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HDL metabolism and function in diabetes mellitus

Nature Reviews Endocrinology (2025)Cite this article

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Abstract

Epidemiological studies have identified an inverse association of high-density lipoprotein (HDL) cholesterol with cardiovascular risk. Preclinical studies have shown that HDLs also exhibit cardioprotective functions in cultured cells and animal models. However, large, randomized, placebo-controlled clinical trials of HDL-raising agents have failed to reduce cardiovascular events in humans. Despite this negative outcome, glycaemic control was considerably improved in the patients with type 2 diabetes mellitus who were recruited into these trials. This finding indicated that HDLs might have anti-diabetic functions. This was shown to be the case in cell studies and animal studies, which have established that HDLs and apolipoprotein A1, the main HDL apolipoprotein, improve pancreatic β-cell function and increase insulin sensitivity. On the other hand, diabetes mellitus adversely affects the structure, anti-diabetic functions and cardioprotective functions of HDLs. These complex, closely linked relationships, which are undoubtedly worthy of further investigation, form the focus of this Review.

Key points

  • High-density lipoproteins (HDLs) improve glycaemic control in vitro and in vivo by increasing insulin sensitivity and improving β-cell function.

  • Diabetes mellitus appears to have a minimal effect on the reverse cholesterol transport pathway.

  • Improving glycaemic control might enhance the antioxidant function of HDLs.

  • Diabetes mellitus impairs the ability of HDLs to improve endothelial dysfunction.

  • Non-enzymatic glycation of HDL apolipoproteins reduces their anti-inflammatory function.

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Fig. 1: HDL metabolism under physiological conditions and diabetic conditions.
Fig. 2: APOA1 and HDLs increase insulin sensitivity.
Fig. 3: APOA1 and HDLs improve β-cell function.

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Acknowledgements

The authors are supported by the National Health and Medical Research Council of Australia (APPP2004064 to K.A.R. and B.J.C.).

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    Blake J. Cochran, Thomas W. King, Kevin Chemello, Shane R. Thomas & Kerry-Anne Rye

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K.A.R., B.J.C., T.W.K. and S.R.T. researched data for the article. K.A.R., B.J.C., T.W.K. and S.R.T. wrote the article. K.A.R. and K.C. reviewed and/or edited the manuscript before submission.

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Cochran, B.J., King, T.W., Chemello, K. et al. HDL metabolism and function in diabetes mellitus. Nat Rev Endocrinol (2025). https://doi.org/10.1038/s41574-025-01176-y

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