In this large pooled analysis of 12 international studies, we observed a weak association between history of diabetes and risk of HNC overall. However, we observed a stronger association between history of diabetes and HNC in never smokers. In addition, we observed a positive association between diabetes diagnosed before age 50 and HNC.
An association between history of diabetes and HNC only in never smokers may exist if the diabetic condition affects an, as yet, unknown causal pathway for HNC among never smokers. Alternatively, a substantial proportion of people who are both heavy smokers and diabetic and who would have developed HNC in the future, may be at particular risk for early death or illness, and may have died before developing HNC. A third possibility is that adjustment for pack years of smoking is not sufficient to remove all confounding among smokers, and that examining the association between a history of diabetes and HNC among never smokers circumvents this source of residual confounding. This possibility is supported by results from studies on the association between HNC and BMI, which is strongly associated with diabetes (39
). A recent INHANCE pooled analysis observed an etiologically improbable reduced risk of HNC associated with overweight and obesity even after adjustment for duration and intensity of smoking (35
). However, when analyses were confined to never smokers, the reduced risk associated with overweight and obesity was attenuated to the null.
We observed a positive association between HNC and diabetes diagnosed before age 50, and no association for those diagnosed after age 50. Only 5 cases and 9 controls were diagnosed with diabetes before age 20, making it unlikely that these results were due to the inclusion of type I diabetics. Cases diagnosed as diabetic before age 50 had a mean age of 55 at HNC diagnosis and a mean duration of diabetes of 15 years, while cases with a diabetes diagnosis over age 50 had a mean age of 64 at HNC diagnosis and a mean diabetes duration of 6 years. These data suggest that a younger age of type II diabetes onset may confer particular risk for subsequent development of HNC, and that these cancers may develop at a relatively young age. The difference according to age may partly be explained by the observation that younger HNC patients are less likely to have extensive histories of tobacco and alcohol use (41
). The longer duration of exposure to the diabetic condition could also explain the increased risk for younger patients. In addition, it has been suggested that adults diagnosed with diabetes at a younger age may represent a more aggressive phenotype than people diagnosed late in life (43
), and thus the diabetic condition in older people may not predispose to HNC to the same degree as in younger diabetics. The exclusion of several studies due to lack of diabetes diagnosis age data and the small numbers in each of the strata limit interpretation of these results.
Results from the majority of studies in these pooled analyses indicated a positive relationship between history of diabetes and HNC, with the notable exception of the North Carolina study, for which an inverse relationship was observed. Subjects from the North Carolina study made up 14% of the total pooled sample, resulting in a relatively heavy influence of this study on the overall results. A notable difference in the North Carolina study is the high prevalence of diabetes among controls (17%) (44
) compared with controls from other US studies and other countries (mean prevalence of 6% in controls for all other studies). The North Carolina study population had a larger proportion of African Americans than other studies; however race is unlikely to play a role because cases and controls were frequency matched on race and estimates were adjusted for race.
Our results support previous research suggesting involvement of abnormal glucose metabolism in HNC. Suba et al. conducted a hospital-based case-control study in Hungary in 2,660 in-patients with confirmed OSCC and 2,980 “complaint-free” controls who volunteered to participate in oral cancer screenings during the same period, and observed that repeatedly elevated (>5.5 mmol/l) fasting glucose over a period of 4 days was strongly associated with oral cancer in females (OR, 1.61; no 95% CI reported; p<0.05), but that no such association existed in males (OR, 0.97; p>0.05) (16
). Cases and controls were matched on age, but no adjustment was made for, or effect modification examined with, known OSCC risk factors. In a study on the risk of multiple cancers in a nationwide cohort of diabetics in Denmark, Wideroff et al. reported increased risk of mouth/pharynx cancer associated with diabetes (20
). However, there were only 30 cases in those analyses. Additionally, the association was only observed in subjects less than 50 years old at diabetes diagnosis (standardized incidence ratios (SIR) based on age, sex and calendar year, 1.8; 95% CI, 1.2–2.6). The estimates were similar for males and females.
In a previous pooled INHANCE study, it was observed that HNC risk is elevated among lean people and reduced among overweight or obese people (35
). If overweight and obesity are negatively associated with HNC, it could be argued that this makes a positive association between diabetes and HNC less likely since obesity is strongly associated with conditions such as metabolic syndrome, and an increased risk of developing insulin resistance, followed by glucose intolerance and type II diabetes (45
). However, glucose intolerance can also occur independently of insulin resistance (46
Diabetes is emerging as more of a heterogeneous disease than initially thought, with subtypes of people who are classified as type II diabetics, but who exhibit defects in insulin secretion with no evidence of insulin resistance. Examples include maturity-onset diabetes of the young (MODY) (49
) and mitochondrial diabetes (50
). There are also populations that have type II diabetes, especially in Asia, who are not overweight or obese by Western criteria. For example, in a study of type II diabetics in Taiwan, only 43% of women and 48% of men had a BMI greater than 25 kg/m2
). These observations suggest that, although there is an association of overweight with diabetes, the diabetic condition is a distinct disease state that frequently also develops in people who are not overweight.
Hyperglycemia and associated biochemical consequences, independent of obesity-linked characteristics of diabetes, may be a mechanism by which diabetes increases the risk of cancer. Interestingly, several prospective cohort studies indicate that cancer risk starts to increase at blood glucose levels even below the diabetic range. Studies in Korea (52
), Austria (53
) and Sweden (54
)found a linear increase in risk for multiple cancers across the entire spectrum of glucose values, regardless of weight.
A limitation of this study is that we were only able to examine self-reported diabetic status, which may have resulted in exposure misclassification. In the United States, it is estimated that one third of type II diabetics are undiagnosed (55
). However, we have no reason to believe that this misclassification would differ between cases and controls; thus any error from this source is most likely to bias results toward the null. The heterogeneity of HNC may also hinder the ability to adequately examine whether diabetes is a risk factor. Weak or inconsistent associations with all HNC may result if the subtypes of HNC are etiologically distinct. Although we performed analyses for separate sites (larynx, hypopharynx, oropharynx, oral cavity, and non-specific pharynx), small sample sizes prevented meaningful interpretation of the results. The inability to control for HPV infection is a further limitation. However, cancers occurring in the oropharynx, as opposed to other HNC sites, are most strongly associated with HPV infection (27
), and we are not aware of any studies that suggest that diabetics are more likely to be infected with HPV.
We did not have sufficient data to adjust for factors such as diabetic medication use or extent of glycemic control in this study. Many diabetics are able to maintain good glycemic control and/or lowered insulin levels by oral hypoglycemic agents, diet, appropriate use of exogenous insulin, etc. In addition, recent evidence suggests that some oral hypoglycemic agents used to treat diabetes, such as metformin, may reduce incidence of a wide variety of cancers (58
). Researchers have observed an association of use of exogenous insulin with increased risk of cancer of the breast, colon, pancreas, prostate, or any solid tumor (59
), and increased risk of death from any type of cancer (60
). Among 710 subjects who reported a history of diabetes and who had data on insulin use in the present study, 33% were insulin users. Between the years 1997 to 2008 in the United States, the proportion of diabetics aged 65–74 using any diabetes medication (pills, insulin or both) ranged from 83.2% to 90.0% (61
). Even if rates of medication use are not this high in our international pooled data, it is nonetheless likely that a large percentage of diabetics were taking oral hypoglycemic agents. Thus, the diabetes effect in the absence of treatment might be stronger than the association observed in our study.
Selection bias may have influenced results in a positive or negative direction. Diabetics are more likely to have multiple hospitalizations than non-diabetics (62
), creating a selection bias when controls are recruited in hospital-based studies. The possible influence of bias due to controls in hospital-based studies was difficult to evaluate because exclusion of the hospital-based studies increased the proportional influence of the North Carolina study on the results, attenuating the odds ratio toward the null. An alternative source of selection bias may occur if control participants are systematically healthier than control non-participants, thus spuriously raising the OR. However, this source of bias is unlikely because the pooled OR for studies with control participation rates less than 90% was almost identical to the OR for studies with control participation above 90%.