Breast cancer is associated to impaired glucose/insulin homeostasis in premenopausal obese/overweight patients

Abstract

The association between breast cancer (BCa) presence and altered glucose/insulin metabolism is controversial likely due to an inaccurate insulin resistance (IR) assessment and inappropriate stratification of patients by body-mass index (BMI) and menopausal state. 148 women with suspect of sporadic BCa were stratified by BMI and menopause. Fasting levels of glucose, insulin, glycohemoglobin and selected IR-related and tumor-derived markers were measured. Glucose/insulin levels during OGTT were used to calculate insulin resistance/sensitivity indexes. Analysis of 77 BCa-bearing patients and 71 controls showed an association between BCa and IR as demonstrated by impaired glucose/insulin homeostasis (increased fasting- and OGTT-induced glucose levels) and deteriorated IR indexes, which was especially patent in premenopausal women. The association between BCa presence and IR was markedly influenced by BMI, being obese BCa patients significantly more insulin resistant than controls. BCa presence was associated to elevated levels of IR (glucose, triglycerides) and tumor-derived (VEGF) markers, especially in overweight/obese patients. BCa presence is associated to IR in overweight/obese premenopausal but not in premenopausal normal weight or postmenopausal women. Our data support a bidirectional relationship between dysregulated/imbalanced glucose/insulin metabolism and BCa, as tumor- and IR-markers are correlated with the impairment of glucose/insulin metabolism in overweight/obese premenopausal BCa patients.

Keywords: OGTT; breast cancer; glucose; insulin; obesity.

Figure 1. Glucose/insulin metabolism parameters in control and breast cancer patients

(A) Fasting glucose, insulin and glycohemoglobin levels were analyzed. Asterisks (*p < 0.05) indicate differences by Mann-Whitney U/Student t-test. (B) Glucose and insulin levels during the OGTT. Asterisks (*p < 0.05; **p < 0.01; ***p < 0.001) indicate significant differences between groups by Fisher's LSD test. (C) Simple Matsuda index, HOMA-IR and Hepatic insulin resistance index. Asterisks (*p < 0.05) indicate differences by Student t-test. Values represent means ± SEM of control (n = 71) and breast cancer (n = 77) groups. C means control subjects and BC means breast cancer patients.

Figure 2. Impact of menopausal status on glucose/insulin metabolism parameters in control and breast cancer patients

(A) Fasting glucose, insulin and glycohemoglobin levels were analyzed. Asterisks (*p < 0.05) indicate differences by Student t-test. (B) Glucose and insulin levels during the OGTT. Asterisks (**p < 0.01; ***p < 0.001) indicate significant differences by Fisher's LSD test. (C) Simple Matsuda index, HOMA-IR and Hepatic insulin resistance index. Values represent means ± SEM. C means control subjects and BC means breast cancer patients.

Figure 3. Glucose/insulin metabolism parameters in normal weight (BMI < 25) and overweight/obese (BMI ≥ 25) control and breast cancer patients

(A) Fasting glucose, insulin and glycohemoglobin levels. (B) Glucose and insulin levels during the OGTT. (C) Simple Matsuda index, HOMA-IR and Hepatic insulin resistance index. Values represent mean ± SEM of each experimental group (normal weight n = 60; overweight n = 88). Asterisks (*p < 0.05; **p < 0.01; ***p < 0.001) indicate significant differences by Bonferroni/Mann-Whitney U/Fisher's LSD post-hoc tests. C means control subjects and BC means breast cancer patients.

Figure 4. Glucose/insulin metabolism parameters in normal weight (BMI < 25), overweight (BMI ≥ 25 < 30) and obese (BMI ≥ 30) control and breast cancer patients

(A) Fasting glucose, insulin and glycohemoglobin levels. (B) Glucose and insulin levels during the OGTT. (C) Simple Matsuda index, HOMA-IR and Hepatic insulin resistance index. Values represent mean ± SEM of each experimental group (normal weight n = 60; overweight n = 54; obese n = 34). Asterisks (*p < 0.05; **p < 0.01; ***p < 0.001) indicate significant differences by Bonferroni/Mann-Whitney U/Fisher's LSD post-hoc tests. C means control subjects and BC means breast cancer patients.

Figure 5. Circulating levels of relevant hormones, factors and molecules in control and breast cancer patients

(A) Obesity-associated markers (TG, NEFA, adiponectin, leptin), (B) tumor-derived factors (VEGF, RANK-L, TNF-α, HIF-1α) and (C) other relevant hormones [PRL, IGF-I, estrogens (E2), cortisol, GH] were determined in plasma of cohort individuals by specific ELISAs. Values represent mean ± SEM of each experimental group (control n = 71; breast cancer n = 77). Asterisks (*p < 0.05) indicate significant differences between groups by Student t-test/Mann-Whitney U test. C means control subjects and BC means breast cancer patients.