Hyperglycemia, insulin resistance, impaired pancreatic β-cell function, and risk of pancreatic cancer.

BACKGROUND Obesity and diabetes mellitus are associated with an increased risk of pancreatic cancer. These associations may be secondary to consequences of peripheral insulin resistance, pancreatic β-cell dysfunction, or hyperglycemia itself. Hemoglobin A1c (HbA1c) is a measure of hyperglycemia, whereas plasma insulin and proinsulin are markers of peripheral insulin resistance, and the proinsulin to insulin ratio marks pancreatic β-cell dysfunction. METHODS This was a prospective, nested case-control study of 449 case patients and 982 control subjects with prediagnostic blood samples and no diabetes history from five prospective US cohorts followed through 2008. Two or three control subjects were matched to each case patient by year of birth, cohort, smoking, and fasting status. Pancreatic cancer risk was assessed by prediagnostic HbA1c, insulin, proinsulin, and proinsulin to insulin ratio with multivariable-adjusted logistic regression. All P values were two-sided. RESULTS The highest vs lowest quintiles of HbA1c, insulin, and proinsulin were associated with with an increased risk for pancreatic cancer (odds ratio [OR] = 1.79; 95% confidence interval [CI] = 1.17 to 2.72, P trend = .04 for HbA1c; OR = 1.57; 95% CI = 1.08 to 2.30; Ptrend = .002 for insulin; and OR = 2.22; 95% CI = 1.50 to 3.29; P trend < .001 for proinsulin). Proinsulin to insulin ratio was not associated with pancreatic cancer risk. Results were similar across studies (all P heterogeneity > .29). In cancers developing 10 or more years after blood collection, the associations with insulin and proinsulin became stronger (highest vs lowest quintile, OR = 2.77; 95% CI = 1.28 to 5.99 for insulin and OR = 3.60; 95% CI = 1.68 to 7.72 for proinsulin). In mutually adjusted models including HbA1c, insulin, and proinsulin, only proinsulin remained statistically significant ( highest vs lowest quintile, OR = 2.55; 95% CI = 1.54 to 4.21; Ptrend < .001). CONCLUSIONS Among participants from five large prospective cohorts, circulating markers of peripheral insulin resistance, rather than hyperglycemia or pancreatic β-cell dysfunction, were independently associated with pancreatic cancer risk.