL3c particles from T2D patients with poor glycemic control displayed additional modifications of their chemical composition. In parallel, antioxidative activity of HDL3c towards oxidation of low-density lipoprotein was diminished. These findings indicate that defective functionality of small, dense HDL particles in patients with T2D is not only affected by the presence of atherogenic dyslipidemia, but also by the level of glycemic control, reflecting compositional alterations of HDL.
INSERM UMR_S 1166, Faculte de Medecine Pitie-Salpetriere, 91 Bld de l'Hopital, 75013 Paris, France; University of Pierre and Marie Curie - Paris 6, Paris, France; Laboratory of Lipids and Atherosclerosis, Department of Clinical Biochemistry, INFIBIOC, University of Buenos Aires, CONICET, Buenos Aires, Argentina.
Leonardo
L
Gomez Rosso
Institute of Cardiometabolism and Nutrition (ICAN), Paris F-75013, France.
Marie
M
Lhomme
Laboratory of Lipids and Atherosclerosis, Department of Clinical Biochemistry, INFIBIOC, University of Buenos Aires, CONICET, Buenos Aires, Argentina.
Tomas
T
Meroño
Ramón Carrillo Centre, La Matanza, Buenos Aires, Argentina.
Ana
A
Dellepiane
Laboratory Service, Italian Hospital, Buenos Aires, Argentina.
Patricia
P
Sorroche
Institute of Cardiometabolism and Nutrition (ICAN), Paris F-75013, France; Ramón Carrillo Centre, La Matanza, Buenos Aires, Argentina.
Lyamine
L
Hedjazi
INSERM UMR_S 1166, Faculte de Medecine Pitie-Salpetriere, 91 Bld de l'Hopital, 75013 Paris, France; University of Pierre and Marie Curie - Paris 6, Paris, France; Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, 8, Baltiyskaya Str., 125315 Moscow, Russia.
Emile
E
Zakiev
INSERM UMR_S 1166, Faculte de Medecine Pitie-Salpetriere, 91 Bld de l'Hopital, 75013 Paris, France; University of Pierre and Marie Curie - Paris 6, Paris, France; Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, 8, Baltiyskaya Str., 125315 Moscow, Russia.
Vasily
V
Sukhorukov
Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, 8, Baltiyskaya Str., 125315 Moscow, Russia; Institute for Atherosclerosis Research, Skolkovo Innovative Center, PO Box #21, 121609 Moscow, Russia.
Alexander
A
Orekhov
Laboratory of Lipids and Atherosclerosis, Department of Clinical Biochemistry, INFIBIOC, University of Buenos Aires, CONICET, Buenos Aires, Argentina.
Julieta
J
Gasparri
INSERM UMR_S 1166, Faculte de Medecine Pitie-Salpetriere, 91 Bld de l'Hopital, 75013 Paris, France; University of Pierre and Marie Curie - Paris 6, Paris, France.
M John
MJ
Chapman
Laboratory of Lipids and Atherosclerosis, Department of Clinical Biochemistry, INFIBIOC, University of Buenos Aires, CONICET, Buenos Aires, Argentina.
Fernando
F
Brites
INSERM UMR_S 1166, Faculte de Medecine Pitie-Salpetriere, 91 Bld de l'Hopital, 75013 Paris, France; University of Pierre and Marie Curie - Paris 6, Paris, France. Electronic address: anatol.kontush@upmc.fr.
Anatol
A
Kontush
D000975:Antioxidants / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood* / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000378:metabolism*; D050171:Dyslipidemias / Q000097:blood / Q000378:metabolism; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism; D038321:Glycemic Index / Q000502:physiology; D006801:Humans; D052456:Hypoalphalipoproteinemias / Q000097:blood / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000097:blood; D008297:Male; D008875:Middle Aged; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology
D000975:Antioxidants; D001786:Blood Glucose; D008076:Cholesterol, HDL; D006442:Glycated Hemoglobin; D008077:Lipoproteins, LDL; C517652:hemoglobin A1c protein, human
Antioxidative activity; Functionality; HDL; Lipidomics; Type 2 diabetes