Postmenopausal women with type 2 diabetes have at least a 25% higher risk of breast cancer than those without diabetes. Regular exercise reduces such risk whereas poor blood sugar control increases it. There is also some evidence that the type of diabetes treatment influences breast cancer risk and outcomes. For example, numerous studies have documented the benefits of the diabetes drug metformin in reducing risk and recurrence. On the other hand, use of insulin, especially long-acting formulations such as Lantus, has been linked to higher risk of recurrence, although these findings are controversial. Now a new study has described an unfavorable signaling profile associated with insulin use in those with type 2 diabetes and linked it to poorer prognosis compared to breast cancer patients with type 2 diabetes who use other diabetes treatments.

High circulating insulin promotes breast cancer

High levels of circulating insulin (hyperinsulinemia) appear to promote breast cancer by acting as a growth promoter. Production and metabolism of insulin-like growth factors are also disturbed in diabetics, and may contribute to increased cancer risk and progression. Hyperinsulinemia, insulin resistance, and diabetes have all been found to be associated with poor breast cancer outcomes. High levels of fasting glucose at diagnosis have also been found to be associated with increased risk of recurrence compared to normal levels. Therefore, women with type 2 diabetes can potentially reduce their risk of recurrence by taking steps to reduce insulin resistance and circulating insulin, as well as keeping their blood sugar under tight control. This can be accomplished in part through appropriate diet, regular exercise, and losing weight if overweight. Given the apparent role of circulating insulin in promoting breast cancer, it is plausible that using insulin as a diabetes treatment could increase the risk of breast cancer and its recurrence.

Metformin counteracts insulin resistance

Numerous studies have reported anti-cancer effects of metformin in all breast cancer subtypes in the laboratory, including in chemotherapy-resistant cells. Population studies also indicate anti-cancer effects of metformin. Metformin influences two important, related pathways that are involved in cancer growth: the insulin/insulin-like growth factor-1 signaling pathway and the adenosine mono-phosphate-activated protein kinase (AMPK) pathway. Metformin reduces circulating insulin levels, increases insulin sensitivity, and reduces insulin resistance-associated excess levels of circulating insulin in the blood. At the cellular level, metformin activates AMPK.

Latest research links insulin use to poorer breast cancer outcomes

The study referenced at the beginning of this news story was designed to investigate the association between treatment with insulin, adipokine levels at diagnosis, and long-term breast cancer outcomes in those with type 2 diabetes (diabetes). Adipokines such as leptin are signaling proteins (cytokines) secreted by fat (adipose) tissue. Adipose tissue dysfunction can produce changes in cytokine signaling that are common to both diabetes and breast cancer. This altered adipokine signaling has been linked directly to changes in diet and body mass index (BMI)—it makes sense that it could also be influenced by type of diabetes treatment.

To conduct the study, the authors initially reviewed data concerning 2,194 women with breast cancer diagnosed between 2003 and 2009. Each patient with diabetes at baseline (the cases) was matched with two non-diabetic patients (the controls) based on age, menopausal status, BMI, ethnicity, and tumor stage. Patients previously treated for breast cancer were excluded. The study included all remaining 97 diabetic cases (as well as 194 controls) with available baseline plasma and tumor biopsies. Plasma adipokine levels (adiponectin, leptin, TNF-α, (CRP), IL-1β, IL-1Ra, IL-6, and C-peptide) were determined and cancer outcomes were assessed. Adjustments were made in the analysis for age, BMI, tumor stage, estrogen receptor (ER) status and other health problems (cumulative comorbidity).

Breast cancer patients treated with insulin were found to have lower C-peptide (a marker of insulin production in the body), and higher IL-6, TNF-α and CRP (all markers of inflammation). Of these, elevated CRP and TNF-α were associated with poorer breast cancer outcomes. Insulin users tended to have higher leptin levels, but the differences were not significant. While non-insulin users were observed to have lower adiponectin levels than non-diabetic controls, insulin use appeared to result in restored adiponectin production. C-peptide levels were lower among insulin users than non-users, approaching levels similar to that of the non-diabetc controls. C-peptide levels lower than 0.75 ng/ml were found to be strongly associated with poorer survival in both cases and controls. The authors conclude that insulin use is associated with elevated leptin, CRP, TNF-α, and lower C-peptide levels and is also linked to poor breast cancer outcomes. More research is needed to verify these findings, according to the authors, since this is among the first research to link pharmacotherapy use, measures of adipose tissue dysfunction, and breast cancer outcomes.

Please see our article on type 2 diabetes for more information.