Risk of Cancer in Diabetes: The Effect of Metformin

Abstract

Cancer is the second cause of death. Association of diabetes as a growing and costly disease with cancer is a major health concern. Meanwhile, preexisting diabetes is associated with an increased risk of all-cause and cancer-specific mortalities. Presence of diabetes related comorbidities, poorer response to cancer treatment, and excess mortality related to diabetes are among the most important explanations. Although diabetes appear to be a risk factor for cancer and is associated with the mortality risk in cancer patients, several factors such as diabetes duration, multiple drug therapy, and the presence of diabetes comorbidities make the assessment of the effect of diabetes treatment on cancer risk and mortality difficult. Metformin is the drug of choice for the treatment of type 2 diabetes. The available evidence from basic science, clinical, and population-based research supports the anticancer effect of metformin. However, randomized controlled clinical trials do not provide enough evidence for a strong protective effect of metformin on cancer incidence or mortality. One of the most important limitations of these trials is the short duration of the followup. Further long-term randomized controlled clinical trials specifically designed to determine metformin effect on cancer risk are needed to provide the best answer to this challenge.

Clinical benefits of metformin in gynecologic oncology

“…Metformin reduces adenosine triphosphate (ATP) production, resulting in an increased AMP:ATP ratio, which leads to activation of the liver kinase B1 (LKB1)-AMPK signaling pathway (2,(21)(22)(23) (2,(24)(25)(26). Additional studies have suggested that metformin may inhibit carcinogenesis and/or cancer cell growth via diverse pathways (15,(27)(28)(29). Phosphorylation of the AMPK catalytic subunit occurs in the presence of LKB1, and is facilitated by AMP.…”

“…1 outlines the potential anticancerogenic effects of metformin. Metformin activates AMPK in the liver and skeletal muscles, thereby reducing gluconeogenesis in the liver and enhancing glucose uptake by the peripheral tissues, resulting in lower blood glucose and insulin levels (2,15,16). Insulin has been found to exert mitogenic activity and thus may, theoretically, have a promotional effect on the growth of tumor cells.…”

“…Metformin, a biguanide frequently used in the treatment of type 2 diabetes, has been demonstrated to exert marked chemopreventative and antiproliferative effects against various types of cancer (1,2,(15)(16)(17)(18)(19)(20). Metformin is able to inhibit cell growth via insulin and non-insulin dependent mechanisms (1,2,(15)(16)(17), while enhancing insulin receptor sensitivity, increasing insulin uptake and therefore reducing systemic insulin levels.…”

“…Metformin is able to inhibit cell growth via insulin and non-insulin dependent mechanisms (1,2,(15)(16)(17), while enhancing insulin receptor sensitivity, increasing insulin uptake and therefore reducing systemic insulin levels. Metformin is also able to inhibit cell proliferation via activation of the growth inhibitory adenosine monophosphate-activated protein kinase (AMPK).…”

“…Metformin is also able to inhibit cell proliferation via activation of the growth inhibitory adenosine monophosphate-activated protein kinase (AMPK). AMPK blocks signaling via the phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) pathways, downstream of the insulin and IGF1 receptors (2,15,16).…”