Diabetes mellitus and prostate cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD 20892, USA.
Cancer Causes and Control (Impact Factor: 2.74). 07/2008; 19(10):1267-76. DOI: 10.1007/s10552-008-9198-6
Source: PubMed


A history of diabetes has been fairly consistently related to a reduced prostate cancer risk, but previous investigations have not always addressed whether the relation with diabetes varies by prostate cancer aggressiveness or the association between diabetes and prostate cancer is modified by physical activity level and body mass, variables closely related to glucose metabolism.
We prospectively examined the diabetes-prostate cancer risk relationship among 33,088 men in the screening arm of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial.
During 8.9 years follow-up, we ascertained 2,058 incident prostate cancer cases. Diabetes history was related to decreased risk of total prostate cancer (RR = 0.80, 95% CI = 0.68-0.95). The apparent protection afforded by diabetes was primarily due to the inverse relation with non-aggressive disease (i.e., the combination of low grade (Gleason sum <8) and low stage (clinical stages I or II); RR = 0.75; 95% CI = 0.62-0.91). In contrast, no association was noted between diabetes and aggressive disease (i.e., high grade or high stage (Gleason sum >or=8 or clinical stages III or IV); RR = 1.04, 95% CI = 0.74-1.45). In further analyses, the association between diabetes and aggressive prostate cancer was suggestively positive for men who were lean (RR = 1.64, 95% CI = 0.87-3.07; BMI < 25 kg/m(2)) and it was positive for men who were the most physically active (RR = 1.63; 95% CI = 1.07-2.62; 3+ hours vigorous activity/week). By comparison, no relations of diabetes to aggressive prostate cancer were noted for their heavier or physically less active counterparts (p-value for tests of interaction = 0.10 and 0.03 BMI and physical activity, respectively).
In this study, diabetes showed divergent relations with prostate cancer by tumor aggressiveness. Specifically, diabetes was inversely associated with early stage prostate cancer but it showed no relation with aggressive prostate cancer. Exploratory analyses suggested a positive association between diabetes and aggressive prostate cancer in the subgroup of men with a low BMI.

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    • "In the PLCO cohort, diabetes, a major risk factor for cardiovascular disease, had divergent relations with prostate cancer by tumour aggressiveness. In these men, diabetes was associated with a reduced risk of total prostate cancer but an increased risk of aggressive prostate cancer among men who were lean or physically active (Leitzmann et al, 2008). Additional adjustment for history of diabetes, however, did not materially change the association between aspirin use and prostate cancer risk in our analysis. "
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    ABSTRACT: Although most epidemiological studies suggest that non-steroidal anti-inflammatory drug use is inversely associated with prostate cancer risk, the magnitude and specificity of this association remain unclear. We examined self-reported aspirin and ibuprofen use in relation to prostate cancer risk among 29 450 men ages 55-74 who were initially screened for prostate cancer from 1993 to 2001 in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Men were followed from their first screening exam until 31 December 2009, during which 3575 cases of prostate cancer were identified. After adjusting for potential confounders, the hazard ratios (HRs) of prostate cancer associated with <1 and ≥ 1 pill of aspirin daily were 0.98 (95% confidence interval (CI), 0.90-1.07) and 0.92 (95% CI: 0.85-0.99), respectively, compared with never use (P for trend 0.04). The effect of taking at least one aspirin daily was more pronounced when restricting the analyses to men older than age 65 or men who had a history of cardiovascular-related diseases or arthritis (HR (95% CI); 0.87 (0.78-0.97), 0.89 (0.80-0.99), and 0.88 (0.78-1.00), respectively). The data did not support an association between ibuprofen use and prostate cancer risk. Daily aspirin use, but not ibuprofen use, was associated with lower risk of prostate cancer risk.
    Full-text · Article · Jun 2012 · British Journal of Cancer
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    • "Insulin also acts at the autonomous nervous system, in hyperinsulinemic conditions, insulin promotes sympathetic nervous system activation which in turn stimulates catecolamines production which could have a trophic effect in tumour cells by decreasing apoptosis (Nandeesha 2008). Leitzmann et al. in a prospective epidemiologic study followed up a cohort of 33 088 men, aged between 55 and 74 years during 8.9 years and has verified an inverse relation between diabetes and prostate cancer development risk, total risk (non-aggressive and aggressive forms) and non-aggressive risk, which suggests that diabetes could act as a protector for initial prostate cancer states (Leitzmann et al. 2008). "
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    ABSTRACT: Obesity has been associated with increased incidence and aggressiveness of prostate cancer. Although controversial, several studies suggest that leptin could influence tumour cell growth and proliferation. The main goal of this study was to assess cellular growth of prostate adenocarcinoma cells in obese mice with different endogenous hormonal environments in what relates to leptin circulating levels and sensitivity. Four groups of mice (n = 6/group) were used, namely obese mice with congenital non-functioning leptin receptor OBR (db/db), obese mice with congenital leptin deficiency (ob/ob), mice with diet induced obesity (DIO) and normal weight C57BL/6J mice (control). All groups of mice were injected subcutaneously with 3.0 x 10(5) RM1 cells/500 microl PBS (murine prostate carcinoma androgen insensitive cells) and tumour growth and angiogenesis were evaluated 14 days after inoculation. The tumours induced in ob/ob and DIO mice were significantly larger (P < 0.001) while those induced in db/db mice were significantly smaller (P = 0.047), when compared with controls. Morphometric analysis revealed that mitotic index and Ki-67 positive nuclear density, both cell proliferation markers, were also significantly lower in the tumours of db/db mice (P < 0.001) when compared to controls. An inverse correlation was observed between leptin plasma levels and tumour weight (r = -0.642, P < 0.001), mitotic index (r = -0.646, P < 0.01) and Ki-67 positive nuclear density (r = -0.795, P < 0.001). These results suggest that high leptin concentrations are not favourable to RM1 cell growth and proliferation. On the contrary, high plasma leptin levels were associated with less cellular proliferation and angiogenesis in vivo.
    Preview · Article · Aug 2010 · International Journal of Experimental Pathology
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    • "Common variants in type 2 diabetes genes relating to cell cycle events and apoptosis, and representing different alleles than those associated to type 2 diabetes, are also associated with various cancers. In addition, the risks of developing diabetes and prostate cancer are correlated in a complex way: overall diabetes risk and prostate cancer risk are inversely correlated, but while diabetes risk and the risk of developing aggressive prostate cancer show no correlation, these two risks are positively correlated in lean men and in men who undertake vigorous physical activity [47]. Systemic administration of agents interfering with the gene products of diabetes genes that are also associated with cancers could, therefore, be beneficial in treating diabetes, but they might be potentially carcinogenic. "
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    ABSTRACT: Type 2 diabetes is a disorder of dysregulated glucose homeostasis. Normal glucose homeostasis is a complex process involving several interacting mechanisms, such as insulin secretion, insulin sensitivity, glucose production, and glucose uptake. The dysregulation of one or more of these mechanisms due to environmental and/or genetic factors, can lead to a defective glucose homeostasis. Hyperglycemia is managed by augmenting insulin secretion and/or interaction with hepatic glucose production, as well as by decreasing dietary caloric intake and raising glucose metabolism through exercise. Although these interventions can delay disease progression and correct blood glucose levels, they are not able to cure the disease or stop its progression entirely. Better management of type 2 diabetes is sorely needed. Advances in genotyping techniques and the availability of large patient cohorts have made it possible to identify common genetic variants associated with type 2 diabetes through genome-wide association studies (GWAS). So far, genetic variants on 19 loci have been identified. Most of these loci contain or lie close to genes that were not previously linked to diabetes and they may thus harbor targets for new drugs. It is also hoped that further genetic studies will pave the way for predictive genetic screening. The newly discovered type 2 diabetes genes can be classified based on their presumed molecular function, and we discuss the relation between these gene classes and current treatments. We go on to consider whether the new genes provide opportunities for developing alternative drug therapies.
    Full-text · Article · Apr 2009 · Current Genomics
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