Modifications in the B10 and B26-30 regions of the B chain of human insulin alter affinity for the human IGF-I receptor more than for the insulin receptor

Slieker, Lawrence J.; Brooke, G. S.; DiMarchi, Richard D.; Flora, David B.; Green, L K; Hoffmann, J. A.; Long, H B; Fan, Ludi; Shields, James E.; Sundell, Karen; Surface, Peggy L.; Chance, Ronald E.

doi:10.1007/s001250051402

Cited by 137 publications

(164 citation statements)

References 37 publications

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“…A correlation between relative IGF-1R affinity and mitogenic potency was described by Slieker and colleagues [20] and Kurtzhals and co-workers [19] and later by Kohn and colleagues [23] (Fig. 3).…”

Section: Understanding Insulin X10mentioning

confidence: 52%

“…In the majority of studies the binding affinity of insulin X10 to IR has been found to be increased 200-400% relative to that of human insulin. It was also noted by these early studies that the binding affinity of insulin X10 to IGF-1R was increased compared with that of human insulin [17,18] but with a fairly low affinity compared with IGF-1 itself, an effect that has subsequently been confirmed by a number of authors [19][20][21][22]. In addition to the increased receptor affinities, [12] insulin X10 was shown to have an increased in vitro ability to stimulate cell growth and DNA synthesis, and Bornfeldt and colleagues speculated that this was due to a substitution in the insulin X10 molecule that made this analogue more chemically similar to the IGF-1 molecule [18].…”

Section: Understanding Insulin X10mentioning

confidence: 79%

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Insulin X10 revisited: a super-mitogenic insulin analogue

et al. 2011

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The molecular safety of insulin analogues has received a great deal of attention over the last year. In particular, attention has been directed to the mitogenic properties of insulin analogues as compared with human insulin. Understanding the mechanisms implicated in mediating mitogenic effects of insulin is therefore of particular interest. In this review we detail the story of the rapid-acting insulin analogue known as X10, which was the first insulin analogue in clinical development, but ended up being discontinued at an early clinical development stage following findings of mammary tumours in female Sprague-Dawley rats. The molecular characteristics of insulin X10, along with its interaction at both the IGF-1 receptor and the insulin receptor, have provided us with important insights into mechanisms implicated in metabolic and mitogenic signalling of insulin analogues.

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Section: Understanding Insulin X10mentioning

confidence: 52%

Section: Understanding Insulin X10mentioning

confidence: 79%

Insulin X10 revisited: a super-mitogenic insulin analogue

et al. 2011

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“…These effects are mediated by prolonged binding to the insulin receptor, or by increased cross-reactivity with the IGF-1 receptor [30,31], and all new insulins are routinely screened for their effects on cell growth in the course of preclinical evaluation. Insulin B10Asp, the first of the analogues to be developed, was based on a single amino acid substitution.…”

Section: Insulin Analogues and Cancermentioning

confidence: 99%

Does diabetes therapy influence the risk of cancer?

2009

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“…This has been demonstrated for AspB10, which is known for its strong tumourigenic action [14]. Generally, the mitogenic potential of a certain insulin analogue may result from (1) an enhanced affinity towards IGF-1R [13]; (2) the time of occupancy of the insulin receptor (InsR) by this analogue [15,16]; and (3) a combination of IGF-1-and InsR-mediated processes.…”

Section: Introductionmentioning

confidence: 98%

“…Despite these advantages, some questions concerning the safety of insulin analogues remain open. It is known that modifications of the insulin molecule in the B10 and B26-B30 region are able to alter the affinity towards the IGF-1 receptor (IGF-1R) [13]. This has been demonstrated for AspB10, which is known for its strong tumourigenic action [14].…”

Section: Introductionmentioning

confidence: 99%

IGF-1 receptor signalling determines the mitogenic potency of insulin analogues in human smooth muscle cells and fibroblasts

et al. 2007

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Aims/hypothesis Mitogenic activity of insulin and insulin analogues and the involvement of the IGF-1 receptor (IGF-1R) is still a controversial issue. We compared levels of the proteins IGF-1R and insulin receptor (InsR) in fibroblasts and smooth muscle cells from healthy donors and assessed the downstream signalling and growth-promoting activity of insulin and insulin analogues. Methods DNA synthesis was monitored in human fibroblasts and coronary artery smooth muscle cells. Using small interfering RNAs, the levels of IGF-1 and InsR were reduced by 95 and 75%, respectively. Results Enhanced mitogenic potency of insulin and insulin analogues was observed which correlated with increased levels of IGF-1R and/or IRS-1. A reduction in the IGF-1R level significantly blunted stimulation of Akt phosphorylation by IGF-1, AspB10 and glargine by 72, 58 and 40%, respectively. Akt phosphorylation in response to insulin remained unaffected. Silencing of InsR did not significantly alter Akt phosphorylation in response to IGF-1, AspB10 and glargine. IGF-1R knockdown reduced the stimulation of DNA synthesis in response to IGF-1 and glargine to a level identical to that produced by insulin. Conclusions/interpretation These data show a prominent role of IGF-1R/Akt signalling in mediating the mitogenic effects of insulin analogues. Regular insulin stimulates DNA synthesis by exclusively activating InsR, whereas insulin analogues mainly signal through IGF-1R. It is suggested that inter-individual differences in the levels of proteins of the IGF-1R system may function as a critical determinant of the mitogenic potency of insulin analogues.

show abstract

Modifications in the B10 and B26-30 regions of the B chain of human insulin alter affinity for the human IGF-I receptor more than for the insulin receptor

Cited by 137 publications

References 37 publications

Insulin X10 revisited: a super-mitogenic insulin analogue

Insulin X10 revisited: a super-mitogenic insulin analogue

Does diabetes therapy influence the risk of cancer?

IGF-1 receptor signalling determines the mitogenic potency of insulin analogues in human smooth muscle cells and fibroblasts

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