The emerging role of HDL in glucose metabolism

Drew, Brian G.; Rye, Kerry-Anne; Duffy, Stephen J.; Barter, Philip; Kingwell, Bronwyn A.

doi:10.1038/nrendo.2011.235

Cited by 307Diabetes, Cardiovascular Risks, and LipoproteinsCholesterol and Lipid MetabolismAdipokines, Inflammation, and Metabolic Diseases

The emerging role of HDL in glucose metabolism

Drew, Brian G., Rye, Kerry-Anne, Duffy, Stephen J., Barter, Philip, Kingwell, Bronwyn A.·2012·Nature Reviews Endocrinology

DOI 10.1038/nrendo.2011.235

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Abstract

A low plasma level of HDL cholesterol is an atherosclerotic risk factor; however, emerging evidence suggests that low HDL levels might also contribute to the pathophysiology of type 2 diabetes mellitus (T2DM) through direct effects on plasma glucose. In the past decade, animal and clinical studies have uncovered a previously undescribed spectrum of HDL actions, indicating that HDL may control glucose homeostasis through mechanisms including insulin secretion, direct glucose uptake by muscle via the AMP-activated protein kinase, and possibly enhanced insulin sensitivity. These effects are mediated by multiple cell types via mechanisms including preservation of cell function through cellular lipid removal and also via direct signaling events. We suggest a paradigm shift from HDL being a bystander to being an active player in diabetic pathophysiology, which raises the possibility that HDL elevation could be a novel therapeutic avenue for T2DM. The entry of HDL-raising agents of the cholesteryl ester transfer protein (CETP) inhibitor class into late-phase clinical trials creates potential for rapid clinical translation. This Review will discuss the emerging evidence for a role of HDL-mediated glucose regulation in the pathophysiology of T2DM, and will also outline the therapeutic potential for HDL elevation for the prevention and management of T2DM.

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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 [34]

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Clinical Update: Cardiovascular Disease in Diabetes Mellitus
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Prevalence of and risk factors for diabetic peripheral neuropathy in youth with type 1 and type 2 diabetes: SEARCH for Diabetes in Youth study
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Lipoprotein Particles and Incident Type 2 Diabetes in the Multi-Ethnic Study of Atherosclerosis
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HDL functionality
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Lipidome as a predictive tool in progression to type 2 diabetes in Finnish men
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Interaction between high-density lipoproteins and inflammation: function matters more than concentration!
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HDL in Atherosclerotic Cardiovascular Disease: In Search of a Role
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Role of HDL Cholesterol and Estimates of HDL Particle Composition in Future Development of Type 2 Diabetes in the General Population: The PREVEND Study
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Reverse Engineering and Evaluation of Prediction Models for Progression to Type 2 Diabetes
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Statins are diabetogenic – Myth or reality?
Sattar, N. A., & Taskinen, M. (2012) · Atherosclerosis Supplements · doi:10.1016/j.atherosclerosissup.2012.06.001 · Cited by 104 · see citing works
HDL endocytosis and resecretion
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Type 2 diabetes mellitus unawareness, prevalence, trends and risk factors: National Health and Nutrition Examination Survey (NHANES) 1999–2010
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Triglycerides to high-density lipoprotein–cholesterol ratio, glycemic control and cardiovascular risk in obese patients with type 2 diabetes
Quispe, R., Martin, S. S., & Jones, S. R. (2016) · Current Opinion in Endocrinology Diabetes and Obesity · doi:10.1097/med.0000000000000241 · Cited by 99 · see citing works
The Triglyceride/HDL Ratio and Triglyceride Glucose Index as Predictors of Glycemic Control in Patients with Diabetes Mellitus Type 2
Babić, N., Valjevac, A., Začiragić, A., Avdagić, N., Zukić, S., & Hasić, S. (2019) · Medical Archives · doi:10.5455/medarh.2019.73.163-168 · Cited by 97 · see citing works
Beginning to Understand High-Density Lipoproteins
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Macrophage Polarization: Implications on Metabolic Diseases and the Role of Exercise
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HDL and glucose metabolism: current evidence and therapeutic potential
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HDL and type 2 diabetes: the chicken or the egg?
Xepapadaki, E., Nikdima, I., Sagiadinou, E. C., Zvintzou, E., & Kypreos, K. E. (2021) · Diabetologia · doi:10.1007/s00125-021-05509-0 · Cited by 89 · see citing works
The Role of High-Density Lipoproteins in Diabetes and Its Vascular Complications
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Insulin sensitivity across the lifespan from obese adolescents to obese adults with impaired glucose tolerance: Who is worse off?
Arslanian, S., Kim, J., Nasr, A., Bacha, F., Tfayli, H., Lee, S., & Toledo, F. (2018) · Pediatric Diabetes · doi:10.1111/pedi.12562 · Cited by 69 · see citing works
Nonlinear relationship between untraditional lipid parameters and the risk of prediabetes: a large retrospective study based on Chinese adults
Li, M., Zhang, W., Zhang, M., Li, L., Wang, D., Yan, G., Qiao, Y., & Tang, C. (2024) · Cardiovascular Diabetology · doi:10.1186/s12933-023-02103-z · Cited by 75 · see citing works
The association between triglyceride-glucose index and the incidence of type 2 diabetes mellitus—a systematic review and dose–response meta-analysis of cohort studies
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Endoplasmic reticulum stress impairs cholesterol efflux and synthesis in hepatic cells
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HDL Cholesterol and Non-Cardiovascular Disease: A Narrative Review
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Effects of High-Density Lipoprotein Elevation With Cholesteryl Ester Transfer Protein Inhibition on Insulin Secretion
Siebel, A. L., Natoli, A. K., Yap, F. Y. T., Carey, A. L., Reddy-Luthmoodoo, M., Sviridov, D., Weber, C. I. K., Meneses‐Lorente, G., Maugeais, C., Forbes, J. M., et al. (2013) · Circulation Research · doi:10.1161/circresaha.113.300689 · Cited by 71 · see citing works
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Effect of Gum Arabic (Acacia Senegal) supplementation on visceral adiposity index (VAI) and blood pressure in patients with type 2 diabetes mellitus as indicators of cardiovascular disease (CVD): a randomized and placebo-controlled clinical trial
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Triglycerides/HDL cholesterol ratio and type 2 diabetes incidence: Panasonic Cohort Study 10
Yuge, H., Okada, H., Hamaguchi, M., Kurogi, K., Murata, H., Ito, M., & Fukui, M. (2023) · Cardiovascular Diabetology · doi:10.1186/s12933-023-02046-5 · Cited by 68 · see citing works
HDL-C and HDL-C/ApoA-I Predict Long-Term Progression of Glycemia in Established Type 2 Diabetes
Waldman, B., Jenkins, A. J., Davis, T. M. E., Taskinen, M., Scott, R. S., O'Connell, R. L., Gebski, V., Ng, M., & KEECH, A. C. (2014) · Diabetes Care · doi:10.2337/dc13-2738 · Cited by 69 · see citing works
Rethinking good cholesterol: a clinicians' guide to understanding HDL
Xiang, A. S., & Kingwell, B. A. (2019) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(19)30003-8 · Cited by 66 · see citing works
Self-citation
HDL-Cholesterol, Its Variability, and the Risk of Diabetes: A Nationwide Population-Based Study
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Authors: Drew, B. G., Rye, K.-A., Duffy, S. J., Barter, P., & Kingwell, B. A.
Affiliations: Baker Heart and Diabetes Institute (AU)
The Heart Research Institute (AU)
The Alfred Hospital (AU)
Corresponding author: Kingwell, Bronwyn A.
ORCID: Drew, Brian G.
Rye, Kerry-Anne
Duffy, Stephen J.
Kingwell, Bronwyn A.
Venue: Nature Reviews Endocrinology
Publisher: Springer Science and Business Media LLC
Published: 2012-01-24
Volume: 8
Issue: 4
Pages: 237-245
ISSN: 1759-5029 (ISSN-L)
1759-5037
DOI: 10.1038/nrendo.2011.235
OpenAlex: W1982981124
Cited by: 307
References: 114
Citations by year: 2026: 14 · 2025: 33 · 2024: 36 · 2023: 29 · 2022: 24 · 2021: 23 · 2020: 16 · 2019: 18 · 2018: 14 · 2017: 22 · 2016: 19 · 2015: 15 · 2014: 21 · 2013: 16 · 2012: 6
FWCI: 2.55
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature Reviews Endocrinology (publishedVersion)
PubMed (publishedVersion)
Funders: State Government of Victoria
National Health and Medical Research Council
National Medical Research Council
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Keywords: high-density lipoprotein, glucose metabolism, glucose homeostasis, type 2 diabetes, insulin secretion, AMPK, muscle glucose uptake, insulin sensitivity, CETP inhibitors, HDL-raising therapy, atherosclerosis, lipid removal
MeSH terms: Animals, Blood Glucose, Diabetes Mellitus, Type 2, Humans, Insulin, Lipoproteins, HDL, Cholesterol, HDL

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