Diabetes and cancer: the mechanistic implications of epidemiological analyses from the Hong Kong Diabetes Registry

Abstract

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, triglyceride 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 dysregulation of cholesterol metabolism, renin-angiotensin system and adenosine 5'-monophosphate-activated protein kinase pathways, all of which may be implicated 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.

Enhancers and attenuators of risk associations of chronic hepatitis B virus infection with hepatocellular carcinoma in type 2 diabetes

“…The activation of the cholesterol pathway can increase RAS signals and other oncogenes resulting in increased cancer risk (Yang et al 2012b). In this connection, the enhanced effect of HBV infection on HCC risk by co-presence of low LDLC plus low TG and its attenuation by use of insulin or statins strongly supported our hypothesis.…”

“…In a recent review article, based on a large body of clinical and experimental findings, we hypothesized that these epidemiological findings might reflect increased oxidative stress and upregulation of the RAS activity, secondary to hyperglycemia (Yang et al 2012b) with inflammation (Yang et al 2010c) and/or dysregulated cholesterol metabolism (Yang et al 2009b) as mediating pathways. In this study, we did not detect significant interaction of co-presence of low LDLC plus albuminuria with HBsAg for HCC.…”

“…Secondly, we adjusted for HbA1c (Yang et al 2010a,b), systolic BP and risk factors in T2D for cancer that showed nonlinear relationships with cancer. These risk factors included LDLC-related risk indicators (LDLC !2.80 mmol/l plus TG !1.7 mmol/l, LDLC !2.80 mmol/l plus albuminuria, LDLC R3.80 mmol/l; Yang et al 2012b) and HDL-cholesterol-related risk indicators (HDLC !1.0 and R1.30 mmol/l; Yang et al 2011b). In addition, we adjusted for use of insulin (Yang et al 2010a), metformin (Yang et al 2011b), RAS inhibitors (Yang et al 2009b(Yang et al , 2010c, gliclazide/glibenclamide (Yang et al 2010d), and rosiglitazone/pioglitazone during follow-up (Yang et al 2012c), which was defined as use of the drug from enrollment to the earliest date of HCC, death, or 30 July 2005, whichever came first.…”

“…Using the Hong Kong Diabetes Registry, we reported a series of drug-subphenotype interactions, based on which we put forth an integrated hypothesis, supported by results from mechanistic studies, to explain the biological links between type 2 diabetes (T2D) and cancer (Yang et al 2012b). These included i) downregulation of the adenosine 5 0 -monophosphate-activated protein kinase (AMPK) pathway suggested by the attenuated cancer risk in metformin users with low HDL cholesterol (HDLC !1.0 mmol/l; Yang et al 2011b); ii) activation of the renin-angiotensin system (RAS) and low-grade inflammation suggested by the attenuated cancer risk in RAS inhibitor users with high white blood cell count (WBC R8.2!10 9 /l; Yang et al 2010c); iii) activation of the RAS and dysregulation of cholesterol metabolism suggested by the attenuated cancer risk in statin users with co-presence of low LDL cholesterol (LDLC; !2.8 mmol/l) plus albuminuria (Yang et al 2009a) with possible cross talks between the RAS and lipid metabolism (Yang et al 2009b); and iv) insulin insufficiency with dysregulation of the insulin-like growth factor 1 (IGF1) and the cholesterol synthesis pathway via the sterol regulatory binding protein 1 (SREBP1), suggested by a synergistic effect of triglyceride (TG) !1.7 mmol/l and LDLC !2.8 mmol/l for cancer (Yang et al 2012a) and attenuated cancer risk in statin users with TG !1.7 mmol/l (Yang et al 2011a).…”

“…Diabetes is associated with increased risk of a spectrum of cancers (Yang et al 2012b) with a linear relationship between HbA1c and all-site cancer risk (Yang et al 2010a). In most surveys, among site-specific cancers, HCC ranks second in terms of strength of association with diabetes (El-Serag et al 2006), only preceded by pancreatic cancer (Everhart & Wright 1995).…”