History of Diabetes Mellitus and Risk of Prostate Cancer in Physicians

K. Zhu1 , I-M. Lee2,3, H. D. Sesso2,3, J. E. Buring2,3, R. S. Levine4 and J. M. Gaziano2

1 United States Military Cancer Institute, Washington, DC.
2 Division of Preventive Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.
3 Department of Epidemiology, Harvard School of Public Health, Boston, MA.
4 Department of Internal Medicine, Meharry Medical College, Nashville, TN.

Received for publication August 14, 2003; accepted for publication March 2, 2004.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Some studies have suggested that diabetes mellitus may decrease the risk of prostate cancer because of lower insulin levels. To further investigate the relation between diabetes and prostate cancer, a nested case-control study was conducted within the US Physicians’ Health Study. Cases (n = 1,110) had been diagnosed with prostate cancer, confirmed on medical record review, during follow-up in 1982–1995. Controls (n = 1,110) were selected randomly from men free of prostate cancer and were matched on age and date of randomization. Information on personal history of diabetes and other diseases, lifestyle habits, and body weight/height was self-reported. Logistic regression analysis showed that the odds ratio for prostate cancer was 0.64 (95% confidence interval (CI): 0.43, 0.95) for men with diabetes, relative to those without the disease, after adjustment for potential confounders. Odds ratio estimates were 0.63 (95% CI: 0.35, 1.14), 0.77 (95% CI: 0.35, 1.72), 0.59 (95% CI: 0.21, 1.66), and 0.59 (95% CI: 0.27, 1.27) for diabetes diagnosed 1–5, 6–10, 11–15, and >=16 years prior to prostate cancer diagnosis (p for trend < 0.05). Adjusted odds ratios were 1.44 (95% CI: 0.34, 6.17) for stage A prostate cancer and 0.48 (95% CI: 0.28, 0.83) for stages B–D. Results suggest that history of diabetes may be associated with a decreased risk of prostate cancer, especially late-stage tumors.

case-control studies; diabetes mellitus; prostatic neoplasms

Abbreviations: Abbreviations: BPH, benign prostatic hypertrophy; CI, confidence interval; IGF, insulin-like growth factor.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Animal studies have shown that induction of diabetes mellitus can reduce the weight of the prostate gland and decrease serum testosterone levels (1, 2). Conversely, such changes can be normalized by insulin administration (1, 3). In humans, men with diabetes mellitus are more likely to have reduced sexual function and impotence because of decreased testosterone levels (4, 5). Increased testosterone is a risk factor for prostate cancer (6). Therefore, it has been hypothesized that history of diabetes may be associated with reduced risk of prostate cancer because of deceased tes-tosterone levels.

Previous epidemiologic studies of diabetes mellitus and prostate cancer have shown mixed results. Five studies showed an inverse association: odds ratios were 0.2 (95 percent confidence interval (CI): 0.0, 0.8) (7) and 0.6 (95 percent CI: 0.3, 1.1) (8) in two case-control studies and 0.75 (95 percent CI: 0.59, 0.95) (9), 0.91 (95 percent CI: 0.87, 0.94) (10), and 0.7 (95 percent CI: 0.7, 0.9) (11) in three follow-up studies. An insignificant inverse association was found in another three studies including a community survey (12) and two case-control studies (13, 14). However, history of diabetes was not associated with risk of prostate cancer in four follow-up studies (1518) and two case-control studies (19, 20).

To provide additional evidence on the hypothesized association, we conducted a nested case-control analysis by using data from the Physicians’ Health Study. The purpose of this study was to investigate whether history of diabetes mellitus was associated with risk of prostate cancer and whether the diabetes–prostate cancer relation varied by tumor stage.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Study subjects
Subjects were selected from the Physicians’ Health Study, a completed randomized trial of aspirin and beta-carotene among 22,071 US male physicians aged 40–84 years conducted from 1982 to 1995. Men were eligible for the study if they did not report a history of cancer (except nonmelanoma skin cancer), myocardial infarction, stroke, transient ischemic attacks, unstable angina, current renal or liver disease, peptic ulcer, or gout or current use of a vitamin A or beta-carotene supplement. Details of enrollment and follow-up have been reported previously (21, 22).

A nested case-control analysis was conducted for this project. Cases were 1,110 prostate cancer patients identified during a 13-year follow-up period. Prostate cancer was self-reported by subjects, then confirmed by medical record review conducted by an endpoints committee. More than 99 percent of self-reported malignant prostate tumors were subsequently confirmed by medical record review including confirmation of pathology reports (23). Unconfirmed cases were not considered in the analyses. Tumor stage at diagnosis was determined according to an A–D staging system, with A representing the earliest stage (24). Controls were 1,110 male physicians matched to cases on age at study enrollment (±2.5 years) and date of randomization. They were randomly selected from the cohort and did not have a history of prostate cancer at the time the case was diagnosed (reference date).

Data collection
Study participants completed questionnaires at enrollment, after the run-in period, every 6 months during the first year, and annually thereafter. Information included self-reported age, race, height, weight, smoking, alcohol consumption, exercise, medical history (diabetes, myocardial infarction, stroke, cerebral ischemia, angina pectoris, hypertension, high cholesterol, gout, arthritis, vasectomy, benign prostatic disease, cancer, renal disease, and osteoporosis), and demographic factors. History of diabetes mellitus and other diseases was defined as onset before the diagnosis of prostate cancer (for cases) or the reference date (for controls). No information was obtained regarding whether diabetes was type 1 or type 2. Information at enrollment was used for other factors.

Statistical methods
Conditional logistic regression was used to analyze the relation between history of diabetes and prostate cancer while adjusting for potential confounding factors (25). Potential confounding factors included aspirin treatment assignment, beta-carotene treatment assignment, and race. Other factors were tested for their effects on the odds ratio estimate and were not included in the models since they did not change the odds ratio estimate for diabetes by 10 percent or more. We first examined whether cases and controls differed according to whether there was a history of diabetes. We then assessed the diabetes–prostate cancer relation in terms of number of years since diabetes diagnosis and of prostate cancer stage.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Table 1 displays the characteristics of cases and controls. The two comparison groups had the same age distribution because of matching. The distribution of racial background was similar. Cases and controls also did not differ regarding smoking, alcohol consumption, body mass index, exercise, and history of vasectomy. The prevalence of history of diabetes tended to be lower in cases than in controls.


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TABLE 1. Characteristics of cases and controls, Physicians’ Health Study, United States, 1982–1995
 
The relation between history of diabetes and prostate cancer is shown in table 2. Compared with controls, cases were less likely to have a history of diabetes (odds ratio = 0.64, 95 percent CI: 0.43, 0.95), after adjustment for randomized treatment assignment and race. Further adjustment for smoking, alcohol consumption, body mass index, exercise, height, weight, and history of myocardial infarction, stroke, cerebral ischemia, angina, hypertension, hypercholesterolemia, vasectomy, gout, arthritis, benign prostatic hyperplasia, renal disease, or osteoporosis did not change the odds ratio estimate.


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TABLE 2. Odds ratios of prostate cancer associated with history of diabetes mellitus, Physicians’ Health Study, United States, 1982–1995
 
When data were analyzed according to number of years from the diagnosis of diabetes to the reference date, the odds ratio estimates did not vary much by the time interval: 0.63 (95 percent CI: 0.35, 1.14), 0.77 (95 percent CI: 0.35, 1.72), 0.59 (95 percent CI: 0.21, 1.66), and 0.59 (95 percent CI: 0.27, 1.27) for 1–5, 6–10, 11–15, and >=16 years, respectively, although the overall p value for trend was lower than 0.05. When the period of 1–5 years from the diagnosis of diabetes to the reference date was used as the baseline, the odds ratio estimates were around one and the 95 percent confidence interval included the null value for each of the time intervals of 6–10, 11–15, and >=16 years. When data were analyzed by tumor stage at diagnosis, the odds ratio estimates appeared decreased for stage B–D tumors, while the corresponding estimate was 1.44 (95 percent CI: 0.34, 6.17) for stage A tumors. When stage B–D tumors were combined, the odds ratio estimate was 0.48 (95 percent CI: 0.28, 0.83).


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Our results suggest that a history of diabetes mellitus may be related to a decreased risk of prostate cancer, especially late-stage tumors. With one known exception (8), previous studies have not examined the diabetes–prostate cancer relation according to tumor stage. In that study (8), prostate cancer cases were compared with controls having benign prostatic hypertrophy (BPH); it was observed that diabetics had a decreased risk of stage B–D prostate cancer but not stage A tumors. While the results of this study were suggestive, the authors did not exclude the possibility of bias due to use of BPH controls if men with BPH were more likely than men without to have diabetes, as has been suggested (26). The present study did not specifically choose men with BPH as controls, decreasing the likelihood of bias due to use of BPH controls. The odds ratio estimate for stage A was not significantly different from the null value in our study, although it appeared slightly increased. The slightly increased odds ratio for stage A tumors might have resulted from the possibility that men with a history of diabetes were more likely to be under medical surveillance and therefore more likely to have had earlier-stage prostate cancer detected.

This study also has several other strengths. First, there were a relatively large number of prostate cancer patients, compared with other studies. Second, subjects were physicians, who are able to report medical history more accurately than other populations. Third, history of diabetes was collected before the diagnosis of prostate cancer, making differential reports by cases and controls unlikely.

However, several limitations deserve discussion. First, we were unable to distinguish the two primary types of diabetes mellitus, insulin-dependent type 1 and non-insulin-dependent type 2 (27). The two types of diabetes differ metabolically; therefore, their effects on prostate cancer risk may also differ. Although type 2 diabetes is more prevalent among adults, type 1 also occurs in the population (27). Combining the two different types may dilute the association of a specific type of diabetes with prostate cancer. Second, misclassification of the exposure, history of diabetes, was possible for both cases and controls since diabetes tends to be underdiagnosed without laboratory tests. However, since the misclassification was unlikely to be differential by case-control status, its impact would likely dilute the true association. Third, residual confounding may have affected our reported odds ratios. Obesity, dietary intake, and smoking are related to diabetes (28, 29) as well as prostate cancer (29, 30). Although we considered the potential confounding impacts by body mass index and smoking, which was minimal, we were unable to control for the potential effects of dietary factors; we did not collect detailed baseline dietary information, and limited dietary data were not available until 1996. Fourth, the study subjects might have been a selective group since they had a low frequency of diabetes and other diseases compared with those contacted but not ultimately randomly selected for the study for various reasons (31). However, this selectivity should not have influenced internal validity of the study.

Our results imply that late-stage prostate cancer may have a risk factor profile different from that of early-stage tumors because of the existence of factors that promote tumor growth. The similar prevalence rates of early-stage, latent prostate cancer in various countries, in contrast to the different incidence rates of late-stage, overt cancer (32, 33), suggest a multiple-step hypothesis for the occurrence of prostate cancer. That is, latent cancers may have undergone an initiating event(s), and the appearance of overt cancer may depend on exposure to promotion factors (34, 35). In this regard, history of diabetes may represent factors that suppress tumor promotion and thus inhibit progression of early-stage prostate cancer to clinical tumors. Therefore, history of diabetes would be less frequent in patients with late-stage cancer.

The mechanisms that underlie the suggested association are not known and may be complex. Reduced androgen levels in diabetics may restrain promotion of latent prostate cancer. In animal experiments (36, 37), administration of testosterone can cause invasive carcinoma in the lateral and anterior prostate in a dose-response fashion (36). The reduced promoting effects of testosterone may also extend to men, by making tumors less likely to progress to clinical stage in diabetics. Another possible mechanism relates to insulin-like growth factor (IGF)-1. It is known that insulin inhibits production of IGF binding protein-1 (38). The reduced IGF binding protein-1 causes increased levels of free IGF-1. Higher levels of IGF-1 can facilitate both initiation and progression of the disease (39, 40), leading to an increased risk of prostate cancer (4143). In diabetics with reduced insulin secretion, circulating IGF-1 levels are reduced (44, 45) and therefore may be suppressing progression of prostate cancer to clinical stage.

Apart from the possible effects of testosterone and IGF-1, the observed association also may result from treatment for diabetes rather than the endogenous changes associated with diabetes. However, Rosenberg et al. (8) showed that specific medications to treat diabetes were not independently associated with prostate cancer after adjustment for diabetes.

In summary, this study indicates that a history of diabetes mellitus may be associated with a decreased risk of prostate cancer, particularly late-stage tumors. The results contribute to the understanding of factors that may delay prostate cancer progression and are helpful for developing therapeutic and preventive interventions. Large studies with similar results will help to solidify the present findings.


    ACKNOWLEDGMENTS
 
This study was supported by grants CA34944, CA40360, HL26490, and HL34595 from the National Institutes of Health.

The authors acknowledge the crucial contributions of the entire staff of the Physicians’ Health Study, under the leadership of Charlene Belanger, as well as Mary Breen, Vadim Bubes, Jean MacFadyen, Geneva McNair, David Potter, Leslie Power, Harriet Samuelson, Dr. Miriam Schvartz, Mickie Sheehey, Joanne Smith, and Phyllis Johnson Wojciechowski.


    NOTES
 
Correspondence to Dr. Kangmin Zhu, United States Military Cancer Institute, Walter Reed Army Medical Center, Building 1, Suite A-109, 6900 Georgia Avenue NW, Washington, DC 20307-5001 (e-mail: kangmin.zhu{at}na.amedd.army.mil). Back


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