Introduction

Excess body weight (i.e., overweight and obesity) has consistently been shown to be associated with higher prostate cancer (PCa) specific mortality.^1,2 However, the mechanisms underlying this relationship are unclear. One hypothesized mediator is insulin resistance, yet epidemiological studies supporting this claim are scarce.^1,3 Despite insulin resistance being hypothesized as one biological mechanism linking excess body weight with PCa death, a formal statistical mediation analysis assessing whether, and, if yes, how much exactly, insulin resistance mediates the effect of excess body weight on PCa death has not been performed to date.

Methods

The present study is, to the best of our knowledge, the first prospective cohort study using state-of-the-art mediation analysis techniques to investigate the interrelations between body mass index (BMI), the TyG index⁴, a simple, yet valid indicator of insulin resistance, and PCa-specific death. Data of 259,884 initially cancer-free men (mean baseline age 43.3 years;  11,760 PCa diagnoses over a mean follow-up time of 19.8 years) were obtained by pooling eight different European population-based cohorts from Austria, Norway, and Sweden. Because of the availability of repeated measurements, we were able to account for intra-individual fluctuations in BMI and TyG index values. Detailed information on participants’ socioeconomic status and tumor characteristics in four Swedish cohorts allowed us to extensively adjust our statistical models, thus minimizing the potential of confounder and/or detection bias.

Results

In case-only analyses, the TyG index was positively associated with time from PCa diagnosis to PCa-specific death (hazard ratio (HR) = 1.11 per 1-standard deviation (SD) increase in TyG index, 95% confidence interval (CI): 1.01 to 1.22). BMI was positively associated with the risk of PCa death (HR_{total effect} = 1.24 per 5-kg/m² BMI increase, 95% CI: 1.14–1.35), and of this total BMI effect, 28% (95% CI: 4% to 52%) were mediated through the TyG index.

In contrast, in full cohort analyses the association between TyG index and PCa-specific death was much weaker (HR = 1.03 per 1-SD increase, 95% CI: 0.94 to 1.13). Of note, the TyG index was slightly negatively associated with PCa incidence (0.96, 95% CI: 0.93 to 1.00). Only 11% (95% CI: −21% to 42%) of the total BMI effect (HR_{total effect} = 1.17, 95% CI: 1.08 to 1.27), and thus a markedly smaller proportion than for the PCa-case only analysis, were mediated through the TyG index.

Discussion

In summary, in PCa-case only analyses more than a quarter of the effect of BMI on PCa death was mediated through the TyG index. The contribution of the TyG index as a mediator to the effect of BMI on PCa-specific death in the full cohort was much smaller, because, in contrast to PCa death, the TyG index was slightly negatively associated with PCa incidence. As the TyG index is indicative of insulin resistance, the findings of our study provide evidence that insulin resistance is an important pathway through which obesity accelerates PCa progression, in line with previous mechanistic studies.^5,6 Our results provide further evidence of the importance of avoiding overweight and/or obesity, in combination with maintaining insulin sensitivity, as targets to slow down PCa progression. Future studies are needed to investigate whether other, more specific, insulin resistance-related factors can explain a higher proportion of the BMI effect on PCa-specific mortality. If our findings are confirmed in future studies, they add to the rationale for investigating novel treatment strategies for PCa targeting insulin resistance as an adjuvant therapy for PCa. Still, despite substantial mediation through the TyG index, major parts of the underlying mechanisms connecting BMI with worse PCa outcomes remain elusive and efforts into investigating other potential mediators are needed.

References

¹Allott EH, Masko EM, Freedland SJ. Obesity and prostate cancer: weighing the evidence. Eur Urol. 2013;63:800–9.

²Jochems SHJ, Stattin P, Häggström C, Järvholm B, Orho-Melander M, Wood AM, et al. Height, body mass index and prostate cancer risk and mortality by way of detection and cancer risk category. Int J Cancer. 2020;147:3328–38.

³Ma J, Li H, Giovannucci E, Mucci L, Qiu W, Nguyen P, et al. Prediagnostic body-mass index, plasma C-peptide concentration, and prostate cancer-specific mortality in men with prostate cancer: a long-term survival analysis. Lancet Oncol. 2008;9:1039–47.

⁴Simental-Mendía LE, Rodríguez-Morán M, Guerrero-Romero F. The product of fasting glucose and triglycerides as surrogate for identifying insulin resistance in apparently healthy subjects. Metab Syndr Relat Disord. 2008;6:299–304.

⁵Perks C, Zielinska H, Wang J, Jarrett C, Frankow A, Ladomery M, et al. Insulin receptor isoform variations in prostate cancer cells. Front Endocrinol. 2016;7:132.

⁶Sarkar PL, Lee W, Williams ED, Lubik AA, Stylianou N, Shokoohmand A, et al. Insulin enhances migration and invasion in prostate cancer cells by up-regulation of FOXC2. Front Endocrinol. 2019;10:481.