Diabetes mellitus, glycated haemoglobin and C-peptide levels in relation to pancreatic cancer risk: A study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort

Aims/hypothesis: There has been long-standing debate about whether diabetes is a causal risk factor for pancreatic cancer or a consequence of tumour development. Prospective epidemiological studies have shown variable relationships between pancreatic cancer risk and blood markers of glucose and insulin metabolism, overall and as a function of lag times between marker measurements (blood donation) and date of tumour diagnosis. Methods: Pre-diagnostic levels of HbA_1c and C-peptide were measured for 466 participants with pancreatic cancer and 466 individually matched controls within the European Prospective Investigation into Cancer and Nutrition. Conditional logistic regression models were used to estimate ORs for pancreatic cancer. Results: Pancreatic cancer risk gradually increased with increasing pre-diagnostic HbA_1c levels up to an OR of 2.42 (95% CI 1.33, 4.39 highest [≥6.5%, 48 mmol/mol] vs lowest [≤5.4%, 36 mmol/mol] category), even for individuals with HbA_1c levels within the non-diabetic range. C-peptide levels showed no significant relationship with pancreatic cancer risk, irrespective of fasting status. Analyses showed no clear trends towards increasing hyperglycaemia (as marked by HbA_1c levels) or reduced pancreatic beta cell responsiveness (as marked by C-peptide levels) with decreasing time intervals from blood donation to cancer diagnosis. Conclusions/interpretation: Our data on HbA_1c show that individuals who develop exocrine pancreatic cancer tend to have moderate increases in HbA_1c levels, relatively independently of obesity and insulin resistance-the classic and major risk factors for type 2 diabetes. While there is no strong difference by lag time, more data are needed on this in order to reach a firm conclusion.