Mitogenic properties of insulin and insulin analogues mediated by the insulin receptor

Abstract

The receptors for insulin and insulin-like growth factor-I (IGF-I) belong to the family of receptor protein tyrosine kinases [1]. Although a vast body of data supports the concept that insulin stimulates cell growth in vitro and in vivo, the question of whether insulin is physiologically a growth factor remains controversial (for review see [2]). Even more controversial is the question of whether insulin is capable of inducing mitogenic effects through its own receptor, or whether the growth-promoting effects of insulin result from its weak interaction with the IGF-I receptor or occur within insulin/IGF-I receptor hybrids [3,4], or via interphosphorylation of the IGF-I receptor by the insulin receptor tyrosine kinase [5]. The response possibly depends on the cell type and its given supply of insulin and IGF-I receptors as well as the subsets of intracellular signalling molecules that are activated by either receptor. (We use the term IGF-I receptor for simplicity to designate the type 1 IGF receptor which binds both IGF-I and II and probably mediates the mitogenic effects of both growth factors [6].) Diabetologia (1997) Summary Insulin has traditionally been considered as a hormone essential for metabolic regulation, while the insulin-like growth factors (IGF-I and IGF-II) are postulated to be more specifically involved in growth regulation. The conventional wisdom is that they share each other's effects only at high concentrations, due to their weak affinity for the heterologous receptor. We discuss here the evidence that in the proper cellular context, insulin can be mitogenic at physiologic concentrations through its own receptor. We studied the insulin and IGF-I binding characteristics of a new model suitable for analysing insulin receptor mediated mitogenesis; that is, a T-cell lymphoma line that depends on insulin for growth, but is unresponsive to IGFs. The cells showed no specific binding of 125 I-IGF-I and furthermore, no IGF-I receptor mRNA was detected by RNAse protection assay in the LB cells, in contrast with mouse brain and thymus. The cells bound at saturation about 3000 insulin molecules to receptors that had normal characteristics in terms of affinity, kinetics, pH dependence and negative co-operativity. A series of insulin analogues competed for 125 I-insulin binding with relative potencies comparable to those observed in other insulin target cells. The full sequence of the insulin receptor cDNA was determined and found to be identical to the published sequence of the murine insulin receptor cDNA. The LB cell line is therefore an ideal model with which to investigate insulin mitogenic signalling without interference from the IGF-I receptor. Using this model, we have started approaching the molecular basis of insulin-induced mitogenesis, in particular the role of signalling kinetics in choosing between mitogenic and metabolic pathways. [Diabetologia (1997) 40: S 25-S 31]

Nonalcoholic fatty liver disease and hepatocellular carcinoma: A weighty connection

“…7,110 Hyperinsulinemia up-regulates the production of insulin-like growth factor-1 (IGF1), which is a peptide hormone that stimulates growth through cellular proliferation and inhibition of apoptosis within the liver. 93,111,112 Insulin also activates insulin receptor substrate-1 (IRS-1), which is involved in cytokine signaling pathways and has been shown to be up-regulated in HCC. 113 The mannose 6-phosphate/IGF2 receptor (M6P/IGF2R) is involved in regulating cell growth by activating growth inhibitor and inactivating IGF2, a growth stimulator.…”

From signal transduction to signal interpretation: An alternative model for the molecular function of insulin receptor substrates

“…Under some conditions, EGF can evoke metabolic responses, e.g. GLUT4 translocation (Gogg and Smith, 2002;Ishii et al, 1994), whereas insulin can be mitogenic (Ish-Shalom et al, 1997;Papa et al, 1997).…”

Mitogenic action of insulin: friend, foe or ‘frenemy’?

“…These aspects of insulin action are collectively known as the 'mitogenic actions' of insulin [7] and because they are so critical to cellular physiology, insulin is always present in cell culture medium for the propagation and maintenance of cells in culture. Although a much weaker mitogen [8] than its cousins, the IGFs, and its more distant relatives such as platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF) and EGF, insulin has a very specific mitogenic action, which modulates cellular responsiveness to all other growth factors, thus potentiating their actions [9,10].…”