In this long-term follow up of 1,612 men and women free of diabetes, a significant association was demonstrated between insulin resistance, as measured by the MCAi, and cancer mortality. No such association was found for the other IR surrogates.
These results reinforce the contribution of IR on the pathophysiology of cancer, exemplified by the 40-50% increased risk for cancer related mortality and specifically in individuals with prediabetes.
A number of previous studies have reported an association between increased fasting glucose plasma levels and cancer mortality (14–16,30). Parekh et al (16) demonstrated, as part of the Third National Health and Nutrition Examination Survey (NHANES III; 1988–1994), with an average follow-up of 8.5 years, that the risk for overall cancer mortality was significant higher for every 50 mg/dl increase in fasting plasma glucose concentrations (HR=1.22; 95% CI: 1.06–1.39). Our findings show a statistically non-significant 10% increased risk for cancer death in individuals in the upper quartile of fasting glucose, similarly to Parekh et al findings. Other studies found hyperinsulinemia to relate with increased risk for cancer incidence and mortality (either by a direct mechanism or by interactions with other hormones such as IGF-1) (16,31–33).
Dankner et al (32) showed on a cohort of 1,695 nondiabetic participants as part of the GOH study, and after a 29 years of follow up, that individuals in the upper quartile of the fasting insulin had a statistically significant borderline increased risk for all-site cancer mortality (HR=1.37, 95% CI 0.94–2.00, P = 0.097). The current analysis showed a 20% non-significant increased risk for the upper fasting insulin quartile as compared to the lower quartiles and a significant 50% higher risk in the upper fasting insulin quartile in pre-diabetics.
The role of ISIs as predictors for death in cancer patients remain unestablished, with inconsistent results (16,33). Perseghin et al (33) showed on a cohort of 2,074 individuals and after 15 years of follow up, as part of the Cremona study, a significant but minor association between abnormal HOMA-IR values and death from cancer (HR=1.003, 95% CI 1.002–1.005, P < 0.001). Other studies did not show such a significant association (16). Our findings support these results as demonstrated by an increased risk for cancer death among individuals in the IR quartiles of the Ln HOMA-IR in pre diabetics individuals (SHR=1.5, 95% CI: 1.0-2.2).
The MCAi was the only IR surrogate that demonstrated a significant association in the total cohort and exhibited the highest risk for cancer mortality compared with other IR surrogates. These findings emphasize the importance of elevated triglycerides on cancer prognosis. A possible link between increased triglycerides and cancer incidence was demonstrated in a number of studies (34,35) through common lipid metabolism pathways (e.g. Malonyl-CoA synthesis) in oncogenesis and adipogenesis (36). Such a positive association with increased cancer mortality was not observed (37–39) and even correlated with better disease-free survival (40) in breast cancer patients. Further investigation is needed in order to establish triglycerides inter-relationship with cancer progression and prognosis.
In the GOH cohort, an increased risk for all-cause mortality was found in individuals in the IR quartiles of the MCAi, the QUICKI and the HOMA-IR (26). However, the MCAi was the only ISI that showed a significant association with cardiovascular mortality, regardless of the presence of diabetes. The current findings suggest that the MCAi may be used as a surrogate for the long-term increased risk of death for both malignancy and cardiovascular morbidities.
The current study did not include participants with the diagnosis of diabetes due to the potential confounding effect of anti-diabetes medications (39,41), as well as the established association between diabetes and cancer mortality (15,16). For example, medications for the treatment of diabetes such as Metformin were negatively associated with mortality among diabetic patient (39) while exogenous insulin use and Sulfonylureas were associated with an increased risk for cancer mortality (41). However these findings are controversial, due to potential methodological flaws (42). In addition, diabetic patients display distinct characteristics such as relatively low levels of endogenous insulin as part of the disease progression, and higher BMI, which may confound the association. As previously mentioned, an association between hyperinsulinemia and increased risk for cancer death was observed in a number of studies and thus, lower levels of insulin could potentially have a protective effect from cancer mortality (32). Moreover, studies have shown a negative association between the metabolic syndrome, and specifically obesity, with cancer risk, and better outcome in cancer patient, suggesting that the metabolic syndrome and increased BMI may serve as good prognostic markers (43).
Strengths and weaknesses of the study
While the standard oral glucose tolerance test (OGTT), as recommended by the American Diabetes Association (44), require the oral administration of 75 gr glucose, in the current study the test was carried out using 100 gr of glucose. This was done due to the absence of clear guidelines at the time of the examination (1979–1982). Furthermore, the ingestion of 100gr of glucose has been shown to improve insulin sensitivity and insulin secretion with minimal effect on the results of the OGTT in terms of the plasma glucose levels measured throughout the test (45).
In addition, the Yemenite population was over sampled in the GOH cohort beyond their normal proportion in the general Israeli population, in order to increase the statistical power and examine cardiovascular risk factor in this ethnic minority. The multivariable analysis adjusted for ethnicity to overcome this potential confounding.
Moreover, although ISI’s that were examined in the study were previously found to show high correlation with the euglycemic insulin clamp (18–21), this method is still considered the gold standard for quantifying insulin resistance. However, this method is invasive and not applicable in large-scale epidemiological studies.
Furthermore, no information on medication or family history were collected during the late 70's intakes. However, the cohort was mainly composed of healthy and employed subjects. In addition, routine screenings for cancer were not widely used at that time. Finally, the current study did not investigate the association between IR surrogates and cancer site-specific mortality due to the small number of subjects per group.
The study however present some clear advantages such as the long follow-up over approximately 40 years, the equal representation of both men and women in addition to the representation of an ethnically diverse population. Moreover, blood tests were drawn in the healthy state for research purposes only and analyzed by a single laboratory, avoiding variability in the blood tests analysis. Furthermore, the statistical analysis was performed by two different approaches with similar findings, reinforcing the study results.