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Hyperglycaemia and reduced risk of prostate cancer

To the Editor: The most comprehensive meta-analysis published to date has demonstrated that the risk of developing prostate cancer may be reduced in men with diabetes mellitus, but the mechanisms responsible for this association remain poorly understood [1]. In their recent Commentary, Frayling et al. summarise currently available data suggesting that this inverse relationship could in part be explained by genetic factors [2]. Of note, it has been shown that the same variation in the HNF1B (also known as TCF2) gene, which is associated with increased prostate cancer risk, confers protection against type 2 diabetes mellitus [3].

Androgens play a key role in the pathogenesis of prostate cancer [4, 5]. The enzyme 5α-reductase is able to convert testosterone to the more active androgen, dihydrotestosterone [4, 5]. Inhibition with finasteride of the type II isoform of 5α-reductase, which is most abundant in prostate tissue [4], is effective in the treatment of benign prostatic hypertrophy [6], and reduces the risk of prostate cancer development [5].

Based on the importance of 5α-reductase inhibition for prostate cancer prevention, we propose a biologically plausible hypothesis that might explain a lower risk of prostate cancer in men with diabetes mellitus. This hypothesis is complementary to effects of genetic factors involving both diseases, as discussed by Frayling et al. [2]. 5α-Reduction of androgens (C19 steroids) to androsterone is dependent on NADPH as a cofactor (reviewed in [7]). Importantly, under hyperglycaemic circumstances cellular NADPH is likely to be decreased in many tissues, consequent to increased aldose reductase-mediated conversion of glucose to sorbitol [8]. We have previously shown that the urinary ratio of androsterone to etiocholanolone (reflecting the proportion of 5α- to 5β-reduced C19 steroids) is lower in type 1 diabetes patients; this ratio is inversely related to the HbA1c level [7]. It thus seems plausible that chronic hyperglycaemia could result in a lower relative 5α-reductase activity via lower cellular NADPH. Hence, hyperglycaemia could contribute to diminished dihydrotestosterone availability in prostate tissue from men with diabetes mellitus.

Obviously, it will be necessary to directly test whether hyperglycaemia decreases 5α-reductase activity in prostate tissue. In view of the proposed hypothesis, it is also relevant to take account of the degree of metabolic control when evaluating the association of diabetes mellitus with prostate cancer in epidemiological studies, which was not done in any of the studies included in the meta-analysis [1].

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Open Access This is an open access article distributed under the terms of the Creative Commons Attribution Noncommercial License (https://creativecommons.org/licenses/by-nc/2.0), which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

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Dullaart, R.P.F. Hyperglycaemia and reduced risk of prostate cancer. Diabetologia 52, 378–379 (2009). https://doi.org/10.1007/s00125-008-1214-6

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  • DOI: https://doi.org/10.1007/s00125-008-1214-6

Keywords

  • Diabetes
  • Hyperglycaemia
  • Prostate cancer
  • 5α-Reductase