Metabolic Syndrome and Risk of Prostate Cancer

Currently, there is a debate whether MeS predicts the incidence of prostate cancer.
The hypothesis was tested using the 27-year follow-up of the prospective cohort of
the Oslo Study in 1972–1973. MeS was found to predict prostate cancer during 27
years of follow-up, indicating an association between insulin resistance and the incidence
of prostate cancer [33]. Features of the MeS, specifically abdominal obesity and
hypertension, are also associated with prostate cancer in African-American men [34],
a population which is more prone to developing MeS symptoms.
A conducted nested case-control study within the Northern Sweden Health and
Disease Cohort Study found an increased risk of prostate cancer in men with elevated
IGF-1, suggesting that circulating IGF-1 may be specifically involved in the early
pathogenesis of prostate cancer [35]. An extension of this study by measuring levels
of IGF-1 and IGFBP-3 in prediagnostic blood samples from a total of 281 men who
were subsequently diagnosed with prostate cancer supported that IGF-1 is an etiologic
factor in prostate cancer. The circulating IGF-1 levels measured at a comparatively
young age may be most strongly associated with prostate cancer risk [36].
Despite a growing amount of epidemiologic literature suggesting an association
between MeS and prostate cancer risk, there is also growing evidence of an inverse association
between history of diabetes – one feature of MeS – and risk of incident prostate
cancer. The CaPSURE Study, a community-based prostate cancer registry study,
revealed that a history of diabetes was not associated with any diagnostic clinical parameter
or with treatment-specific recurrence rates for prostate cancer. Only among men
with a low prognostic risk or who were younger at prostate cancer diagnosis, being diabetic
(versus not being diabetic), was there a tendency of association in a multivariate
analysis with an elevated risk of recurrence after radiation therapy [37]. The NIH-AARP
Diet and Health Study disclosed an inverse association between diabetes and prostate
cancer which was particularly strong among men in the highest category of routine
physical activity at work or at home [38]. This relationship strengthens the importance
of high levels of routine physical activity, either for the prevention of prostate cancer
and/or cancer in general [39] and MeS. Gonzalez-Perez and Garcia Rodriguez [9] used
the General Practitioner Research Database in the UK and found that diabetic patients
had a decreased risk of prostate cancer. Interestingly, this association was observed
among treated diabetics but not among untreated diabetics. They discussed the possibility
that the observed risk could be restricted to users of insulin or sulfonylureas, a very
provocative hypothesis considering the mode of action of these therapeutics.
Werny et al. [40] investigated the association between diabetes and prostate-specific
antigen levels, controlling for potential confounders, in a nationally representative
cross-sectional survey of the US population (National Health and Nutrition Examination
Survey, 2001–2002). The reported results are consistent with the hypothesis that
long-term diabetes is associated with a lower risk of prostate cancer.
Diabetes seems to be associated with a reduced risk of prostate cancer, but whether
the MeS is also associated with prostate cancer is marginally established. Therefore,
Tande et al. [41] assessed this association in the Atherosclerosis Risk in Communities
(ARIC) Study. When diabetic participants were excluded, the inverse association
between MeS and prostate cancer incidence was slightly strengthened.
Diabetes may be a protective factor for prostate cancer since both were found to be
negatively associated. Based on the same genetic background, parents of diabetic
patients might show similar risks concerning cancers. Meyer et al. [42] investigated
family history in as far as genetic factors may play an important role in the negative
association between diabetes and prostate cancer. Mothers of diabetic patients
showed an increased history of cancers of the liver and biliary tract. Fathers of
patients suffering from type 2 diabetes were diagnosed less frequently with prostate
cancer compared to fathers of non-diabetic controls. The first genome-wide association
scan to search for sequence variants conferring risk of prostate cancer was performed
within a population of 1,501 Icelandic men with prostate cancer and 11,290
controls. It was found that two variants on chromosome 17 confer prostate cancer
risk; one of the variants is in TCF2 (HNF1), a gene known to be mutated in individuals
with maturity-onset diabetes of the young type 5. However, results from eight
case-control groups, including one West African and one Chinese, demonstrate that
this wild-type confers protections against type 2 diabetes [43].
Prostate cancer is an example of the complexity of carcinogenesis associated with
MeS and/or diabetes. On the one hand, an association between diabetes, IGF-1,
hyperinsulinemia and insulin resistance appears plausible, but on the other, these features
can be somewhat counterbalanced as well and reduce hereby the risk for the
development of one of the leading cancer entities worldwide.