Elsevier

European Journal of Cancer

Volume 41, Issue 18, December 2005, Pages 2887-2895
European Journal of Cancer

Hyperinsulinaemia: A prospective risk factor for lethal clinical prostate cancer

https://doi.org/10.1016/j.ejca.2005.09.003Get rights and content

Abstract

Previous studies have suggested that hyperinsulinaemia and other components of metabolic syndrome are risk factors for clinical prostate cancer. This prospective study tested the hypothesis that hyperinsulinaemia and other components of metabolic syndrome are risk factors for lethal clinical prostate cancer. The clinical, haemodynamic, anthropometric, metabolic and insulin profile at baseline in men who had died from clinical prostate cancer during follow-up was compared with the profile of men who were still alive at follow-up. If the hypothesis is true, men with an unfavourable prognosis would have a higher profile at baseline than those with a favourable prognosis. A total of 320 patients in whom clinical prostate cancer, stages T2–3, had been diagnosed were consecutively included in the study during 1995–2003. Height, body weight, waist measurement, hip measurement and blood pressure were determined. Body mass index and waist/hip ratio (WHR) were calculated. Blood samples were collected to determine triglycerides, total cholesterol, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, uric acid, alanine aminotransferase and fasting plasma insulin level. The prostate gland volume was measured using transrectal ultrasound. The annual benign prostatic hyperplasia (BPH) growth rate was calculated. The diagnosis of prostate cancer was established using transrectal ultrasound-guided automatic needle biopsy of the prostate gland. All patients with clinical prostate cancer were followed up until their death or until the study was terminated on 31 December 2003. At follow-up, 54 patients had died from prostate cancer and 219 were still alive. The results showed that the men who died of clinical prostate cancer during the follow-up period were older (P < 0.001), had a larger prostate gland volume (P < 0.001), a faster BPH growth rate (P < 0.001), a higher prevalence of type 2 diabetes (P < 0.035) and treated hypertension (P < 0.023), a higher stage (P < 0.001) and grade (P = 0.028) of clinical prostate cancer, a higher prostate-specific antigen (PSA) level (P < 0.001) and a higher PSA density (P < 0.001) at baseline than men still alive with clinical prostate cancer at follow-up. These men also had a lower HDL-cholesterol level (P = 0.027), a higher fasting plasma insulin level (P = 0.004), a higher WHR (P = 0.097) of borderline significance and a higher uric acid level (P = 0.079) of borderline significance. Eliminating the effect on mortality of higher stage and grade of the clinical prostate cancer and PSA at baseline, the following statistically significant correlations remained: a higher fasting plasma insulin level (P = 0.010) and a lower HDL-cholesterol level of borderline significance (P = 0.065). In conclusion, hyperinsulinaemia and five other previously established components of metabolic syndrome are shown to be prospective risk factors for deaths that can be ascribed to prostate cancer. These findings confirm previous study, which indicate that prostate cancer is a component of metabolic syndrome. Moreover, these data indicate that hyperinsulinaemia and other metabolic disorders precede deaths caused by prostate cancer. Thus, our data support the hypothesis that hyperinsulinaemia is a promoter of clinical prostate cancer. Furthermore, our data suggest that the insulin level could be used as a marker of prostate cancer prognosis and tumour aggressiveness, regardless of the patient’s prostate cancer stage, cancer grade and PSA level.

Introduction

In a previous cross-sectional study, it was found that benign prostatic hyperplasia (BPH) growth rate, hypertension, obesity, dyslipidaemia, hyperuricaemia, hyperinsulinaemia and high alanine aminotransferase (ALAT) levels were risk factors for the development of clinical prostate cancer, measured by stage and grade [1]. These findings suggested that clinical prostate cancer is a component of metabolic syndrome, i.e., one of the so-called ’diseases of Western civilisation’, in addition to hypertension, obesity, dyslipidaemia and hyperinsulinaemia. Barnard and colleagues [2] reached the same conclusion, based on a series of findings in a recent review.

This previous cross-sectional study has also generated the hypothesis of a link between insulin levels and clinical prostate cancer [1]. The hypothesis stated that insulin levels were not involved in the carcinogenesis, but in the promotion of the growth of an established prostate cancer. Our findings indicated that several factors known to be associated with hyperinsulinaemia, such as a large prostate gland volume 3, 4, 5, 6, fast-growing BPH 3, 4, 5, 6, hypertension 7, 8, 9, 10, obesity 9, 11, 12, dyslipidaemia 9, 10, hyperuricaemia 10, 13, 14, and high ALAT levels [15] were linked to advanced clinical prostate cancer, as measured by stage and grade. In fact, a statistically significant relationship was found between clinical prostate cancer grade and fasting plasma insulin level. In patients with G1 tumours, the median fasting plasma insulin level was 8.6 mU/l, while in those with G2 tumours it was 9.6 mU/l and in patients with G3 tumours 11.0 mU/l. Our data were in line with the results of a population-based case control study in China, suggesting that, regardless of overall and abdominal adiposity, higher serum insulin levels involve a higher risk of prostate cancer [16]. In another more recent population-based study, it was found that insulin resistance is associated with a higher risk of prostate cancer and that insulin sensitivity is associated with a reduced risk of prostate cancer among Chinese men [17]. In yet another recent study, a high serum insulin level was associated with an increased risk of prostate cancer recurrence [18]. The same authors have also reported that serum insulin levels were significantly higher in high-risk prostate cancer patients than in low- or intermediate-risk patients [19]. On the other hand, a prospective Swedish nested case-control study has shown no association between plasma insulin and prostate cancer [20].

Thus, our previous study showed that hyperinsulinaemia and other components of metabolic syndrome were associated with high stage and high grade clinical prostate cancer [1]. However, an important limitation of our previous study was that it was cross-sectional. Thus, the presence of hyperinsulinaemia and other components of metabolic syndrome could be a consequence rather than the cause of high stage and high grade clinical prostate cancer.

Another way of testing the hypothesis that hyperinsulinaemia and other components of metabolic syndrome are risk factors for the development of clinical prostate cancer would be prospectively to compare the clinical, haemodynamic, anthropometric, metabolic and insulin profile at baseline in men with poor prognosis, with the profile of men with a good prognosis. If the hypothesis were true, men with an unfavourable prognosis would have a higher profile at baseline than men with a favourable prognosis.

Section snippets

Patients and methods

A total of 320 patients referred to the Urological Section, Department of Surgery, Varberg Hospital, Varberg, Sweden, in whom clinical prostate cancer had been diagnosed, were consecutively included in this study during 1995–2002. Clinical prostate cancer was defined as a prostate tumour indicated by a digital rectal examination or by ultrasound, and verified histopathologically using transrectal ultrasound-guided automatic needle biopsy of the prostate gland. The core biopsy was

Results

Table 1 shows the profile at baseline of the stable factors in men with clinical prostate cancer, stages T2–3, all PSA values accepted. The table also shows a comparison between men who died from clinical prostate cancer during follow-up, and men who were still alive at follow-up. At this comparison, men who died from clinical prostate cancer were older, had a larger prostate gland volume and a faster BPH growth rate. They also had a higher cancer stage and grade, a higher PSA level and a

Discussion

The most important finding in this report is that our data support the hypothesis that hyperinsulinaemia is a promoter of clinical prostate cancer. Our data also suggest that the insulin level could be used as a marker of the prostate cancer prognosis and the tumour aggressiveness, regardless of the patient’s prostate cancer stage and grade and the patient’s PSA level. The fasting plasma insulin level is interesting as a prognostic risk factor, because it is modifiable through lifestyle,

Conflict of interest statement

None declared.

Acknowledgements

Supported by funding from The Swedish Cancer Society and The Scientific Council, County of Halland, Sweden.

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