Biological Effects of Insulin and Its Analogs on Cancer Cells With Different Insulin Family Receptor Expression

Abstract

Hyperinsulinemia is a likely cause of the increased cancer incidence and mortality in diabetic patients, but its role is difficult to define in vivo. Previous in vitro studies testing the mitogenic potential of insulin and its analogs provided incomplete and sometimes contradictory results. To better evaluate cancer cell responsiveness to insulin, to its analogs and to IGF-I, we measured under identical experimental conditions cell proliferation, invasiveness, and foci formation in six cancer cell lines with different insulin receptor family expression levels. The cancer cells studied have a different expression of insulin receptor (IR), its isoforms (IR-A and IR-B), and of the IGF-I receptor. The data indicate that insulin stimulates proliferation in all cancer cell lines, invasiveness in some, and foci formation in none. Cancer cell responses to insulin (and IGF-I) are not related to receptor expression levels; moreover, hormone-stimulated proliferation and invasiveness are not correlated. IGF-I is a more potent stimulator than insulin in most but not all cancer cell lines. Insulin analogs including M1 and M2 Glargine metabolites stimulate cancer cells similar to insulin. However, exceptions occur for specific analogs in particular cancer cells. In conclusion, in vitro insulin is an effective growth factor for all cancer cells but the biological response to insulin cannot be predicted on the basis of receptor expression levels. In the clinical setting, these observations should be taken in account when deciding treatment for diabetic patients who are at risk of undiscovered cancer or survivors of oncological diseases.

Treatment with insulin (analogues) and breast cancer risk in diabetics; a systematic review and meta-analysis of in vitro, animal and human evidence

“…Seven of ten in vitro studies found an increased proliferative potential of glargine in comparison with human insulin [ 22 , 25 , 28 , 29 , 31 , 34 , 35 ] (Table 1 ). Two studies found proliferation of glargine as well, but human insulin was not included as a reference compound, therefore they could not confirm an increased proliferative response [ 32 , 33 ].…”

“…Like glargine, detemir is a long-acting insulin analogue. In general, it is assumed that detemir has a lower mitogenic potential compared to human insulin [ 22 , 28 , 31 , 34 ], but in a number of in vitro studies similar proliferation or even increased proliferation of determir has been observed [ 25 , 29 , 35 ] (Table 1 ). The binding characteristics of detemir to albumin are different among species.…”

Insulin, insulin receptors, and cancer

“…Moreover, we have to consider that the role of the IR must be evaluated in a complex system like a malignant cell in which other factors are aberrantly activated to promote cancer growth. In vitro, insulin is a growth stimulator more potent that IGF-1 in some cancer cells but the malignant cell biological response to insulin cannot be predicted only on the basis of the insulin receptor content [98] (Fig. 8).…”

Insulin Receptor Plasma Membrane Levels Increased by the Progesterone Receptor Membrane Component 1

“…Changes in insulin signaling have been linked to multiple diseases, most typically diabetes (Alghamdi et al, 2014), but also loss of cognitive function (de la Monte, 2012) and cancer progression (Malaguarnera and Belfiore, 2011;Sciacca et al, 2014;Forest et al, 2015). Insulin receptor (IR) is a tetramer comprised of 2a (ligand binding) and 2b (kinase domain) chains that is expressed in numerous tissues.…”