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Drug–subphenotype interactions for cancer in type 2 diabetes mellitus

Nature Reviews Endocrinology volume 11, pages 372–379 (2015)Cite this article

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Abstract

On the basis of data obtained from a prospective cohort of Chinese patients with type 2 diabetes mellitus (T2DM), we discuss cancer subphenotypes (risk factors) in patients with T2DM, which can lead to drug–cancer subphenotype interactions. These subphenotypes include HDL cholesterol levels <1.0 mmol/l, co-occurrence of LDL cholesterol levels <2.8 mmol/l and triglyceride levels <1.7 mmol/l, and co-occurrence of LDL cholesterol levels <2.8 mmol/l and albuminuria. The increased risk of cancer associated with low levels of HDL cholesterol, low LDL cholesterol levels plus low triglyceride levels, and low levels of LDL cholesterol plus albuminuria can be reduced by treatment with metformin, renin–angiotensin system (RAS) inhibitors and statins, respectively. Mechanistic studies support the hypothesis that dysregulation of the 5′-AMP-activated protein kinase pathway and crosstalk between the RAS and insulin-like growth factor 1–cholesterol pathways create a cancer-promoting milieu in patients with T2DM. These findings highlight that in Chinese individuals, multiple pathways are implicated in the link between T2DM and cancer, which can generate multiple subphenotypes as well as drug–subphenotype interactions.

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Figure 1: Hypothetical consequences of insulin deficiency and activation of the RAS and IGF-1–cholesterol pathways.

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Acknowledgements

X.Y., H.M.L. and J.C.N.C. acknowledge H. Gerstein, McMaster University, Canada, for advice regarding this article, and thank all clinical and supporting staff involved in setting up the Hong Kong Diabetes Registry and all patients for donating their anonymized data for research and education purposes.

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Authors and Affiliations

  1. Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Tianjin, 300070, Heping District, China

    Xilin Yang

  2. Department of Medicine and Therapeutics, Hong Kong Institute of Diabetes and Obesity, and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, 30–32 Ngan Shing Street, Hong Kong SAR, Shatin, New Territories, China

    Heung M. Lee & Juliana C. N. Chan

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X.Y. and J.C.N.C. contributed equally to researching data for the article, to providing substantial contributions to discussions of the content, to writing the article and to reviewing and/or editing of the manuscript before submission. H.M.L. provided a substantial contribution to discussions of the content and reviewed and/or edited the manuscript before submission.

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Correspondence to Xilin Yang or Juliana C. N. Chan.

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Competing interests

J.C.N.C. declares that she is a board member of the Asia Diabetes Foundation, has acted as a consultant for AstraZeneca, Bayer, Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, Sanofi and Qualigenics, and that she has received honoraria, travel expenses and/or payments from AstraZeneca, Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Merck Serono, Merck Sharp & Dohme, Nestle Nutrition Institute, Novo Nordisk, Pfizer, Roche, Sanofi and Takeda for giving lectures. H.M.L. and X.Y. declare no competing interests.

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Yang, X., Lee, H. & Chan, J. Drug–subphenotype interactions for cancer in type 2 diabetes mellitus. Nat Rev Endocrinol 11, 372–379 (2015). https://doi.org/10.1038/nrendo.2015.37

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