Skip to main content
NCBI home page
American Journal of Cancer Research logoLink to American Journal of Cancer Research
. 2016 Oct 1;6(10):2334–2344.

Association of insulin resistance with breast, ovarian, endometrial and cervical cancers in non-diabetic women

Wanwan Sun 1,*, Jieli Lu 1,*, Shengli Wu 2,*, Yufang Bi 1, Yiming Mu 3, Jiajun Zhao 4, Chao Liu 5, Lulu Chen 6, Lixin Shi 7, Qiang Li 8, Tao Yang 9, Li Yan 10, Qin Wan 11, Yan Liu 12, Guixia Wang 12, Zuojie Luo 13, Xulei Tang 14, Gang Chen 15, Yanan Huo 16, Zhengnan Gao 17, Qing Su 18, Zhen Ye 19, Youmin Wang 20, Guijun Qin 21, Huacong Deng 22, Xuefeng Yu 23, Feixia Shen 24, Li Chen 25, Liebin Zhao 1, Tiange Wang 1, Jichao Sun 1,26, Min Xu 1, Yu Xu 1, Yuhong Chen 1, Meng Dai 1, Jie Zhang 1, Di Zhang 1, Shenghan Lai 1,27, Donghui Li 28, Guang Ning 1,26, Weiqing Wang 1
PMCID: PMC5088296  PMID: 27822422

Abstract

Hyperinsulinemia and insulin resistance were reported to play a crucial role in diabetes-cancer relationship. This study aimed to explore the associations between insulin resistance and several female cancers in a non-diabetic population. This cross-sectional study was conducted in 121,230 middle-aged and elderly non-diabetic women. Cancer diagnosis was self-reported and further validated by medical records. Insulin resistance was defined as homeostasis model assessment of insulin resistance (HOMA-IR) ≥ 2.50. The prevalence of both premenopausal and postmenopausal breast cancer, postmenopausal ovarian cancer and premenopausal endometrial cancer were higher in insulin-resistant participants than in insulin-sensitive participants (premenopausal breast cancer, 0.45 vs 0.28%; postmenopausal breast cancer, 0.86 vs 0.63%; postmenopausal ovarian cancer, 0.17 vs 0.09%; premenopausal endometrial cancer, 0.43 vs 0.25%, respectively, all P < 0.05). Individuals with insulin resistance had higher odds ratio (OR) of breast cancer, both premenopausal and postmenopausal (OR 1.98, 95% confidence interval (CI) 1.19-3.32; OR 1.29, 95% CI 1.01-1.63), postmenopausal ovarian cancer (OR 2.17, 95% CI 1.10-3.40) as well as total endometrial cancer (OR 1.47, 95% CI 1.02-2.12). Subgroup analysis revealed that the possitive association between insulin resistance and risk of prevalent breast cancer was observed in popualtion with younger age, overweight or obesity, higher education and impaired glucose tolerance (IGR). No relationships were observed for the risk of prevalent cervical cancers with insulin resistance. Non-diabetic women with insulin resistance had higher risk of prevalent breast, ovarian and endomatrial cancer, which suggests special attentions to these female cancer screening and prevention.

Keywords: Insulin resistance, non-diabetic, breast, ovarian, endometrial and cervical cancers

Introduction

Diabetes has been recognized as a risk factor for certain female cancers [1-6]. Insulin resistance is believed to play a crucial role in diabetes-cancer relationship. Previous research indicated that in diabetes patients, as a consequence of insulin resistance, elevated level of insulin and signaling transduction through the IGF-1 receptor pathway could stimulate cell proliferation and inhibit apoptosis, thus contribute to tumor promotion and metastasis [4,5,7,8]. Another biological mechanism that linking diabetes and female cancer is the elevated level of sex hormones that was caused by insulin-mediated reduction of hepatic sex hormone binding globulin and increase of endogenous sex steroid hormones [9]. However, in spite of the large amount of epidemiological evidence on the association of diabetes and female cancers, especially breast and endometrial cancers [10,11], fewer studies have directly assessed the association between insulin resistance and female cancers in non-diabetic population.

Cancers of the breast, ovary, endometrium and cervix are common cancers with high incident rates in women. Breast cancer comprised 25.2% of the cancers diagnosed in women, making it the most common female cancer [12]. Worldwide, ovarian cancer contributed to 160,000 deaths in 2010, up from 113,000 cases in 1990 [13]. Endometrial cancer affect approximately 320,000 women and kill 76,000 cases every year, making it the sixth most common cancer in women [12]. In 2012, 528,000 cervical cancer cases and 266,000 deaths was reported worldwide [12], making it the fourth in both cancer incidence and mortality in women [12].

Previous studies directly regarding the relationship between insulin resistance and several female cancers were limited, especially in Chinese population, and didn’t provided consistence information [7,14-18]. Given the pandemic of female cancers in China, it is imperative to detect whether insulin resistance in non-diabetic population posed a higher risk for female cancers. Here, we investigated the association between insulin resistance and female cancers, including breast, ovarian, endometrial and cervical cancers, in a large population of Chinese non-diabetic women aged 40 years and older.

Materials and methods

Study population and data collection

The study population was drawn from the Risk Evaluation of cAncers in Chinese diabeTic Individuals: a lONgitudinal (REACTION) study which is a multicenter prospective study designed to evaluate the association between glucose metabolism and cancer risks [19,20]. The study cohort consisted of 259,657 participants aged 40 years or older, recruited from 25 communities across mainland China during 2011 to 2012 [19-22]. The design and methodology of REACTION study has previously been described in details [19,20]. Briefly, a personal interview was conducted to collect information on sociodemographic characteristics, lifestyle factors, medical history, and family history of cancer and type 2 diabetes mellitus (T2DM) among the first degree relatives. A 2-hour oral glucose tolerance (OGTT) test was performed and a blood sample was collected for measuring insulin, HbA1c and lipid protein levels.

The current analysis is a cross-sectional study using the baseline data of the REACTION study. There are a total of 169,628 female participants in the REACTION study. For the current study, we excluded 5251 subjects with missing blood glucose value, 14,114 with missing insulin value and 29,033 women with diabetes. This comes to a total of 121,230 non-diabetic women in the current analysis.

Ethics, consent and permissions

The REACTION study is supported by the Chinese Society of Endocrinology and led by Rui Jin Hospital affiliated to Shanghai Jiao-Tong University School of Medicine. The Institutional Review Board of Shanghai Jiao-Tong University School of Medicine approved the study protocol. Written informed consents were obtained from all study participants.

Assessment of diagnosed cancer

Cancer status were self reported by participants themselves, as well as information on cancer type, diagnosis date and the treatment history. The accuracy of the data was verified by the Adjudication Committee, which was composed of clinical experts of radiologists, pathologists and endocrinologist. The accuracy rate of these data is more than 90%.

Definition of variables analyzed in this study

Overweight was defined as body mass index (BMI, kg/m2) ≥ 25 but < 30, obesity as BMI ≥ 30, central obesity as waist circumference ≥ 80 cm. Systolic blood pressure (SBP) ≥ 140 mmHg or diastolic blood pressure (DBP) ≥ 90 mmHg was considered as hypertension. Dyslipidemia was defined as total cholesterol (TC) ≥ 6.22 mmol/L or triglycerol (TG) ≥ 2.26 mmol/L or low density lipid protein cholesterol (LDL-C) ≥ 4.14 mmol/L or high density lipid protein cholesterol (HDL-C) ≤ 1.04 mmol/L. Insulin resistance was defined as homeostasis model assessment of insulin resistance (HOMA-IR) higher than 2.50. In accordance with the 1999 World Health Organization (WHO) diagnostic criteria [23], diabetes was defined as fasting plasma glucose (FPG) ≥ 7.0 mmol/L, and/or OGTT-2 h postload plasma glucose (PPG) ≥ 11.1 mmol/L, and/or previous diagnosis for diabetes. Fasting glucose higher than 6 mmol/L and less then 7 mmol/L, and/or post challenge plasma glucose (PPG) higher than 7.8 mmol/L and less than 11.1 mmol/L in participants, and/or without previous diagnosis for diabetes was considered as impaired glucose regulation (IGR). FPG < 6.1 mmol/L and OGTT-2h PPG < 7.8 mmol/L was defined as normal glucose regulation (NGR). Cases were defined as premenopausal and postmenopausal based on self-report of age at menopause and the date of first diagnosis of any kind of those female cancers obtained from self-report.

Statistical analysis

All statistical analyses were performed using SAS version 9.3 (SAS Institute Inc, Cary, NC, USA). Continuous variables were presented as Mean ± SD and categorical variables were presented as proportions. Comparisons of means and proportions were performed with the Student’s t tests and χ2 test, respectively.

To investigate the association between insulin resistance and each type of female cancers, the multivariate adjusted logistic regression analysis models were used to assess odds ratios (OR) and corresponding 95% confidence intervals (CI). The OR were adjusted for age, obesity(normal weight/overweight or obesity), dyslipidemia, hypertension, status of menstruation, history of cigarette smoking and alcohol drinking, family history of cancer, education and physical activity, age of menarche, number of child births and usage of contraceptive. In the adjustment, age, age at menarche and number of births were adjusted as continuous variables, overweight or obesity (yes/no), dyslipidemia (yes/no), hypertension (yes/no), status of menstruation (yes/no), history of cigarette smoking and alcohol drinking (yes/no), family history of cancer (yes/no), high education (yes/no), physical activity (low/moderate/high) were fitted as categorical variables. A p value of less than 0.05 was considered as statistically significant.

Results

General characteristics of the study population

In this study of 121,230 female, the prevalence of breast, ovarian, endometrial and cervical cancers was 0.55% (n=667), 0.09% (n=109), 0.34% (n=411) and 0.12% (n=146), respectively. The demographic and biochemical characteristics of this study population by strata of cancer types are shown in Table 1.

Table 1.

Baseline characteristics of the study population by status of breast, ovarian, endometrial and cervical cancer (2011-2012)

Breast cancer Ovarian cancer Endometrial cancer Cervical cancer
Yes No Yes No Yes No Yes No
N (%) 667 (0.55) 120563 (99.45) 109 (0.09) 121121 (99.91) 411 (0.34) 120819 (99.66) 146 (0.12) 121084 (99.88)
Age (years)a 57.67±8.73** 55.96±9.29 55.05±7.40 55.97±9.29 54.82±8.81** 55.97±9.29 53.38±7.10* 55.97±9.29
High school education or above N (%)b 294 (44.08)** 39398 (32.68) 52 (47.71)* 39640 (32.73) 164 (39.90)* 39528 (32.72) 53 (36.30)** 39639 (32.74)
Current smoker N (%)b 7 (1.05) 1615 (1.34) 2 (1.83) 1620 (1.34) 6 (1.46) 1616 (1.34) 6 (4.11)* 1616 (1.33)
Current drinker N (%)b 4 (0.6)* 2123 (1.76) 4 (3.67) 2123 (1.75) 8 (1.95) 2119 (1.75) 5 (3.42) 2122 (1.75)
MET-min/weekc 1386 (198-2772)* 1386 (0-2772) 1386 (0-2772) 1386 (0-2772) 1386 (0-2772)* 1386 (0-2772) 1386 (0-2772) 1386 (0-2772)
BMI (kg/m2)a 24.28±3.32 24.21±3.51 24.44±3.60 24.21±3.51 24.56±3.40 24.21±3.51 24.28±3.37* 24.21±3.51
Normal weight N (%)b 413 (61.92) 77002 (63.91) 64 (58.72) 77351 (63.9) 249 (60.58) 77166 (63.91) 89 (60.96) 77326 (63.90)
Overweight N (%)b 218 (32.68) 37238 (30.91) 38 (34.86) 37418 (30.9) 132 (32.12) 37324 (30.91) 51 (34.93) 37405 (30.91)
Obesity N (%)b 36 (5.4) 6250 (5.19) 7 (6.42) 6279 (5.19) 30 (7.3) 6256 (5.18) 6 (4.11) 6280 (5.19)
Waist circumference (cm)a 83.24±9.11* 82.04±9.56 81.98±8.51 82.05±9.56 83.12±9.09 82.04±9.56 82.32±9.87* 82.05±9.55
Central obesity N (%)b 436 (65.37)** 69226 (57.42) 65 (59.63) 69597 (57.46) 263 (63.99) 69399 (57.44) 87 (59.59) 69575 (57.46)
SBP (mmHg)a 130.17±19.87 129.92±20.76 124.86±19.90* 129.92±20.76 128.66±20.38 129.92±20.76 126.58±18.03 129.92±20.76
DBP (mmHg)a 76.90±10.31 76.73±10.93 75.62±10.61 76.73±10.92 77.20±11.82 76.73±10.92 77.35±11.03 76.73±10.92
Hypertension N (%)b 274 (41.08)* 44604 (37.00) 31 (28.44) 44847 (37.03) 155 (37.71) 44723 (37.02) 50 (34.25) 44828 (37.02)
TG (mmol/L)c 1.35 (1.00-1.97)** 1.24 (0.90-1.75) 1.30 (0.91-1.84) 1.24 (0.90-1.75) 1.25 (0.88-1.74) 1.24 (0.90-1.75) 1.25 (0.99-1.77) 1.24 (0.90-1.75)
TC (mmol/L)a 5.01±1.16 4.95±1.12 4.96±1.14 4.95±1.12 4.84±1.08* 4.95±1.12 5.13±1.09 4.95±1.12
LDL-C (mmol/L)a 2.89±0.89 2.85±0.86 2.90±0.82 2.85±0.86 2.79±0.83* 2.85±0.86 3.02±0.88 2.85±0.86
HDL-C (mmol/L)a 1.34±0.34* 1.38±0.35 1.34±0.32 1.38±0.35 1.34±0.33 1.38±0.35 1.38±0.34* 1.38±0.35
Dyslipidemia N (%)b 294 (44.08)** 41567 (34.48) 40 (36.7) 41821 (34.53) 146 (35.52) 41715 (34.53) 54 (36.99) 41807 (34.53)
FPG (mmol/L)a 5.41±0.53 5.40±0.54 5.37±0.53 5.40±0.54 5.41±0.56 5.40±0.54 5.41±0.52 5.40±0.54
PPG (mmol/L)a 7.25±1.67** 6.90±1.62 6.80±1.43 6.90±1.62 7.02±1.68 6.90±1.62 6.96±1.66 6.90±1.62
HbA1c (%)c 5.8 (5.5-6.0)** 5.7 (5.5-6.0) 5.8 (5.6-6.1) 5.7 (5.5-6.0) 5.4 (5.8-6.0) 5.5 (5.7-6.0) 5.7 (5.4-6.0) 5.7 (5.5-6.0)
Fasting insulin (IU/ml)c 7.60 (5.50-10.50)** 6.70 (4.90-9.20) 7.60 (5.40-10.80) 6.70 (4.90-9.20) 7.10 (5.20-9.80)* 6.70 (4.90-9.20) 7.30 (5.60-10.00)* 6.70 (4.90-9.20)
HOMA-IRc 1.81 (1.29-2.55)** 1.61 (1.15-2.26) 1.78 (1.25-2.59) 1.61 (1.15-2.26) 1.72 (1.22-2.40)* 1.61 (1.15-2.26) 1.82 (1.27-2.38)* 1.61 (1.15-2.26)
Insulin resistance N (%)b 173 (25.94)** 23135 (19.19) 31 (28.44)* 23277 (19.22) 93 (22.63) 23215 (19.21) 30 (20.55) 23278 (19.22)
Family history of cancer N (%)b 146 (21.89)** 13662 (11.33) 27 (24.77)** 13781 (11.38) 68 (16.55)* 13740 (11.37) 22 (15.07)** 13786 (11.39)
Family history of diabetes N (%)b 85 (12.74) 12884 (10.69) 19 (17.43)* 12950 (10.69) 51 (12.41) 12918 (10.69) 21 (14.38) 12948 (10.69)
Menopause N (%)b 413 (80.19)** 60830 (64.66) 68 (85.00)** 61175 (64.73) 85 (47.75)** 61158 (64.78) 95 (89.62)** 61148 (64.72)
Age at menarche (years)a 15.18±2.04* 15.45±2.05 15.24±2.45 15.45±2.05 14.95±2.03* 15.45±2.05 15.18±2.08 15.45±2.05
Usage of contraceptive N (%)b 33 (4.95)* 4096 (3.40) 7 (6.42) 4122 (3.40) 21 (5.11) 4108 (3.40) 6 (4.11) 4123 (3.41)
Number of birthsa 1.56±0.91* 1.82±1.11 1.54±0.81* 1.82±1.11 1.60±0.91* 1.82±1.11 1.56±0.87* 1.82±1.11
Open in a new tab
a

Data are represented as means±standard deviation.

b

Data are represented as number(percentage).

c

Data are represented as medians (interquartile range).

Abbreviation: MET, metabolic equivalent; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; TG, triglycerides; TC, total cholesterol; LDL-c, low density lipoprotein; HDL-c, high density lipoprotein; FPG, fasting plasma glucose; PPG, post-challenge plasma glucose; HOMA-IR, homeostasis model assessment of insulin resistance. Comparisons of means and proportions were performed with the Student’s tests and χ2 test.

*

P < 0.05;

**

P < 0.0001.

In comparison to individuals without breast cancer, those with breast cancer were older, more educated and had higher frequencies of central obesity, insulin resistance, family history of cancer, using contraceptive, being postmenopausal, they also had an earlier age at menarche, higher level of TG, PPG, fasting insulin, HbA1c, and HOMA-IR. On the other hand, breast cancer patients had lower level of alcohol consumption and physically activity, and fewer numbers of child birth, compared with those without breast cancer (all P < 0.05).

In comparison to participants without ovarian cancer, ovarian cancer patients were more educated, having a higher level of SBP and higher frequencies of insulin resistance, family history of cancer and diabetes and being postmenopausal, but fewer child births (all P < 0.05).

Patients with endometrial cancer were younger, having an earlier age at menarche, fewer child births, a higher level of education and a lower level of physical activity, as well as a higher frequency of family history of cancer and being postmenopausal than those without endometrial cancer. Participants with endometrial cancer also had a higher level of fasting insulin and HOMA-IR, but lower levels of TC and LDL-c (all p < 0.05).

Patients with cervical cancers were younger, less educated, and more likely to be a smoker, having fewer child births, a higher level of BMI, waist circumference, fasting insulin, HOMA-IR, a higher frequency of family history of cancer and being premenopausal, but having a lower level of HDL-C than those without cervical cancer.

Association between insulin resistance and female cancers

The prevalence of breast cancer, both premenopausal and postmenopausal, postmenopausal ovarian cancer and premenopausal endometrial cancer were higher in patients with insulin resistance compared with those who were insulin sensitive (premenopausal breast cancer, 0.45 vs 0.28%; postmenopausal breast cancer, 0.86 vs 0.63%; postmenopausal ovarian cancer, 0.17 vs 0.09%; premenopausal endometrial cancer, 0.43 vs 0.25%, respectively, all P < 0.05) (Figure 1). No significant difference in the prevalence of cervical cancers by strata of insulin sensitivity was observed (Figure 1).

Figure 1.

Figure 1

Open in a new tab

Prevalence of breast, ovarian, endometrial and cervical cancer according to menopause status and insulin sensitivity. Prevalence of both premenopausal and postmenopausal breast cancer, postmenopausal ovarian cancer and premenopausal endometrial cancer were significantly higher in insulin-resistant participants than in insulin-sensitive participants (premenopausal breast 0.45 vs 0.28%; postmenopausal breast cancer, 0.86 vs 0.63%; postmenopausal ovarian cancer, 0.17 vs 0.09%; premenopausal endometrial cancer, 0.43 vs 0.25%, respectively). No significant difference in the prevalence of cervical cancer by status of insulin sensitivity.

Mulitivariable logistic regression analysis demonstrated that breast cancer was positively and significantly correlated with insulin resistance (Table 2). In fully adjusted models, the risk of premenopausal and postmenopausal breast cancer were raised by 98% (95% CI=1.19-3.32) and 29% (95% CI=1.01-1.63), respectively, for insulin-resistant participants in comparison to insulin-sensitive participants (Table 2). Individuals with insulin resistance conferred a 117% (95% CI=1.22-3.89, P=0.022) higher risk of postmenopausal ovarian cancer compared with those who were insulin sensitive (Table 2).

Table 2.

Association between insulin resistance and female cancers risk by status of menopause

Breast cancer Ovarian cancer Endometrial cancer Cervical cancer
Insulin Insulin Insulin Insulin Insulin Insulin Insulin Insulin
sensitive resistant sensitive resistant sensitive resistant sensitive resistant
Total population Number of cancers, n/N 494/97922 173/23308 78/97922 31/23308 318/97792 93/23308 116/97922 30/23308
Prevalence of cancers, % 0.50 0.74 0.08 0.13 0.32 0.40 0.12 0.13
OR (95% CI) ref 1.39 (1.12-1.72) ref 1.86 (1.07-3.23) ref 1.47 (1.02-2.12) ref 1.31 (0.80-2.12)
Premenopausal population Number of cancers, n/N 78/28012 24/5335 11/28012 1/5335 70/28012 23/5335 8/28012 3/5335
Prevalence of cancers, % 0.28 0.45 0.04 0.02 0.25 0.43 0.03 0.06
OR (95% CI) ref 1.98 (1.19-3.32) ref 0.45(0.05-3.90) ref 1.51 (0.86-2.65) ref 2.30 (0.53-10.08)
Postmenopausal population Number of cancers, n/N 304/48623 109/12620 46/48623 22/12620 62/48623 23/12620 72/48623 23/12620
Prevalence of cancers, % 0.63 0.86 0.09 0.17 0.13 0.18 0.15 0.18
OR (95% CI) ref 1.29 (1.01-1.63) ref 2.17 (1.22-3.89) ref 1.46 (0.87-2.44) ref 1.23 (0.73-2.05)
Open in a new tab

Age, age at menarche and number of births were adjusted as continuous variables. Hypertension (yes/no), dyslipidemia (yes/no), status of menopause (yes/no), status of smoking and drinking (yes/no), family history of cancer (yes/no), higher education (low/moderate/high), vigorous activity (yes/no) and usage of contraceptive (yes/no) were adjusted as category variables.

However, the association between insulin resistance and endometrial cancer was only observed in total popualtion, with 47% increased risk of endomatrial cancer in insulin resistant participants compared to insulin-sensitive participants (95% CI=1.02-2.12). No significant relationships were found between insulin resistance and cervical cancer.

Subgroup analysis of association between breast cancer and insulin resistance

To assess the potential interactions of insulin resistance with known risk factors for breast cancer, we conducted subgroup analysis by the strata of age, BMI, education level and status of glucose metabolism.

The association between insulin resistance and prevalent breast cancer remained significant in women with younger age, overweight or obesity, higher education level and impaired glucose regulation (IGR). The corresponding Ors (95% CI) is 1.42 (1.09-1.86), 1.40 (1.03-1.88), 1.49 (1.08-2.05) and 1.50 (1.10-2.03), respectively (all P < 0.05) (Figure 2). On the other hand, this relationship was absent or non-statistically significant in older, normal-weight, less educated and NGR women. There were no interaction between the covariates and insulin resistance on breast cancer.

Figure 2.

Figure 2

Open in a new tab

Odds of breast cancer according to status of IR stratified by potential risk modifiers. Age, age at menarche and number of births were adjusted as continuous variables. Hypertension (yes/no), dyslipidemia (yes/no), status of menopause (yes/no), status of smoking and drinking (yes/no), family history of cancer (yes/no), higher education (low/moderate/high), vigorous activity (yes/no) and usage of contraceptive (yes/no) were adjusted as category variables. (Except for each stratified factor).

Discussion

This research investigated the association between insulin resistance and female cancers in a large population of non-diabetic women in China. Our study demonstrated that insulin resistance was associated with increased risk of prevalent breast cancer, ovarian cancer and endomentrial cancer, but not with the risk of prevalent cervical cancer.

Hyperinsulinemia has been considered as a possible risk factor for breast cancer with supporting laboratory evidence [7]. However, epidemiological studies on the association of insulin resistance and risk of breast cancers, especially in different menopausal status, were inconsistent [7,14-16,24]. In our study, we observed a stronger association of insulin resistance with prevalent breast cancer in non-diabetic women, both in premenopausal 98% (95% CI=1.19-3.32) and postmenopausal women (OR, 1.29, 95% CI=1.01-1.63). Sieri et al. reported that [25] only in women with breast cancer diagnosed after 55 years, most of whom were postmenopausal, the highest HOMA-IR quartile confered higher breast cancer risk (OR, 1.56, 95% CI, 1.01-2.41), however, in breast cancer diagnosed before 55 years, no significant association was observed. Lawlor et al. demonstrated that risk of breast cancer for one unit increase in HOMA-IR was 1.31 (95% CI, 0.99-1.74), only borderline significant. These inconsistent findings may be due to variations in the different population and insufficient sample size. Our findings regarding the effect of menopausal status were in agreement with results of previous studies. A study conducted by Del Giudice ME et al. suggested that the risk of breast cancer increased with the level of insulin in non-diabetic premenopausal women (OR, 2.83, 95% CI, 1.22-6.58) [26]. Marc J. Gunter [27] et al. revealed a positive association between fasting insulin level and risk of breast cancer (OR, 1.46, 95% CI, 1.00-2.13) in non-diabetic postmenopausal women. However, these research only found association between fasting insulin level and breast cancer, we used HOMA-IR as an indicator of insulin resistance, which reflects euglycemic clamp insulin resistance more accurately than fasting insulin levels alone [28]. Moreover, in stratification analysis, significant association was found between insulin resistance and breast cancer in overweight or obese, high educated or IGR population, while in their counterparts, no significant association was observed. As obesity, sedentary lifestyle and IGR are known risk factors for insulin resistance, these factors might also contribute to development of breast cancer.

The potential pathophysiological mechanism linking insulin resistance and breast cancer risk is not fully established. Insulin is a pleiotropic hormone, promoting cell proliferation and tumorigenesis in animal models [29]. Insulin could also promote breast cancer development by increased angiogenesis, bioactivity of estrogens and testosterone as well as decreased adiponectin [30].

Previous studies focusing on the relationship between insulin resistance and ovarian cancer provide limited information. In a case control study conducted by Otokozawa S et al. [17], an increased risk of ovarian cancer was obeserved in high tertile of serum insulin level compared with the low tertile (P trend < 0.001). While, a study with small sample size demonstrated that HOMA-IR was not a valid predictor for risk of ovarian tumor [18]. Moreover, several studies revealed insulin could stimulate ovarian steroid production, probably via insulin receptors found in ovarian stroma, thecal cells and granulosa cells [31,32]. It was proposed that insulin cooperating with follicle stimulating hormone (FSH) lead to higher levels of estrogen than did either insulin or FSH alone [33].

Previous prospective research findings revealed increased risk of endometrial cancer (HR, 2.33, 95% CI, 1.13-4.82) with elevated circulating insulin levels, independent of estrogen level [34]. It was reported that the expression of total insulin receptor and insulin receptor α increased in endometrial carcinomas compared to normal endometria, and overexpression of insulin receptor α enhances the growth of endometrial cancer cells in vitro [35]. These results suggested that activation of insulin signaling is directly involved in the development of endometrial cancer in vivo.

Very few studies [36] have investigated the association between insulin resistances with cervical cancer. Human papillomavirus (HPV) infection is the most important risk factor for cervical cancer and other risk factors included starting sex at a young age and having many sexual partners. The failure in demonstrating an association of insulin resistance and cervical cancer may suggest that insulin plays a less important role in cervical cancer [37].

There are several strengths in our study, including a large representative sample of the Chinese women, diagnosis of diabetes based on both fasting and postprandial glucose level. Our study has several potential limitations that merit comment. First, a major limitation of this study is that it is cross-sectional and may confuse cause and effect, as cancer-related weight loss might improve insulin sensitivity and beta-cell dysfunction and insulin resistance may appear in cancer patients after systemic treatment [38]. Therefore, prospective studies are needed to clarify their precise interrelationship. Secondly, the study may subject to a selection bias due to the self-reported diagnosis of female cancer. We can’t exclude the possibility that certain patients with female cancers in serious conditions did not take part in the survey. Thirdly, although our analyses were adjusted for an extensive set of confounding factors, residual confounding due to the measurement error in the assessment of confounding factors, unmeasured factors such as dietary factors and other chronic diseases cannot be excluded. Last but not the least, possitive associations were found between obesity and endometrial, ovarian and postmenopausal breast cancer, even cervical cancer [24,39-41]. In our study, we only investigated the influence of BMI on the association between IR and breast cancer but not other female cancers, since the average prevalence of the other female cancers were lower than breast cancers, the statistical power is insufficient for subgroup analysis. Recently, study results suggested that metabolic health may be more biologically relevant and more useful for female cancer risk stratification than adiposity per se [42].

In conclusion, our research results added to the existing epidemiological evidence that insulin resistance are associated with increased prevalent breast, ovarian and endometrial cancer even in non-diabetic females. Further prospective study is required to confirm these observations. These findings highlight the need for increased attention and efforts in preventing and screening some female cancers, even in non-diabetic females with insulin resistance, to reduce the burden of these cancers.

Acknowledgements

The authors are highly appreciative of all the field workers and participants who contributed to this research and the REACTION Study Group. This work is supported by the grants 2013BAI09B13 from the National Clinical Research Center for Metabolic Diseases, 201502007 from the Ministry of Health, 2015BAI12B14 and 2016YFC0901200 from the Ministry of Science and Technology, 2015CB553601 from the National Basic Research Program of China (973 Program), and 81321001, 81390350, 81130016, 81561128019 from the National Natural Science Foundation of China.

Disclosure of conflict of interest

None.

References

  • 1.Friberg E, Orsini N, Mantzoros CS, Wolk A. Diabetes mellitus and risk of endometrial cancer: a meta-analysis. Diabetologia. 2007;50:1365–1374. doi: 10.1007/s00125-007-0681-5. [DOI] [PubMed] [Google Scholar]
  • 2.Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA, Pollak M, Regensteiner JG, Yee D. Diabetes and cancer: a consensus report. Diabetes Care. 2010;33:1674–1685. doi: 10.2337/dc10-0666. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Xu HL, Fang H, Xu WH, Qin GY, Yan YJ, Yao BD, Zhao NQ, Liu YN, Zhang F, Li WX, Wang N, Zhou J, Zhang JL, Zhao LY, Li LQ, Zhao YP. Cancer incidence in patients with type 2 diabetes mellitus: a population-based cohort study in Shanghai. BMC Cancer. 2015;15:852. doi: 10.1186/s12885-015-1887-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA, Pollak M, Regensteiner JG, Yee D. Diabetes and cancer: a consensus report. CA Cancer J Clin. 2010;60:207–221. doi: 10.3322/caac.20078. [DOI] [PubMed] [Google Scholar]
  • 5.Richardson LC, Pollack LA. Therapy insight: Influence of type 2 diabetes on the development, treatment and outcomes of cancer. Nat Clin Pract Oncol. 2005;2:48–53. doi: 10.1038/ncponc0062. [DOI] [PubMed] [Google Scholar]
  • 6.Li C, Balluz LS, Ford ES, Okoro CA, Tsai J, Zhao G. Association between diagnosed diabetes and self-reported cancer among U. S. adults: findings from the 2009 Behavioral Risk Factor Surveillance System. Diabetes Care. 2011;34:1365–1368. doi: 10.2337/dc11-0020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Khandwala HM, McCutcheon IE, Flyvbjerg A, Friend KE. The effects of insulin-like growth factors on tumorigenesis and neoplastic growth. Endocr Rev. 2000;21:215–244. doi: 10.1210/edrv.21.3.0399. [DOI] [PubMed] [Google Scholar]
  • 8.Gapstur SM, Gann PH, Lowe W, Liu K, Colangelo L, Dyer A. Abnormal glucose metabolism and pancreatic cancer mortality. JAMA. 2000;283:2552–2558. doi: 10.1001/jama.283.19.2552. [DOI] [PubMed] [Google Scholar]
  • 9.Tamimi RM, Byrne C, Colditz GA, Hankinson SE. Endogenous hormone levels, mammographic density, and subsequent risk of breast cancer in postmenopausal women. J Natl Cancer Inst. 2007;99:1178–1187. doi: 10.1093/jnci/djm062. [DOI] [PubMed] [Google Scholar]
  • 10.Weiderpass E, Gridley G, Persson I, Nyren O, Ekbom A, Adami HO. Risk of endometrial and breast cancer in patients with diabetes mellitus. Int J Cancer. 1997;71:360–363. doi: 10.1002/(sici)1097-0215(19970502)71:3<360::aid-ijc9>3.0.co;2-w. [DOI] [PubMed] [Google Scholar]
  • 11.Hjalgrim H, Frisch M, Ekbom A, Kyvik KO, Melbye M, Green A. Cancer and diabetes--a follow-up study of two population-based cohorts of diabetic patients. J Intern Med. 1997;241:471–475. doi: 10.1111/j.1365-2796.1997.tb00004.x. [DOI] [PubMed] [Google Scholar]
  • 12.Organization WH. International Agency for Research on Cancer. World Cancer Report 2014. 2014 ISBN 978-92-832-0432-9. [Google Scholar]
  • 13.Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, Abraham J, Adair T, Aggarwal R, Ahn SY, Alvarado M, Anderson HR, Anderson LM, Andrews KG, Atkinson C, Baddour LM, Barker-Collo S, Bartels DH, Bell ML, Benjamin EJ, Bennett D, Bhalla K, Bikbov B, Bin Abdulhak A, Birbeck G, Blyth F, Bolliger I, Boufous S, Bucello C, Burch M, Burney P, Carapetis J, Chen H, Chou D, Chugh SS, Coffeng LE, Colan SD, Colquhoun S, Colson KE, Condon J, Connor MD, Cooper LT, Corriere M, Cortinovis M, de Vaccaro KC, Couser W, Cowie BC, Criqui MH, Cross M, Dabhadkar KC, Dahodwala N, De Leo D, Degenhardt L, Delossantos A, Denenberg J, Des Jarlais DC, Dharmaratne SD, Dorsey ER, Driscoll T, Duber H, Ebel B, Erwin PJ, Espindola P, Ezzati M, Feigin V, Flaxman AD, Forouzanfar MH, Fowkes FG, Franklin R, Fransen M, Freeman MK, Gabriel SE, Gakidou E, Gaspari F, Gillum RF, Gonzalez-Medina D, Halasa YA, Haring D, Harrison JE, Havmoeller R, Hay RJ, Hoen B, Hotez PJ, Hoy D, Jacobsen KH, James SL, Jasrasaria R, Jayaraman S, Johns N, Karthikeyan G, Kassebaum N, Keren A, Khoo JP, Knowlton LM, Kobusingye O, Koranteng A, Krishnamurthi R, Lipnick M, Lipshultz SE, Ohno SL, Mabweijano J, MacIntyre MF, Mallinger L, March L, Marks GB, Marks R, Matsumori A, Matzopoulos R, Mayosi BM, McAnulty JH, McDermott MM, McGrath J, Mensah GA, Merriman TR, Michaud C, Miller M, Miller TR, Mock C, Mocumbi AO, Mokdad AA, Moran A, Mulholland K, Nair MN, Naldi L, Narayan KM, Nasseri K, Norman P, O'Donnell M, Omer SB, Ortblad K, Osborne R, Ozgediz D, Pahari B, Pandian JD, Rivero AP, Padilla RP, Perez-Ruiz F, Perico N, Phillips D, Pierce K, Pope CA 3rd, Porrini E, Pourmalek F, Raju M, Ranganathan D, Rehm JT, Rein DB, Remuzzi G, Rivara FP, Roberts T, De Leon FR, Rosenfeld LC, Rushton L, Sacco RL, Salomon JA, Sampson U, Sanman E, Schwebel DC, Segui-Gomez M, Shepard DS, Singh D, Singleton J, Sliwa K, Smith E, Steer A, Taylor JA, Thomas B, Tleyjeh IM, Towbin JA, Truelsen T, Undurraga EA, Venketasubramanian N, Vijayakumar L, Vos T, Wagner GR, Wang M, Wang W, Watt K, Weinstock MA, Weintraub R, Wilkinson JD, Woolf AD, Wulf S, Yeh PH, Yip P, Zabetian A, Zheng ZJ, Lopez AD, Murray CJ, AlMazroa MA, Memish ZA. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380:2095–2128. doi: 10.1016/S0140-6736(12)61728-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Garmendia ML, Pereira A, Alvarado ME, Atalah E. Relation between insulin resistance and breast cancer among Chilean women. Ann Epidemiol. 2007;17:403–409. doi: 10.1016/j.annepidem.2007.01.037. [DOI] [PubMed] [Google Scholar]
  • 15.Eliassen AH, Tworoger SS, Mantzoros CS, Pollak MN, Hankinson SE. Circulating insulin and c-peptide levels and risk of breast cancer among predominately premenopausal women. Cancer Epidemiol Biomarkers Prev. 2007;16:161–164. doi: 10.1158/1055-9965.EPI-06-0693. [DOI] [PubMed] [Google Scholar]
  • 16.Michels KB, Solomon CG, Hu FB, Rosner BA, Hankinson SE, Colditz GA, Manson JE. Type 2 diabetes and subsequent incidence of breast cancer in the Nurses’ Health Study. Diabetes Care. 2003;26:1752–1758. doi: 10.2337/diacare.26.6.1752. [DOI] [PubMed] [Google Scholar]
  • 17.Otokozawa S, Tanaka R, Akasaka H, Ito E, Asakura S, Ohnishi H, Saito S, Miura T, Saito T, Mori M. Associations of Serum Isoflavone, Adiponectin and Insulin Levels with Risk for Epithelial Ovarian Cancer: Results of a Case-control Study. Asian Pac J Cancer Prev. 2015;16:4987–4991. doi: 10.7314/apjcp.2015.16.12.4987. [DOI] [PubMed] [Google Scholar]
  • 18.Serin IS, Tanriverdi F, Yilmaz MO, Ozcelik B, Unluhizarci K. Serum insulin-like growth factor (IGF)-I, IGF binding protein (IGFBP)-3, leptin concentrations and insulin resistance in benign and malignant epithelial ovarian tumors in postmenopausal women. Gynecol Endocrinol. 2008;24:117–121. doi: 10.1080/09513590801895559. [DOI] [PubMed] [Google Scholar]
  • 19.Ning G. Risk Evaluation of cAncers in Chinese diabeTic Individuals: a lONgitudinal (REACTION) study. J Diabetes. 2012;4:172–173. doi: 10.1111/j.1753-0407.2012.00182.x. [DOI] [PubMed] [Google Scholar]
  • 20.Bi Y, Lu J, Wang W, Mu Y, Zhao J, Liu C, Chen L, Shi L, Li Q, Wan Q, Wu S, Yang T, Yan L, Liu Y, Wang G, Luo Z, Tang X, Chen G, Huo Y, Gao Z, Su Q, Ye Z, Wang Y, Qin G, Deng H, Yu X, Shen F, Zhao L, Zhang J, Sun J, Dai M, Xu M, Xu Y, Chen Y, Lai S, Bloomgarden ZT, Li D, Ning G. Cohort profile: risk evaluation of cancers in Chinese diabetic individuals: a longitudinal (REACTION) study. J Diabetes. 2014;6:147–157. doi: 10.1111/1753-0407.12108. [DOI] [PubMed] [Google Scholar]
  • 21.Lu J, Bi Y, Wang T, Wang W, Mu Y, Zhao J, Liu C, Chen L, Shi L, Li Q, Wan Q, Wu S, Qin G, Yang T, Yan L, Liu Y, Wang G, Luo Z, Tang X, Chen G, Huo Y, Gao Z, Su Q, Ye Z, Wang Y, Deng H, Yu X, Shen F, Chen L, Zhao L, Dai M, Xu M, Xu Y, Chen Y, Lai S, Ning G. The relationship between insulin-sensitive obesity and cardiovascular diseases in a Chinese population. Int J Cardiol. 2014;172:388–394. doi: 10.1016/j.ijcard.2014.01.073. [DOI] [PubMed] [Google Scholar]
  • 22.Ning G, Bloomgarden Z. Diabetes and cancer: Findings from the REACTION study REACTION. J Diabetes. 2015;7:143–144. doi: 10.1111/1753-0407.12240. [DOI] [PubMed] [Google Scholar]
  • 23.Organization WH. Definition, Diagnosis and Classification of Diabetes Mellitus and Its Complications. Report of WHO Consultation WHO, Geneva, 1999. 1999 [Google Scholar]
  • 24.Goodwin PJ. Obesity, insulin resistance and breast cancer outcomes. Breast (Edinburgh, Scotland) 2015;24(Suppl 2):S56–59. doi: 10.1016/j.breast.2015.07.014. [DOI] [PubMed] [Google Scholar]
  • 25.Sieri S, Muti P, Claudia A, Berrino F, Pala V, Grioni S, Abagnato CA, Blandino G, Contiero P, Schunemann HJ, Krogh V. Prospective study on the role of glucose metabolism in breast cancer occurrence. Int J Cancer. 2012;130:921–929. doi: 10.1002/ijc.26071. [DOI] [PubMed] [Google Scholar]
  • 26.Del Giudice ME, Fantus IG, Ezzat S, McKeown-Eyssen G, Page D, Goodwin PJ. Insulin and related factors in premenopausal breast cancer risk. Breast Cancer Res Treat. 1998;47:111–120. doi: 10.1023/a:1005831013718. [DOI] [PubMed] [Google Scholar]
  • 27.Gunter MJ, Hoover DR, Yu H, Wassertheil-Smoller S, Rohan TE, Manson JE, Li J, Ho GY, Xue X, Anderson GL, Kaplan RC, Harris TG, Howard BV, Wylie-Rosett J, Burk RD, Strickler HD. Insulin, insulin-like growth factor-I, and risk of breast cancer in postmenopausal women. J Natl Cancer Inst. 2009;101:48–60. doi: 10.1093/jnci/djn415. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Ikeda Y, Niimi M, Kan S, Shatari T, Takami H, Kodaira S. Clinical significance of tissue blood flow during esophagectomy by laser Doppler flowmetry. J Thorac Cardiovasc Surg. 2001;122:1101–1106. doi: 10.1067/mtc.2001.117835. [DOI] [PubMed] [Google Scholar]
  • 29.Tran TT, Medline A, Bruce WR. Insulin promotion of colon tumors in rats. Cancer Epidemiol Biomarkers Prev. 1996;5:1013–1015. [PubMed] [Google Scholar]
  • 30.Rose DP, Haffner SM, Baillargeon J. Adiposity, the metabolic syndrome, and breast cancer in African-American and white American women. Endocr Rev. 2007;28:763–777. doi: 10.1210/er.2006-0019. [DOI] [PubMed] [Google Scholar]
  • 31.Poretsky L, Grigorescu F, Seibel M, Moses AC, Flier JS. Distribution and characterization of insulin and insulin-like growth factor I receptors in normal human ovary. J Clin Endocrinol Metab. 1985;61:728–734. doi: 10.1210/jcem-61-4-728. [DOI] [PubMed] [Google Scholar]
  • 32.Barbieri RL, Makris A, Randall RW, Daniels G, Kistner RW, Ryan KJ. Insulin stimulates androgen accumulation in incubations of ovarian stroma obtained from women with hyperandrogenism. J Clin Endocrinol Metab. 1986;62:904–910. doi: 10.1210/jcem-62-5-904. [DOI] [PubMed] [Google Scholar]
  • 33.Garzo VG, Dorrington JH. Aromatase activity in human granulosa cells during follicular development and the modulation by follicle-stimulating hormone and insulin. Am J Obstet Gynecol. 1984;148:657–662. doi: 10.1016/0002-9378(84)90769-5. [DOI] [PubMed] [Google Scholar]
  • 34.Gunter MJ, Hoover DR, Yu H, Wassertheil-Smoller S, Manson JE, Li J, Harris TG, Rohan TE, Xue X, Ho GY, Einstein MH, Kaplan RC, Burk RD, Wylie-Rosett J, Pollak MN, Anderson G, Howard BV, Strickler HD. A prospective evaluation of insulin and insulin-like growth factor-I as risk factors for endometrial cancer. Cancer Epidemiol Biomarkers Prev. 2008;17:921–929. doi: 10.1158/1055-9965.EPI-07-2686. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Wang CF, Zhang G, Zhao LJ, Qi WJ, Li XP, Wang JL, Wei LH. Overexpression of the insulin receptor isoform A promotes endometrial carcinoma cell growth. PLoS One. 2013;8:e69001. doi: 10.1371/journal.pone.0069001. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
  • 36.Nagamani M, Stuart CA, Van Dinh T. Steroid biosynthesis in the Sertoli-Leydig cell tumor: effects of insulin and luteinizing hormone. Am J Obstet Gynecol. 1989;161:1738–1743. doi: 10.1016/0002-9378(89)90960-5. [DOI] [PubMed] [Google Scholar]
  • 37.Jee SH, Ohrr H, Sull JW, Yun JE, Ji M, Samet JM. Fasting serum glucose level and cancer risk in Korean men and women. JAMA. 2005;293:194–202. doi: 10.1001/jama.293.2.194. [DOI] [PubMed] [Google Scholar]
  • 38.Lu LJ, Gan L, Hu JB, Ran L, Cheng QF, Wang RJ, Jin LB, Ren GS, Li HY, Wu KN, Kong LQ. On the status of beta-cell dysfunction and insulin resistance of breast cancer patient without history of diabetes after systemic treatment. Med Oncol. 2014;31:956. doi: 10.1007/s12032-014-0956-x. [DOI] [PubMed] [Google Scholar]
  • 39.Berger NA. Obesity and cancer pathogenesis. Ann N Y Acad Sci. 2014;1311:57–76. doi: 10.1111/nyas.12416. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Bhaskaran K, Douglas I, Forbes H, dos-Santos-Silva I, Leon DA, Smeeth L. Body-mass index and risk of 22 specific cancers: a population-based cohort study of 5.24 million UK adults. Lancet. 2014;384:755–765. doi: 10.1016/S0140-6736(14)60892-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Benedetto C, Salvagno F, Canuto EM, Gennarelli G. Obesity and female malignancies. Best Pract Res Clin Obstet Gynaecol. 2015;29:528–540. doi: 10.1016/j.bpobgyn.2015.01.003. [DOI] [PubMed] [Google Scholar]
  • 42.Gunter MJ, Xie X, Xue X, Kabat GC, Rohan TE, Wassertheil-Smoller S, Ho GY, Wylie-Rosett J, Greco T, Yu H, Beasley J, Strickler HD. Breast cancer risk in metabolically healthy but overweight postmenopausal women. Cancer Res. 2015;75:270–274. doi: 10.1158/0008-5472.CAN-14-2317. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from American Journal of Cancer Research are provided here courtesy of e-Century Publishing Corporation

RESOURCES