Diabetes, a prevalent chronic disease, is known for its detrimental impact, arising not solely from the disease itself but also from associated complications stemming from abnormal blood sugar levels. The damage caused by diabetes extends to vital organs and blood vessels, resulting in serious conditions such as stroke, blindness, heart attack, kidney failure, and skin ulcers[19]. Furthermore, the high-sugar environment created by diabetes within the human body has been shown to stimulate the growth of certain cancer cells, including those in the endometrium[2], pancreas[3], colon[4], thyroid[5], and other types of cancers.
Controversies persist in the literature regarding the relationship between diabetes and prostate cancer. Some scholars contend that no statistical difference exists in the clinical symptoms and classification of prostate cancer between diabetics and non-diabetics[20]. At the same time, meta-analyses have yielded diverging outcomes indicating a reduced risk of developing prostate cancer for diabetes patients, however, this association has been shown to have little or no impact on the progression of the disease[21]. It should be noted that this meta-analysis was limited by the small number of papers included and a restricted clinical sample. Various studies have suggested a negative correlation between diabetes and prostate cancer, but this conclusion can be impacted by the ethnicity of the participants, with a positive correlation evident between these two conditions among Asian populations[10]. This finding stresses the significance of genetic factors in determining the relationship between diabetes and prostate cancer, thus calling attention to the potential of investigating novel genetic markers or pathways to shed light on this topic further.
However, several studies have presented contrasting findings, suggesting that diabetes may have a detrimental impact on the prognosis of prostate cancer and escalate the mortality rate among prostate cancer patients[11]. These studies imply that the relationship between diabetes and prostate cancer is intricate and necessitates further and in-depth investigation. Due to the extensive duration of the disease cycle in diabetic patients, the study of this disease inevitably involves the incorporation of numerous confounding factors. For instance, diabetic individuals commonly endure obesity[22], and obesity has been linked to an increased risk of prostate cancer. This association indicates a positive correlation with the heightened susceptibility to the disease, and obesity may serve as a significant risk factor for PCa[23]. The impact of long-term use of hypoglycemic drugs on prostate cancer development in patients warrants consideration. Metformin, a commonly prescribed drug for T2DM, has been associated with a reduced risk of prostate cancer in some studies[24]. Its mechanism of action in various tumor types involves the activation of the AMP kinase pathway, p53 activation, downregulation of cyclin D1, and inhibition of HER2 oncoprotein expression. Inhibitory effects have been observed in preclinical models of prostate[25], breast[26], pancreas[27], lung[28], and colon[29] cancer.
Given the influence of confounding factors such as obesity, drug effects, and deliberate changes in living and eating habits following the diagnosis of T2DM, some studies have indicated the necessity of employing experimental designs with fewer interfering factors to further elucidate the association between diabetes mellitus (DM) and prostate cancer (PCa)[21]. In this study, we leverage the methodology of Mendelian randomization research to investigate the impact of T2DM on prostate cancer and to analyze whether a causal relationship exists between the two at a genetic level. This approach allows the analysis results to mitigate many confounding factors in the development of the disease, thereby providing a more convincing demonstration of the relationship between T2DM and prostate cancer[30].
This study utilized the most recent extensive summary data from public resources in GWAS and IEU databases to examine the impact of T2DM on prostate cancer through a two-sample Mendelian analysis approach. From a genetic standpoint, it was observed that an increase in T2DM in the population considerably raises the incidence of prostate cancer. Throughout the analysis process, we strictly adhered to the three major assumptions of Mendelian randomization: firstly, we employed a stringent criterion (p < 5E-08) to establish a strong correlation, thereby preliminarily excluding SNPs, thus ensuring a strong correlation between SNPs and exposure factors; secondly, we carried out linkage disequilibrium analysis (R2 < 0.001) to further enhance the screening of SNPs, guaranteeing their independence from confounding factors; finally, to comply with the "exclusivity hypothesis," sensitivity analysis was conducted, specifically involving sex-based and MR-PRESSO analyses, both demonstrating the absence of horizontal pleiotropy, thus ensuring that SNPs solely impact outcomes through exposure factors.
This study also has several limitations. Firstly, the analysis was only conducted on data from the European population, which may limit the generalizability of the findings to the broader human population. Secondly, there might be an insufficiency of prostate cancer cases, and the inclusion of additional cases may introduce bias. Thirdly, the study could not establish correlations between different stages of prostate cancer due to the lack of detailed data. This limitation prevents a more refined conclusion regarding the causal relationship between T2DM and prostate cancer.