Insulin and its analogues and their affinities for the IGF1 receptor

Abstract

Insulin analogues have been developed in an attempt to achieve a more physiological replacement of insulin and thereby a better glycaemic control. However, structural modification of the insulin molecule may result in altered binding affinities and activities to the IGF1 receptor (IGF1R). As a consequence, insulin analogues may theoretically have an increased mitogenic action compared to human insulin. In view of the lifelong exposure and large patient populations involved, insulin analogues with an increased mitogenic effect in comparison to human insulin may potentially constitute a major health problem, since these analogues may possibly induce the growth of pre-existing neoplasms. This hypothesis has been evaluated extensively in vitro and also in vivo by using animal models. In vitro, all at present commercially available insulin analogues have lower affinities for the insulin receptor (IR). Although it has been suggested that especially insulin analogues with an increased affinity for the IGF1R (such as insulin glargine) are more mitogenic when tested in vitro in cells expressing a high proportion of IGF1R, the question remains whether this has any clinical consequences. At present, there are several uncertainties which make it very difficult to answer this question decisively. In addition, recent data suggest that insulin (or insulin analogues)-mediated stimulation of IRs may play a key role in the progression of human cancer. More detailed information is required to elucidate the exact mechanisms as to how insulin analogues may activate the IR and IGF1R and how this activation may be linked to mitogenesis.

IGF2 knockdown in two colorectal cancer cell lines decreases survival, adhesion and modulates survival-associated genes

“…Extracellular IGF2 is regulated by several serum IGFbinding proteins which are thought to regulate the amount of free extracellular IGF2, but also appear to possess activities independent of IGF binding [5]. Insulin, IGF1, and IGF2 are ligands for a series of receptor tyrosine kinases which include two isoforms of the insulin receptor (A and B), the insulinrelated receptor and the IGF1 receptor [6,7]. One further receptor, the IGF2 receptor, which also functions as a cell surface receptor for mannose-6 phosphate, lacks tyrosine kinase activity and is thought to be involved in the extracellular regulation of IGF2 content.…”

Novel players in cardioprotection: Insulin like growth factor-1, angiotensin-(1–7) and angiotensin-(1–9)

“…The most mammalian cells express both the IGF-1R and the IR. Thus, based on the high sequence identity (~58%) between IGF-1R and IR, they can heterodimerize forming IGF-1R/IR hybrids receptors [30]. On this regard, Slabby et al proposed that IGF-1R/IR hybrid receptors have low insulin and high IGF-1 affinity, independent of the IR splice variant [31].…”

Mass Spectrometry Characterization of a Novel Insulin Mimetic Peptide s597

“…An additional drawback of several insulin analogues is an enhanced mitogeniticity [8]. On these grounds, insulin mimetic peptides can be proposed as potential drug candidates in the treatment of diabetes due to their smaller size, simple structure and insulin-like activity with low mitogenic response, which are critical issues in the development of effective and safe pharmaceuticals.…”