Diabetes and the Prostate: Elevated Fasting Glucose, Insulin Resistance and Higher Levels of Adrenal Steroids in Prostate Cancer

Although epidemiological studies suggest a lower prostate cancer incidence rate in patients with type 2 diabetes, cancer survival is markedly reduced. Underlying mechanisms that connect the two diseases are still unclear. Potential links between type 2 diabetes and prostate cancer are hallmarks of the metabolic syndrome, such as hyperglycemia and dyslipidemia. Therefore, we explored the systemic metabolism of 103 prostate cancer patients with newly diagnosed and yet untreated prostate cancer compared to 107 healthy controls, who were carefully matched for age and BMI. Here, we report that patients with prostate cancer display higher fasting blood glucose levels and insulin resistance, without changes in insulin secretion. With respect to lipid metabolism, serum triglyceride levels were lower in patients with prostate cancer. In addition, we report increased adrenal steroid biosynthesis in these patients. Our results indicate that higher fasting glucose levels in patients with prostate cancer may be explained at least in part by insulin resistance, due to the enhanced synthesis of adrenal steroids.


Introduction
Epidemiological studies suggest a lower prostate cancer (PCa) incidence in patients with type 2 diabetes [1,2]. However, the cancer survival in the case of coexisting diabetes is clearly reduced [3]. Both diabetes and PCa rank among the most frequent diseases in males worldwide with an enormous impact on morbidity and mortality. Although both diseases share several common risk factors, the precise causal links between them are not fully understood.
Important factors that may link PCa and diabetes are hallmarks of the metabolic syndrome, i.e., hyperglycemia and dyslipidemia [4]. In general, patients with higher blood glucose levels have more aggressive PCa [5]. Strong evidence exists for the impact of hyperglycemia on PCa recurrence after primary surgical or radiation therapy [6] and hyperglycemia-induced chemoresistance of PCa [7]. Vice versa, the commonly used first line androgen deprivation therapy for advanced PCa often causes metabolic disturbances, namely insulin resistance and hyperglycemia [8].

Discussion
Although epidemiological studies indicated lower PCa risk in men with type 2 diabetes, the precise relationships between PCa and hyperglycemia are not well understood. In particular, it is unclear whether hyperglycemia may modulate PCa risk and vice versa. Moreover, antidiabetic medication may also impact on PCa risk through different mechanisms independently of lowering blood glucose levels [13]. In the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC) with a median follow-up of 14.7 years, increased fasting glucose was identified as a predictor of PCa development [13]. Although we excluded patients with diabetes, men with PCa in our study clearly displayed higher fasting glucose levels, compared to carefully matched controls. Thus, our results are in line with the aforementioned Finnish study.

Discussion
Although epidemiological studies indicated lower PCa risk in men with type 2 diabetes, the precise relationships between PCa and hyperglycemia are not well understood. In particular, it is unclear whether hyperglycemia may modulate PCa risk and vice versa. Moreover, antidiabetic medication may also impact on PCa risk through different mechanisms independently of lowering blood glucose levels [13]. In the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC) with a median follow-up of 14.7 years, increased fasting glucose was identified as a predictor of PCa development [13]. Although we excluded patients with diabetes, men with PCa in our study clearly displayed higher fasting glucose levels, compared to carefully matched controls. Thus, our results are in line with the aforementioned Finnish study.
In another study, Gerlini et al. could show that glucose intolerance and insulin resistance regulate adipocyte transcription in human obesity [14]. As we found hyperglycemia and insulin resistance in PCa, it is tempting to speculate that comparable transcriptional effects might exist in the prostate.
Interestingly, the metabolic pattern of hyperglycemia in the context of low circulating triglycerides was associated with poor prognosis and increased risk of PCa death in a previous study [4]. The role of triglycerides in PCa is not fully understood yet. However, lipid metabolism seems essential for prostate cancer cells, while they do not depend on increased aerobic glycolysis [15]. As we detected lower triglycerides in PCa patients, while liver fat content was comparable to healthy controls, triglyceride uptake might be higher in prostate cancer cells. This hypothesis needs to be addressed in future studies.
One known determinant of insulin sensitivity/insulin resistance, which might further support our findings, are steroid hormones. PCa was reported to release miRNA, which affect steroid biosynthesis mainly in the adrenal gland [16,17]. We therefore measured key steroid hormones in our patients.
PCa is a hormone-dependent cancer, and androgen signaling represents a key driver for cancer cell growth. However, in a collaborative analysis investigating direct correlations between risk of PCa and serum concentrations of circulating sex steroids, no associations were found [18]. In spite of this, complex interactions between diabetes and sex steroids exist [19]. We hypothesized that hyperglycemia in PCa patients may be linked to the elevated synthesis of sex steroids. Testosterone synthesis has been reported to be reduced in patients with diabetes [20], but continued androgen receptor (AR) activation in the presence of low circulating levels of testosterone have been proposed, indicating alternative AR ligands to bypass the testosterone/dihydrotestosterone-mediated AR activation [10]. Therefore, we assessed adrenal steroids as androgen precursors. Indeed, we found elevated levels of cortisol, androstenedione, DHEA-Sulfate, progesterone and estradiol in PCa. Of note, serum levels of gonadal steroid testosterone were comparable between the groups ( Table 1). The adrenal hormones may, on the one hand, activate at least mutated AR, a frequent mechanism in PCa to provoke resistance to hormonal therapy [21], but on the other hand, also elevate fasting glucose levels in PCa patients by introducing insulin resistance. Unfortunately, unlike in our study, most previous studies did not perform the rigorous matching for anthropometric determinants of steroid hormones and may, therefore, have missed to detect differentially regulated hormones in cancer vs. control. Nevertheless, our results are supported by a previous report showing higher levels of estradiol in PCa [22]. Several reports exist suggesting a proliferative role of estradiol in PCa especially via activating the estrogen receptor α [23]. Androstenedione seems relevant for AR activation with regard to being largely unaffected by ADT or orchiectomy in spite of testosterone/dihydrotestosterone [24].
Among the limitations of our work is the cross-sectional study design that can never fully uncover changes over time. The prostate cancer cases were heterogeneous in grade and stage which might have impacted our findings (see Supplementary Tables S1 and S2). Due to the available sample size, we could not investigate potential differences due to cancer grade/stage in further subgroups in more detail. Clearly, additional experimental studies are needed to unravel the molecular links between steroid hormones, diabetes and PCa.
Our results suggest that higher fasting glucose levels in patients with PCa may be explained at least in part by insulin resistance, due to the enhanced synthesis of adrenal steroids. This may pave the way for new therapeutic approaches in coexisting diabetes and PCa.   Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.

Data Availability Statement:
The data are not publicly available as they contain information that could compromise research participant privacy/consent.