Hyperglycemia, Obesity, and Cancer Risks on the Horizon

THE PREVALENCE OF DIABETES MELLITUS HAS INcreased substantially over the past several decades, in part because of the growing epidemic of obesity. Approximately 8% of the US population has diabetes, with more than 90% of cases classified as type 2 diabetes, and with insulin resistance as the major underlying pathophysiology. Much of the emphasis in diabetes management focuses on reducing end-organ complications, including retinopathy, neuropathy, nephropathy, and macrovascular disease. Several recent epidemiological studies, including the report by Jee et al in this issue of JAMA, have also shown an association between diabetes and several common cancers, including pancreas and colon cancer. How important is this effect and what are the public health implications? The prospective cohort study of nearly 1.3 million people conducted by Jee et al took advantage of data collected by the insurance provider for all government employees, teachers, and their dependents in Korea. A cohort of individuals was enrolled over 4 years at the time of required biennial medical examinations and was then followed up for as long as a decade. Outcomes were measured through national registration of death certificates, a national cancer registry, and hospitalization records. The main finding was that elevated fasting serum glucose levels were associated with a 27% increase in cancer mortality among men and a 31% increase among women. A dose-response trend was evident, with higher fasting glucose levels associated with higher cancer mortality rates. Cancer incidence rates followed similar patterns. One of the unique aspects of this study is that Korea has a low rate of obesity in the population. The average body mass index (BMI) in the study population was 23.2, with approximately one fourth of the population considered overweight (defined as BMI 25.0). By comparison, recent National Health and Nutrition Examination Survey data demonstrate that approximately 65% of US men and women are overweight or obese, nearly one third are obese (defined as BMI 30), and 5% are extremely obese (defined as BMI 40). If current trends continue, 40% of the US population will be classified as obese in 2010. In the United States, diabetes is tightly linked to obesity, and the proportion of individuals with diabetes who meet the definitions of overweight and obese is higher than in the general population (79% and 46%, respectively). For the first time, this Korean study has made significant progress toward separating the specific effects of elevated blood glucose from the compendium of other metabolic abnormalities observed in obesity. The investigators were able to demonstrate a direct relationship between fasting serum glucose levels and cancer mortality across all BMI groups ( 20, 20 to 23, and 23). A wealth of epidemiological data supports the association between obesity and various types of malignancies, including postmenopausal breast cancer and cancers of the colon, pancreas, endometrium, esophagus (adenocarcinoma), kidney, gallbladder, and gastric cardia. The link between obesity and cancer may be mediated by insulin resistance and hyperinsulinemia. However, several complex physiological changes also result from obesity, including alterations in sex steroid levels. For example, obesity is associated with increased levels of bioavailable estrogen due to enhanced biosynthesis in adipocytes and reduced sex hormone–binding globulin levels. Thus, in the complex setting of obesity, it is difficult to tease out the specific molecular alterations that lead to cancer, and these contributions are likely to be site-specific. Well-designed cohort studies can provide compelling observational data, and the study by Jee et al has several methodological strengths. First, it is likely that the cohort is reasonably representative of Korea, since the insurance provider covers more than 10% of the Korean population, and only 2.1% of the participants were excluded on the basis of incomplete data. Second, important information about other risk factors was collected by these investigators through use of a lifestyle and medical history questionnaire. In contrast, many other population-based cohort studies rely on national linkage registries that do not have this type of in-