The Epidemiologic Relationship

The Epidemiologic Relationship
between Diabetes and Cancer
Kurt S. Zänker

Institute of Immunology and Experimental Oncology, University of Witten/Herdecke,
Witten, Germany Abstract There is a growing amount of epidemiologic literature suggesting an association between history of metabolic syndrome/diabetes and risk of developing a variety of cancers. Data of populations from different hospital- and community-based case-control studies, from cancer registries and a health survey suggest that metabolic syndrome/diabetes mellitus type 2 are associated with an increased risk of cancer or are even independent predictors of mortality from cancer of the colon, pancreas, hepatocellular carcinoma, femalebreast and endometrium, and in men of liver and bladder. However, the association is still complex because
some studies show controversial results of even a lower risk of cancer, e.g. for prostate cancer, in diabetic than in non-diabetic subjects. An association between diabetes, hyperinsulinemia, insulin resistance, insulin-like growth factors, lipotoxicity, obesity, adipokines, Western-style dietary habits and carcinogenesis appears plausible, yet clusters of increased or reduced risk factors need to be confirmed in future studies. Evidence from the intensive care literature indicates that achieving glucose control leads to a better outcome in clinical
oncology. If so, continued improvement of cancer outcomes may also depend upon improved diabetes control. As the general population ages, the magnitude of both health problems continues to grow and could overwhelm health systems. It is prime time to break the growing tsunami of both diseases by community-based prevention programs. Copyright © 2008 S. Karger AG, Basel The metabolic syndrome (MeS) encompasses a constellation of metabolic disorders that places patients at high risk for the development of cardiovascular diseases and diabetes mellitus type 2, and possibly cancer. The MeS is the concurrence of hypertension, abdominal obesity, impaired fasting blood glucose, dyslipidemia, e.g. low levels of high-density lipoproteins (HDL) cholesterol, and insulin resistance. The diagnostic concept of MeS is still controversially discussed, which is illustrated on the basis of
recent primary-care data from Germany and the Centers for Disease Control and
Prevention. In Germany, the prevalence ranges from 19 to 31% [1] and in the USA
about 22% of the adults have MeS according to the currently existing definitions. The
book on MeS as a clinically valuable indicator for estimating the risk of diabetes
The Epidemiologic Relationship between Diabetes and Cancer 85 mellitus type 2, cardiovascular morbidity and mortality is not yet closed. However,
many people afflicted by MeS will develop type 2 diabetes. By 2010 it is suggested that 30 million people in Europe will suffer from diabetes, creating a huge burden on the health service and the economy, not to forget the individuals themselves; to close thiscircuit of syndromes, many of these people will have features of the MeS.
Although the pathogenesis of MeS is under debate, it is now realized that insulin
resistance plays a principle role in initiating and perpetuating the pathological manifestations of the MeS [2]. Studies have shown that MeS and its consequent biochemical derangements in the various phases of diabetes may contribute to carcinogenesis and clinical study protocols are designed to understand in more detail the role of insulin and insulin resistance in cancer-struck subjects [3]. Therefore, basic and clinical science will face a twofold problem in the future, timely summarized by the following questions: (1) how does a clinically manifested diabetes or prediabetes (comorbidity) influence the outcome of a cancer disease (mortality), and (2) how is type 2 diabetes associated with cancer incidence?
A recently published study on the glucose tolerance status and 20-year cancer incidence within a sample of a Jewish Israeli population (n
2,780) showed an increased long-term cancer risk for individuals with impaired fasting glucose or diabetes [4].

The Vasterbotten Intervention Project of Northern Sweden showed an association of
hyperglycemia with total cancer risk in women and in women and men combined for
several cancer sites, independently of obesity [5]. A case-control study of 306 colorectal cancer cases and 595 matched controls nested in the Northern Sweden Health and Disease Cohort supports the view that the presence of obesity, hypertension and hyperglycemia increase the risk of colorectal cancer [6].
A cross-sectional study investigated the question of comorbidity and reduced
health-related quality of life (HRQL) in patients that have either diabetes or cancer.

The data from the Public Use File of the Canadian Community Health Survey
revealed that individuals with diabetes and cancer had a clinically important and significantly lower HRQL than those with either conditions alone [7].
An association between diabetes mellitus type 2 and cancerogenesis appears
plausible, considering the complexity of the mode of action of insulin (pro- and
pre-insulin), insulin-like growth factor and the appropriate receptors, including the
type of oral antidiabetic drugs. It was found that patients with type 2 diabetes
exposed to sulfonylureas and exogenous insulin had a significantly increased risk of
cancer-related mortality compared with patients exposed to metformin; the cause
of this in-/decreased risk-related effect remains speculative [8]. Interestingly, an
evaluation of the General Practitioner Research Data in the UK suggests that
patients with diabetes have a reduced risk for prostate cancer when using insulin or
sulfonylureas [9].

All the epidemiological studies involving diabetes mellitus type 2 and malignancies
do have limitations, e.g. differences in treatment modalities, lifestyle and nutrition behavior, race and genetics of participants. A promising way to give some
86 Zänker answers is to focus on specific tumor entities in order to develop tumor-specific and individualized management strategies.