Plasma C‐peptide and glycated albumin and subsequent risk of cancer: From a large prospective case‐cohort study in Japan

To elucidate the individual impacts of insulin and blood glucose on cancer risk, we investigated the association of plasma C‐peptide, a surrogated marker of insulin and glycated albumin (GA), a more stable marker of blood glucose, with all‐site and site‐specific cancer risk by mutually accounting for their confounding effects. The study was prospectively conducted with nearly 4,000 cancer cases arising in our population‐based cohort of 33,736 subjects who answered the baseline questionnaire and supplied blood samples. After exclusion of subjects with apparent DM, analysis was done in 3,036 cancer cases and 3,667 subcohort subjects. Among men and women combined, highest levels of C‐peptide were statistically significantly associated with an increased risk of all‐site [Hazard ratio (HR): 1.21; 95% confidence interval: 1.02–1.42], colon [1.73; 1.20–2.47], liver [3.23; 1.76–5.91], kidney, renal pelvis and ureter cancers [2.47; 1.07–5.69], compared to the respective lowest levels, after adjustment for GA levels. Among these C‐peptide‐related cancers, colon and liver cancers also showed an increased risk associated with elevated GA levels independently of C‐peptide levels. The corresponding HRs for colon and liver cancers compared to the highest and lowest GA levels were 1.43 [1.02–2.00] and 2.02 [1.15–3.55], respectively. Effect modification by gender was only evident for the association between C‐peptide and colon cancer (p for interaction = 0.04). Higher insulin levels, independently of higher blood glucose levels, may be relevant to DM‐related carcinogenesis for several cancer sites. Examination of circulating insulin levels is a plausible option in evaluating cancer risk even in individuals who have not developed DM. What's new? While diabetes mellitus (DM) is associated with an increased cancer risk, carcinogenesis may not be explained by the influence of higher blood glucose levels only. This prospective case‐cohort study shows that higher levels of surrogate insulin marker C‐peptide are significantly associated with an increased risk of all‐site, colon, liver, kidney, renal pelvis, and ureter cancers after adjustment for blood glucose levels. (Colon and liver cancers also showed an increased risk associated with elevated blood glucose levels independently of C‐peptide levels.) Higher insulin levels, independently of higher blood glucose levels, may thus be relevant to DM‐related carcinogenesis for several cancer sites.