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Cited by 443Diabetes, Cardiovascular Risks, and LipoproteinsMetabolism, Diabetes, and CancerCholesterol and Lipid Metabolism

High-Density Lipoprotein Modulates Glucose Metabolism in Patients With Type 2 Diabetes Mellitus

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Drew, Brian G., Duffy, Stephen J., Formosa, Melissa F., Natoli, Alaina K., Henstridge, Darren C., Penfold, Sally A., Thomas, Walter G., Mukhamedova, Nigora +10 more·2009·Circulation
DOI 10.1161/circulationaha.108.843219
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Abstract

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. Methods and 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±0.3mmol/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 β-cell function index (at 4 hours rHDL=18.9±5.9; placebo=8.6±4.4%; P =0.025). Acetyl-CoA carboxylase β 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.

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  • The finding of lower risk of new-onset diabetes with obicetrapib is consistent with previous mechanistic evidence linking CETP inhibition and HDL-C elevation to improved glucose metabolism.

    “This finding is consistent with previous mechanistic evidence linking CETP inhibition and HDL-C elevation to improved glucose metabolism [33,34].”

    From Efficacy and safety of obicetrapib in patients with dyslipidemia: An updated meta-analysis of randomized controlled trials (2025) · cites this paper as [33]

    The Clinical Perspective reports that short-term HDL elevation reduced plasma glucose through increased insulin and muscle glucose uptake. But the Clinical Implications section says no data had been published on the glucose-metabolic actions of CETP-inhibiting HDL-raising agents, so this paper does not provide mechanistic evidence for that part of the claim. Page numbers were not available in our copy. (LLM, conf=0.88)

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  31. CLINICAL PERSPECTIVE Low plasma high-density lipoprotein (HDL) is an important risk factor for cardiovascular disease. Low HDL has also been associated with metabolic syndromes, whereas high HDL associated with physical training occurs in conjunction with enhanced glucose tolerance. Despite such associations, this is the first clinical study to describe a mechanistic link between HDL and glucose metabolism. The primary observation of reduced plasma glucose after short-term HDL elevation is underpinned by at least 2 mechanisms: elevated plasma insulin and enhanced muscle glucose uptake via AMP-activated protein kinase. Of clinical relevance is whether long-term HDL elevation reduces plasma glucose and by what mechanisms. Intense interest currently exists in HDL-raising therapeutics to combat atherosclerosis. Cholesteryl ester transfer protein inhibitors are currently the most potent class of HDL-raising agents. Although the first large cholesteryl ester transfer protein inhibitor clinical trial was stopped because of off-target effects, second-generation cholesteryl ester transfer protein inhibitors show promise, as do agents that increase apolipoprotein AI gene expression. Although ongoing clinical trials will determine the efficacy of these agents to combat vascular disease, the present data suggest efficacy in the management of metabolic syndromes including diabetes mellitus. On this basis, metabolic parameters such as glucose and insulin should be examined in large trials of HDL-raising agents. In addition, mechanistic trials using gold-standard metabolic analyses to examine the effects of long-term HDL elevation on insulin secretion, insulin resistance, and glucose turnover parameters are warranted. If positive, such trials would provide a rationale for HDL-raising agents beyond vascular disease to manage type 2 diabetes mellitus. Go to http://cme.ahajournals.org to take the CME quiz for this article.

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Authors
Drew, B. G., Duffy, S. J., Formosa, M. F., Natoli, A. K., Henstridge, D. C., Penfold, S. A., Thomas, W. G., Mukhamedova, N., de Courten, B., Forbes, J. M., Yap, F. Y., Kaye, D. M., van Hall, G., Febbraio, M. A., Kemp, B. E., Sviridov, D., Steinberg, G. R., & Kingwell, B. A.
Affiliations
  • Commonwealth Scientific and Industrial Research Organisation (AU)
  • From Baker IDI Heart and Diabetes Institute, Melbourne, Australia (B.G.D., S.J.D., M.F.F., A.K.N., D.C.H., S.A.P., W.G.T., N.M., B.d.C., J.M.F., F.Y.Y., D.M.K., M.A.F., D.S., B.A.K.); Department of Medicine, Monash University, Clayton, Australia (B.G.D., D.C.H.); Copenhagen Muscle Research Centre, Copenhagen, Denmark (G.v.H.); St Vincent’s Institute of Medical Research and Department of Medicine, Fitzroy, Australia (B.E.K., G.R.S.); and Commonwealth Scientific and Industrial Research Organization,...
ORCID
Venue
Circulation
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2009-04-21
Volume
119
Issue
15
Pages
2103-2111
ISSN
  • 0009-7322 (ISSN-L)
  • 1524-4539
DOI
10.1161/circulationaha.108.843219
OpenAlex
W2033590944
Cited by
443
References
10
Citations by year
2026: 10 · 2025: 28 · 2024: 28 · 2023: 35 · 2022: 34 · 2021: 26 · 2020: 26 · 2019: 29 · 2018: 24 · 2017: 18 · 2016: 21 · 2015: 19 · 2014: 28 · 2013: 34 · 2012: 30
FWCI
20.15
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Circulation (publishedVersion)
  • PubMed (publishedVersion)
  • Figshare (submittedVersion, cc-by)
  • Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
Funders
CSL Behring
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords
high-density lipoprotein, reconstituted HDL, type 2 diabetes, glucose metabolism, plasma glucose, insulin, beta-cell function, AMPK, acetyl-CoA carboxylase, skeletal muscle, apolipoprotein A-I, ABCA1, glucose uptake, HDL-raising therapy
MeSH terms
Insulin Secretion, Animals, Cells, Cultured, Diabetes Mellitus, Type 2, Double-Blind Method, Fatty Acids, Female, Glucose, Humans, Infusions, Intravenous, Insulin, Islets of Langerhans, Lipoproteins, HDL, Lipoproteins, LDL, Male, Middle Aged, Phenformin, Signal Transduction, Apolipoprotein A-I, Calcium-Calmodulin-Dependent Protein Kinases, Muscle, Skeletal, ATP-Binding Cassette Transporters, Cross-Over Studies, Calcium Signaling, Muscle Cells, Mice, AMP-Activated Protein Kinases, ATP Binding Cassette Transporter 1

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