Fasting proinsulin levels are significantly associated with 20 year cancer mortality rates. The Hoorn Study

Abstract

Aims/hypothesis Proinsulin is possibly associated with cancer through activation of insulin receptor isoform A. We sought to investigate the associations between proinsulin and 20 year cancer mortality rates. Methods The study was performed within the Hoorn Study, a population-based study of glucose metabolism in individuals aged 50-75 years in the Dutch population. Fasting proinsulin levels were measured twice by a doubleantibody radioimmunoassay. Participants were continuously followed to register mortality; causes of death were derived from medical records. Cox survival analyses were performed to assess the 20 year risk of death from cancer in relation to proinsulin. All analyses were adjusted for age and sex, with additional adjustments for traditional risk factors. The effect modification of glucose metabolism and sex was tested.Results Proinsulin levels were measured in 438 individuals (41% normal glucose tolerance, 35.7% impaired glucose metabolism, 23.3% type 2 diabetes). Of these participants, 53 died from cancer. After adjustment for age and sex, proinsulin >16.5 pmol/l (the upper tertile) was significantly associated with a twofold risk of cancer mortality (HR 2.01, 95% CI 1.16, 3.46) compared with individuals with lower proinsulin levels. Additional adjustment for glucose metabolism, BMI and smoking did not substantially change the results (HR 1.91, 95% CI 1.04, 3.52). No interaction with glucose metabolism or sex was observed. Conclusions/interpretation Individuals with fasting proinsulin levels >16.5 pmol/l have a twofold risk of cancer mortality over a 20 year time span. These findings provide population-based evidence for the independent association between high proinsulin levels and cancer mortality rates.

Sex- and site-specific differences in colorectal cancer risk among people with type 2 diabetes

“…Furthermore, tumor suppressor genes, point mutations, genetic instability, and responses of cells to growth stimulating hormones, such as IGF, may differ by CRC subsite [11]. As it is hypothesized that both diabetes and CRC involve over-expression of both the insulin and IGF receptors [32], this potentially even more complicates the association. Epidemiological evidence also links hyperinsulinemia to changes in sex steroids [33].…”

GLP-1 Analog Liraglutide Enhances Proinsulin Processing in Pancreatic β-Cells via a PKA-Dependent Pathway

“…At present, disproportional hyperproinsulinemia has been found in the individuals of type 2 diabetes (25,26), impaired glucose tolerance (27,28), and even nondiabetic first-degree relatives of the families with those with type 2 diabetes (29). In addition, several studies have shown that disproportionately elevated proinsulin is associated with all-cause and cardiovascular mortality (30), obesity (31), hepatic steatosis (32), and cancer mortality rates (33). Therefore, it is highly necessary to monitor the proinsulin to insulin ratio in diabetes.…”

A comprehensive approach to the molecular determinants of lifespan using a Boolean model of geroconversion

“…It has been postulated that peripheral insulin resistance induces a compensatory hypersecretion of insulin by the pancreas. Indeed, the largest epidemiological studies on this subject have identified hyperinsulinemia (or circulating C‐peptide or proinsulin) as a specific prognostic factor for cancer‐related mortality (Ma et al ., ; Wolpin et al ., ; Perseghin et al ., ; Walraven et al ., ). We have therefore simulated the normal and T2DM models as previously described, but with increasing levels of insulin (for each simulation, initial condition for insulin set to 0, 0.5 and 1) as the unique changing parameter.…”

“…The ratios of dT under hyperinsulinemia (insulin level = 1) compared to the 0.5 or 0 insulin levels are 1.56 and 2.39, respectively (dT insulin_1 /dT insulin_0.5 = 67.6/43.3 = 1.56; and dT insulin_1 /dT insulin_0 = 67.6/28.2 = 2.39). This is very close to the hazard ratios for cancer‐related mortality concerning patients with hyperinsulinemia, ranging between 1.62 and 2.38 (see Materials and methods for details; Walraven et al ., ; Perseghin et al ., ; Wolpin et al ., ; Ma et al ., ). Concerning the T2DM model, insulin level barely modifies the calculated dTs (Fig.…”

“…Four large epidemiological studies have evaluated the relation between hyperinsulinemia (or surrogate markers like circulating C‐peptide or proinsulin) and cancer‐related mortality. For unselected cancer types, high levels of circulating proinsulin or insulin are associated with hazard ratios of 2.01 and 1.62 for mortality in 438 and 2011 individuals, respectively (Perseghin et al ., ; Walraven et al ., ). For colorectal and prostate cancers, high levels of circulating C‐peptide are associated with hazard ratios of 1.87 and 2.38 for mortality in 373 and 2546 patients, respectively (Ma et al ., ; Wolpin et al ., ).…”