Insulin analogs and cancer

Abstract

Today, insulin analogs are used in millions of diabetic patients. Insulin analogs have been developed to achieve more physiological insulin replacement in terms of time-course of the effect. Modifications in the amino acid sequence of the insulin molecule change the pharmacokinetics and pharmacodynamics of the analogs in respect to human insulin. However, these changes can also modify the molecular and biological effects of the analogs. The rapid-acting insulin analogs, lispro, aspart, and glulisine, have a rapid onset and shorter duration of action. The long-acting insulin analogs glargine and detemir have a protracted duration of action and a relatively smooth serum concentration profile. Insulin and its analogs may function as growth factors and therefore have a theoretical potential to promote tumor proliferation. A major question is whether analogs have an increased mitogenic activity in respect to insulin. These ligands can promote cell proliferation through many mechanisms like the prolonged stimulation of the insulin receptor, stimulation of the IGF-1 receptor (IGF-1R), prevalent activation of the extracellular-signaling-regulated kinase (ERK) rather than the protein kinase B (PKB/AKT) intracellular post-receptor pathways. Studies on in vitro models indicate that short-acting analogs elicit molecular and biological effects that are similar to those of insulin. In contrast, long-acting analogs behave differently. Although not all data are homogeneous, both glargine and detemir have been found to have a decreased binding to receptors for insulin but an increased binding to IGF-1R, a prevalent activation of the ERK pathway, and an increased mitogenic effect in respect to insulin. Recent retrospective epidemiological clinical studies have suggested that treatment with long-acting analogs (specifically glargine) may increase the relative risk for cancer. Results are controversial and methodologically weak. Therefore prospective clinical studies are needed to evaluate the possible tumor growth-promoting effects of these insulin analogs.

Keywords: IGF-1 receptor; cancer; insulin analogs; insulin receptor; insulin receptor isoforms.

Figure 1

Insulin receptors (IR-A and IR-B), IGF-1 receptor (IGF-1R), and hybrid receptors (IR-A/IR-B, IGF-1R/IR-A, and IGF-1R/IR-B). Insulin binds with high affinity to IR-A, IR-B, and hybrid receptors IR-A/IR-B (black arrow), whereas binds with low affinity to IGF-1R (black dotted arrow). IGF-1 binds with high affinity IGF-1R and hybrid receptors IGF-1R/IR-A and IGF-1R/IR-B (red arrow), whereas it binds with low affinity to IR-A, IR-B, and hybrid receptors IR-A/IR-B (red dotted arrow). IGF-2 binds with high affinity to IR-A, IGF-1R, and hybrid receptors IR-A/IR-B and IGF-1R/IR-A (green arrow). IR-A, IGF-1R, and hybrid receptors IR-A/IR-B and IGF-1R/IR-A predominantly mediate mitogenic effects. IR-B mediates prevalently metabolic effects.

Figure 2

Molecular mechanisms potentially involved in the mitogenic effects of long-acting insulin analogs. Two main molecular mechanisms have been hypothesized to influence the balance of metabolic and mitogenic actions of long-acting insulin analogs: the longer residence of the ligand on the IR and/or an increased binding affinity of the insulin analog for IGF-1R may predominantly activate the mitogenic signaling.