Insulin, insulin receptors, and cancer

Abstract

Insulin is a major regulator of cell metabolism but, in addition, is also a growth factor. Insulin effects in target cells are mediated by the insulin receptor (IR), a transmembrane protein with enzymatic (tyrosine kinase) activity. The insulin receptor, however, is represented by a heterogeneous family of proteins, including two different IR isoforms and also hybrid receptors resulting from the IR hemireceptor combination with a hemireceptor of the cognate IGF-1 receptor. These different receptors may bind insulin and its analogs with different affinity and produce different biologic effects. Since many years, it is known that many cancer cells require insulin for optimal in vitro growth. Recent data indicate that: (1) insulin stimulates growth mainly via its own receptor and not the IGF-1 receptor; (2) in many cancer cells, the IR is overexpressed and the A isoform, which has a predominant mitogenic effect, is more represented than the B isoform. These characteristics provide a selective growth advantage to malignant cells when exposed to insulin. For this reason, all conditions of hyperinsulinemia, both endogenous (prediabetes, metabolic syndrome, obesity, type 2 diabetes before pancreas exhaustion and polycystic ovary syndrome) and exogenous (type 1 diabetes) will increase the risk of cancer. Cancer-related mortality is also increased in patients exposed to hyperinsulinemia but other factors, related to the different diseases, may also contribute. The complexity of the diseases associated with hyperinsulinemia and their therapies does not allow a precise evaluation of the cancer-promoting effect of hyperinsulinemia, but its detrimental effect on cancer incidence and mortality is well documented.

Insulin action and resistance in obesity and type 2 diabetes

“…It promotes glucose intolerance and type 2 diabetes with associated comorbidities, as well as increasing the risk of cancer 162 . Yet the etiology of insulin resistance is complicated and multifaceted, involving both cell autonomous mechanisms and inter-organ communications (Figure 2).…”

MANAGEMENT OF ENDOCRINE DISEASE: Morbidity in polycystic ovary syndrome

“…Furthermore, obesity, smoking and ingestion of more fat in patients with PCOS could increase the risk of several other cancer types. Insulin is an important growth factor and the insulin receptor was overexpressed in cancer cells (125). Insulin resistance and the following hyperinsulinemia in PCOS could therefore be an independent risk factor of malignant disease (125).…”

“…Insulin is an important growth factor and the insulin receptor was overexpressed in cancer cells (125). Insulin resistance and the following hyperinsulinemia in PCOS could therefore be an independent risk factor of malignant disease (125). The majority of brain tumors originated from the pituitary gland (122) and the increased risk of brain tumors remained significant after omitting cases diagnosed within the first year after PCOS diagnosis (122).…”

Structural Perspectives of Insulin Receptor Isoform-Selective Insulin Analogs

“…It is possible that IR-A in the brain is the receptor, not only for insulin but also for IGF-2, whose important roles in neural tissues become evident (36). Moreover, the expression of IR-A plays an important role in both insulin and IGF-2 signaling in cancer cells and tumors (37, 38). …”