Diabetes and cancer: the mechanistic implications of epidemiological analyses from the Hong Kong Diabetes Registry Xilin Yang 1,4 * Wing-Yee So 1,2,3 Ronald CW Ma 1,2,3 Alice PS Kong 1,2,3 Gang Xu 1,2,3 Juliana CN Chan 1,2,3 * 1 Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China 2 Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong SAR, China 3 Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China 4 Department of Epidemiology, Public Health College, Tianjin Medical University, Tianjin, China *Correspondence to: Xilin Yang, Department of Epidemiology, Public Health College, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin 300070, China. E-mail: yxl@hotmail.com Juliana CN Chan, Department of Medicine and Therapeutics, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China. Email: jchan@cuhk.edu.hk Summary Diabetes is a disorder of energy metabolism associated with increased cancer risk, but the underlying mechanism is poorly understood. In a prospective cohort of patients enrolled in the Hong Kong Diabetes Registry, we explored risk factors for cancer including drug usage in type 2 diabetes. In a series of published papers, we reported a linear risk association of cancer with glycated haemoglobin with a threshold at 6.0%–6.5% and non-linear risk associations of body mass index, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycer- ide and white blood cell (WBC) count in V-shaped or A-shaped manners. Detailed pharmacoepidemiological analysis revealed markedly attenuated cancer risk in patients treated with insulin and oral anti-diabetic drugs compared with non-users of these drugs. We further observed significant drug–subphenotype interactions with attenuated cancer risk in metformin users with low high-density lipoprotein cholesterol, renin-angiotensin system (RAS) inhibitor users with high WBC count and statin users with co-presence of low low-density lipoprotein cholesterol plus albuminuria or low triglyceride. These novel observations corroborate with experimental findings of possible consequences of hyperglycaemia on dysre- gulation of cholesterol metabolism, renin-angiotensin system and adenosine 5′-monophosphate-activated protein kinase pathways, all of which may be impli- cated in carcinogenesis. On the basis of these epidemiological and experimental findings, we argue for the strong need to strengthen the health care system to ensure that type 2 diabetes subjects receive appropriate drugs to optimize internal milieu to reduce all events including cancer. Apart from mechanistic studies, large-scale, randomized clinical trials using medications such as statin, renin-angiotensin system inhibitors and metformin in patients with risk- conferring subphenotypes are needed to confirm their anti-cancer effects. Copyright © 2012 John Wiley & Sons, Ltd. Keywords diabetes; cancer; cholesterol; risk factor; mechanism Abbreviations AMPK, adenosine 5’-monophosphate-activated protein ki- nase; APOA-I, apolipoprotein A-I; ACEIs, angiotensin-converting enzyme inhibi- tors; ARBs, angiotensin II receptor blockers; IGF, insulin-like growth factor; HDL-C, high-density lipoprotein cholesterol; HMGCR, hydroxymethylglutaryl- CoA reductase; LDL-C, low-density lipoprotein cholesterol; LKB1, human tumour suppressor, serine/threonine kinase 11; mTOR, mammalian target of rapamycin; RAS, renin angiotensin system; SREBPs, sterol regulatory element- binding proteins; WBC, white blood cell Introduction Diabetes is a global epidemic with rapidly rising prevalence in developing areas such as Asia [1,2]. In addition to cardiovascular and renal diseases, diabetic REVIEW ARTICLE Received: 6 October 2011 Revised: 11 December 2011 Accepted: 21 January 2012 Copyright © 2012 John Wiley & Sons, Ltd. DIABETES/METABOLISM RESEARCH AND REVIEWS Diabetes Metab Res Rev 2012; 28: 379–387. Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/dmrr.2287