Obesity, type 2 diabetes, and cancer: the insulin and IGF connection

Abstract

Epidemiological studies suggest a positive association between obesity and type 2 diabetes mellitus (T2D) with the risk of cancer and cancer-related mortality. Insulin resistance, hyperinsulinemia, increased levels of IGF, elevated levels of steroid and peptide hormones, and inflammatory markers appear to play a role in the connection between these different diseases. Medications, such as metformin and exogenous insulin, used to treat T2D may affect the risk of cancer and cancer-related mortality. Newer therapies targeting the insulin and IGF1 systems are being developed for use in cancer therapy.

GPER1 is regulated by insulin in cancer cells and cancer-associated fibroblasts

“…In this regard, it should be pointed out that in cancer patients affected by insulin resistance, increased insulin levels combine with frequent INSR overexpression leading to abnormal stimulation of nonmetabolic effects mediated by INSR, such as cell survival, proliferation, and migration (Belfiore & Malaguarnera 2011). For instance, high insulin levels have been associated with an increased risk of breast cancer and breast cancer relapses in diabetic and nondiabetic women (Duggan et al 2011, Cohen & Le Roith 2012, Sieri et al 2012. Taking into account these data and the results of the present study, it would be interesting to evaluate in future studies the actual role performed by estrogenic GPER1 signaling in different pathophysiological conditions characterized by insulin resistance.…”

“…Moreover, in cancer patients affected by insulin resistance, increased insulin levels combine with frequent INSR overexpression in tumor cells, leading to abnormal stimulation of nonmetabolic effects mediated by INSR, such as cell survival, proliferation, and migration (Belfiore & Malaguarnera 2011). In particular, high insulin levels are associated with an augmented risk of breast cancer and breast cancer relapses in diabetic and nondiabetic women (Duggan et al 2011, Cohen & Le Roith 2012, Sieri et al 2012. It has been well established that a cooperative crosstalk between insulin and estrogen signaling pathways triggers multiple biological events in breast carcinogenesis (Rose & Vona-Davis 2012, Catsburg et al 2014.…”

Metformin, cancer and glucose metabolism

“…Insulin may favour cancer cell proliferation and mitogenic processes (Cohen & LeRoith 2012). The gene encoding the insulin receptor (IR), by alternative splicing of exon 11, yields two isoforms: IR-A and IR-B.…”

IUGR prevents IGF-1 upregulation in juvenile male mice by perturbing postnatal IGF-1 chromatin remodeling

“…IGF-1 disruption has been implicated in aberrant growth and development of metabolic syndrome in both IUGR humans and animal models (3-6). In particular, decreased IGF-1 have been observed in IUGR humans who ultimately develop metabolic syndrome as adults (7,8).The IGF-1 gene is an ideal candidate to examine IUGR's effects not only because of its growth and metabolic properties but because of its complex gene structure allowing for developmental-and tissue-specific expression. The majority of serum IGF-1 is synthesized from the liver (9).…”

“…IGF-1 disruption has been implicated in aberrant growth and development of metabolic syndrome in both IUGR humans and animal models (3-6). In particular, decreased IGF-1 have been observed in IUGR humans who ultimately develop metabolic syndrome as adults (7,8).…”