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

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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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Additional file 2 of Cholesterol reprograms glucose and lipid metabolism to promote proliferation in colon cancer cells
Mayengbam, S. S., Singh, A., Yaduvanshi, H., Bhati, F. K., Deshmukh, B., Athavale, D., Ramteke, P. L., & Bhat, M. K. (2023) · Figshare · doi:10.6084/m9.figshare.24136373
Additional file 1 of Triglyceride-rich lipoprotein and LDL particle subfractions and their association with incident type 2 diabetes: the PREVEND study
Sokooti, S., Flores-Guerrero, J. L., Heerspink, H. J. L., Connelly, M. A., Bakker, S. J. L., & Dullaart, R. P. F. (2021) · Figshare · doi:10.6084/m9.figshare.15071330
Additional file 1 of Impact of stress hyperglycemia ratio, derived from glycated albumin or hemoglobin A1c, on mortality among ST-segment elevation myocardial infarction patients
Liao, W., Chen, Y., Gao, Q., Gan, R., Li, M., Liu, Z., Liang, J., Cui, H., Ren, K., Liu, Y., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26650488
Additional file 1 of 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) · Figshare · doi:10.6084/m9.figshare.26664112
Additional file 6 of Impact of stress hyperglycemia ratio, derived from glycated albumin or hemoglobin A1c, on mortality among ST-segment elevation myocardial infarction patients
Liao, W., Chen, Y., Gao, Q., Gan, R., Li, M., Liu, Z., Liang, J., Cui, H., Ren, K., Liu, Y., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26650503
Additional file 2 of 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. (2024) · Figshare · doi:10.6084/m9.figshare.26637552
Additional file 2 of Impact of stress hyperglycemia ratio, derived from glycated albumin or hemoglobin A1c, on mortality among ST-segment elevation myocardial infarction patients
Liao, W., Chen, Y., Gao, Q., Gan, R., Li, M., Liu, Z., Liang, J., Cui, H., Ren, K., Liu, Y., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26650491
Additional file 5 of Impact of stress hyperglycemia ratio, derived from glycated albumin or hemoglobin A1c, on mortality among ST-segment elevation myocardial infarction patients
Liao, W., Chen, Y., Gao, Q., Gan, R., Li, M., Liu, Z., Liang, J., Cui, H., Ren, K., Liu, Y., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26650500
Additional file 2 of 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) · Figshare · doi:10.6084/m9.figshare.26664118
Additional file 3 of Impact of stress hyperglycemia ratio, derived from glycated albumin or hemoglobin A1c, on mortality among ST-segment elevation myocardial infarction patients
Liao, W., Chen, Y., Gao, Q., Gan, R., Li, M., Liu, Z., Liang, J., Cui, H., Ren, K., Liu, Y., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26650494
Additional file 4 of Impact of stress hyperglycemia ratio, derived from glycated albumin or hemoglobin A1c, on mortality among ST-segment elevation myocardial infarction patients
Liao, W., Chen, Y., Gao, Q., Gan, R., Li, M., Liu, Z., Liang, J., Cui, H., Ren, K., Liu, Y., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26650497
Additional file 1 of Longitudinal trajectories of atherogenic index of plasma and risks of cardiovascular diseases: results from the Korean genome and epidemiology study
Chun, D.-W., Lee, Y.-J., Lee, J.-H., & Lee, J.-W. (2024) · Figshare · doi:10.6084/m9.figshare.26618086
Additional file 1 of Non-linear relationship between high-density lipoprotein cholesterol and incident diabetes mellitus: a secondary retrospective analysis based on a Japanese cohort study
Cao, C., Hu, H., Zheng, X., Zhang, X., Wang, Y., & He, Y. (2022) · Figshare · doi:10.6084/m9.figshare.20098757
Additional file 1 of Cholesterol reprograms glucose and lipid metabolism to promote proliferation in colon cancer cells
Mayengbam, S. S., Singh, A., Yaduvanshi, H., Bhati, F. K., Deshmukh, B., Athavale, D., Ramteke, P. L., & Bhat, M. K. (2023) · Figshare · doi:10.6084/m9.figshare.24136370
Additional file 1 of Association between atherogenic index of plasma and gestational diabetes mellitus: a prospective cohort study based on the Korean population
Zhang, J., Suo, Y., Wang, L., Liu, D., Jia, Y., Fu, Y., Fan, W., & Jiang, Y. (2024) · Figshare · doi:10.6084/m9.figshare.26744576
Additional file 3 of 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) · Figshare · doi:10.6084/m9.figshare.26664124
Additional file 1 of The relationship between the ratio of gamma-glutamyltransferase to high-density lipoprotein cholesterol and the risk of diabetes mellitus using publicly available data: a secondary analysis based on a longitudinal study in Japan
Zhao, Y., Xin, X., & Luo, X.-P. (2024) · Figshare · doi:10.6084/m9.figshare.26561869
Additional file 1 of 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. (2024) · Figshare · doi:10.6084/m9.figshare.26637549
Mediating effects of maternal blood lipids and glucose on the relationship between pre-pregnancy body mass index and newborn birth weight in women with gestational diabetes mellitus
Li, H., Xiang, Z., Li, H., Xie, C., Zeng, L., Liang, Y., Gao, L., & Li, Z. (2025) · BMC Pregnancy and Childbirth · doi:10.1186/s12884-025-08264-x
Hydroxychloroquine alters lipoprotein particle concentrations and composition
Mendes, T. B., Miller, R. G., & Toledo, F. G. S. (2026) · Journal of clinical lipidology · doi:10.1016/j.jacl.2026.01.012
The Association between Triglycerides to High-density Lipoprotein Cholesterol (TG/HDL-C) Ratio and 10-year Prospective Risk of Type 2 Diabetes Mellitus: Yazd Healthy Heart Project
Poorebrahimi, M., Mirjalili, S. R., Soltani, S., Marques-Vidal, P. M., Namayandeh, S. M., & Sarebanhassanabadi, M. (2026) · Advanced Biomedical Research · doi:10.4103/abr.abr_221_25
Linear associations of triglyceride-glucose body mass index and atherogenic index of plasma with the risk of diabetes: a retrospective cohort study
Wang, S., Li, K., Wang, X., Zhou, L., Deng, C., & Xu, G. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2026.1812819

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
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › 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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