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Although diabetes affects nearly 30% of the US population >65 years, and prostate cancer (PCa) occurs most often in older men, the influence of diabetes on PCa progression has been poorly studied, despite the frequent co-existence of these disorders [1, 2]. Indeed, while the relationship between diabetes and risk of PCa diagnosis has been heavily examined, only eight studies have compared outcomes such as disease-specific mortality and recurrence in men with diabetes vs men without [3-10]. Among these, only four studies, including an earlier study from our group, had >600 men available for analysis [6, 8-10].
Within this limited literature, there is substantial disagreement: one study reported increased PCa-specific mortality in men with diabetes while others found no association [4-7]. To date, diabetes has not been shown to affect biochemical recurrence (BCR) after surgery or radiation [5, 8-10]. Interestingly, in a subgroup analysis from our previous study, we found that, among men undergoing radical prostatectomy (RP), obesity modified the effect of diabetes on PCa aggressiveness in white men (P-interaction = 0.006), leading to greater BCR risk in obese white men (hazard ratio [HR] 2.52, P = 0.002), but not in other patient groups .
Extending this work, we sought to determine if diabetes also influences time to metastasis, which is a more definitive clinical endpoint than BCR. To do this, we retrospectively examined the association between diabetes and PCa metastasis among men undergoing RP in the Shared Equal-Access Regional Cancer Hospital (SEARCH) database, using models adjusting for preoperative features and, separately, for clinical and postoperative findings. As our past work suggested that obesity and race might modify the relationship between diabetes and PCa aggressiveness, we further stratified by these characteristics and tested for interactions with diabetes . Finally, given that secondary treatments may influence progression to metastasis, we compared rates of postoperative radiation and androgen deprivation therapy (ADT) in men with diabetes vs men without diabetes.
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Among the few studies examining diabetes and PCa outcomes, there remains significant disagreement, with one report noting higher PCa-specific mortality in men with diabetes while several others found no association [3-8]. Most recently, among men undergoing RP, we found that diabetes was associated with higher BCR risk in obese white men but not in other patient groups, suggesting race and obesity may modify the effect of diabetes on PCa progression .
In the present study, we found diabetes was not associated with metastasis risk after RP regardless of race. Although consistent with most previous studies concluding that diabetes does not influence BCR or PCa-specific mortality [5-10], our results differ from those of Hammarsten and Högstedt  who, in a cohort of 320 Swedish patients with T2-3 disease, found men with type 2 diabetes were more likely to die from PCa; however, this analysis did not control for age, PSA or BMI, despite the known relationship of these factors to both PCa progression and diabetes [4, 13-17]. Thus, it is unclear if the increased PCa-specific mortality was attributable to diabetes or a confounding factor.
Although diabetes was not associated with metastasis risk overall, when stratified by obesity, we found diabetes predicted a nearly fourfold higher metastasis risk in obese men (P = 0.009) while, in non-obese men, there was a suggestion that diabetes was protective (HR 0.37, P = 0.19). Moreover, the formal test of interaction between diabetes and obesity was significant (P-interaction = 0.037), suggesting synergy between these two disorders. Specifically, while we found that neither diabetes nor obesity independently raised metastasis risk, their co-existence predicted a higher likelihood of developing metastases (HR 2.80, P = 0.017). Interestingly, we found obese men with diabetes received more aggressive secondary treatment than obese men without diabetes; thus, inadequate therapy cannot explain the higher metastasis risk in obese men with diabetes. Conversely, among non-obese men, diabetes predicted less aggressive secondary treatment yet was linked with equal or lower metastasis risk.
These results support earlier findings from our group linking diabetes to increased BCR risk after RP, but only in obese white men (P = 0.002) . In our previous report, the formal test of interaction between diabetes and obesity was significant (P-interaction = 0.006), and there was also a suggestion that race may modify the effect of diabetes on BCR and PSA doubling time (all P-interaction ≤0.11) ; however, in the current analysis, we observed no significant interaction between race and diabetes. Our latest findings mostly agree with a recent study of 998 men undergoing biopsy at the Durham VAMC, a cohort partially overlapping that of the SEARCH database . In that study, while diabetes was linked with risk of high grade disease (Gleason > 7) overall, on additional subanalysis, this observation was significant only for obese white men (P = 0.038). In the same study, the interaction between diabetes and obesity approached significance (P-interaction = 0.088 in white men) whereas the interaction between diabetes and race did not (P-interaction = 0.60) . Finally, in a recent analysis from the REDUCE trial, we found a borderline significant interaction between diabetes and obesity for predicting high grade PCa (P-interaction = 0.053) . Taken together, these results suggest that obesity, but not race, modifies the effect of diabetes on PCa aggressiveness.
Possible biological mechanisms for our findings include changes in the hormonal milieu of obese men with diabetes, particularly decreased plasma concentrations of total and free testosterone, as well as elevated levels of insulin and IGF-1 [20-23]. While the role of androgens in PCa risk is controversial, with a recent large meta-analysis showing no association between plasma androgens and PCa risk, there are increasing data that among men with PCa, low androgen levels are associated with aggressive disease [24-29]. Whether this results from selection bias (i.e. only more aggressive tumours can grow in the low-androgen environment) or whether a low-androgen environment directly promotes the development of a more aggressive phenotype is unclear. As such, though a low androgen environment may certainly be one explanation for our observations, much more research is needed regarding the role of obesity, diabetes, androgens and PCa progression.
As diabetes and obesity both disturb endocrine homeostasis, their combined effect on growth factor signalling may explain our observations of higher metastasis risk in men with both disorders [30-32]. Notably, several previous studies have found elevated fasting insulin and C-peptide levels, a marker of insulin secretion, to predict higher PCa-specific mortality [4, 30]. Studies have also linked attributes of metabolic syndrome, which is characterized by insulin resistance and secondary hyperinsulinaemia, to aggressive PCa [4, 31, 32]. Together, these findings implicate insulin as a key promoter of PCa progression, which is particularly suggestive given hyperinsulinaemia is a hallmark of both obesity and early type 2 diabetes.
Interestingly, while early type 2 diabetes leads to insulin excess, advanced diabetes is characterized by diminished insulin secretion due to progressive pancreatic β-islet cell loss, so men with type 2 diabetes eventually become hypo- rather than hyperinsulinaemic. Indeed, the majority of reports examining the risk of PCa diagnosis (as opposed to progression, which was the focus of the present study) have noted a lower PCa risk with longer diabetes duration, supporting the hypothesis that a transition from a hyper- to hypoinsulinaemic state is protective [33-36]. Interestingly, we found herein that a longer duration of diabetes predicted a higher metastasis risk. Thus, while the hypoinsulinaemia of long-standing diabetes may reduce the risk of PCa diagnosis, our latest findings suggest that for men already diagnosed with PCa, long-standing diabetes may actually increase the likelihood of metastasis, perhaps by starving the tumour of needed growth stimuli and thereby selecting for the biologically fittest cells within. That a lesion is able to survive and expand in such a harsh environment to the point of being detected clinically would suggest it is likely to be highly aggressive. Since one consequence of inadequate insulin is poor glycaemic control, it is noteworthy that several other studies have indeed linked elevated HbA1c levels with higher grade tumours at RP [37, 38]. Our results showing that longer duration of diabetes is associated with a higher metastasis risk will, of course, require confirmation through other studies. If verified, however, the clinical implication is that men with long-standing diabetes who develop PCa may harbour a more aggressive variant, and this possibility should be kept in mind when determining treatment.
Unfortunately, a true comparison of metastasis risk between type 1 and type 2 diabetes could not be performed as the vast majority of our cases (97%) had type 2 disease. We also lacked information on diabetes severity and treatment. Since these factors might alter plasma insulin levels, such information would be important to future studies investigating the biological underpinnings of our epidemiological observations; however, these data were not available to us. Additionally, the present analysis accounted only for men with diabetes at the time of RP, which may have biased our results toward the null if many in the group without diabetes demonstrated glucose intolerance at surgery but were only formally diagnosed with diabetes later. Nevertheless, on sensitivity analysis including all men ever diagnosed with diabetes, results remained similar. Our groups also differed significantly in baseline clinical characteristics, with men with diabetes more likely to be non-white and to have a higher BMI and lower PSA levels; however, these differences accurately reflect the known demographics of type 2 diabetes, and we further controlled for these covariates in our regression models [1, 13, 14].
Another significant limitation was the rarity of metastatic disease (n = 49). Despite this, the present results are consistent with previous findings from largely the same population of men within the SEARCH database examining the association of diabetes with BCR risk, an intermediate endpoint predictive of progression to metastasis and mortality, for which substantially more events (n = 401) were available for analysis [10, 39].
Finally, the present analysis was retrospective in nature and prone to selection bias (specifically, it included only men neither too obese nor too ill to preclude surgery), changes in clinical practice over time, and unknown confounders.
The strengths of our study include the fact that it comprised a large, racially diverse cohort drawn from a single equal-access healthcare system, determination of BMI from direct measurements, and identification of diabetes through detailed chart review. The SEARCH database also did not include men receiving preoperative radiation or ADT, thus eliminating confounding by multiple treatment types. We further performed sensitivity analysis by eliminating men undergoing adjuvant radiation or ADT and observed that our results did not change. It should be noted, however, that our cohort included only men undergoing RP. Thus, our results may not be applicable to all men with PCa, and additional studies will be required to validate these findings in other patient populations such as men treated with external beam radiation or brachytherapy, or those enrolled in active surveillance. Nevertheless, given the paucity of studies on diabetes and PCa progression, our results shed valuable light on this important yet little-examined topic and suggest that diabetes in combination with obesity results in particularly aggressive PCa.
To conclude, in retrospective analysis, diabetes was not associated with metastasis risk after RP; however, when stratified by obesity, diabetes resulted in a nearly fourfold higher metastasis risk in obese men despite predicting more aggressive secondary treatment. By contrast, among non-obese men, diabetes resulted in a nonsignificant trend toward lower metastasis risk. Obesity, but not race, modified the effect of diabetes on metastasis risk. Finally, among men with diabetes, a longer duration of diabetes was associated with a higher risk of developing metastases. Our findings add to the limited research on diabetes, obesity, and PCa progression, suggesting men with diabetes and obesity together might harbour particularly aggressive PCa.