Insulin Receptor Isoforms and Insulin Receptor/Insulin-Like Growth Factor Receptor Hybrids in Physiology and Disease

Abstract

In mammals, the insulin receptor (IR) gene has acquired an additional exon, exon 11. This exon may be skipped in a developmental and tissue-specific manner. The IR, therefore, occurs in two isoforms (exon 11 minus IR-A and exon 11 plus IR-B). The most relevant functional difference between these two isoforms is the high affinity of IR-A for IGF-II. IR-A is predominantly expressed during prenatal life. It enhances the effects of IGF-II during embryogenesis and fetal development. It is also significantly expressed in adult tissues, especially in the brain. Conversely, IR-B is predominantly expressed in adult, well-differentiated tissues, including the liver, where it enhances the metabolic effects of insulin. Dysregulation of IR splicing in insulin target tissues may occur in patients with insulin resistance; however, its role in type 2 diabetes is unclear. IR-A is often aberrantly expressed in cancer cells, thus increasing their responsiveness to IGF-II and to insulin and explaining the cancer-promoting effect of hyperinsulinemia observed in obese and type 2 diabetic patients. Aberrant IR-A expression may favor cancer resistance to both conventional and targeted therapies by a variety of mechanisms. Finally, IR isoforms form heterodimers, IR-A/IR-B, and hybrid IR/IGF-IR receptors (HR-A and HR-B). The functional characteristics of such hybrid receptors and their role in physiology, in diabetes, and in malignant cells are not yet fully understood. These receptors seem to enhance cell responsiveness to IGFs.

Insulin X10 revisited: a super-mitogenic insulin analogue

“…2, but in addition the issue of different IR isoforms and IR/IGF-1R hybrids must be taken into account. It has been speculated that an increase in the mitogenic properties of an insulin analogue could alternatively (or additionally) reflect a binding preference for the shorter IR-A isoform of IR relative to the longer IR-B isoform [30,33]. This hypothesis is derived from the observation that IR-A has high affinity for binding IGF-2 and is extensively expressed in fetal tissue, where it mediates growth responses.…”

“…IR-A expression is also associated with undifferentiated cells, and overexpression occurs in some cancer cells. This raises the possibility that this IR isoform may be relevant for the mitogenesis of cancer cells [33]. However, studies have shown that both the binding affinity and the activation of the two IR isoforms are very similar after stimulation with insulin X10 [22,30,34,35].…”

Metformin and Cancer Risk in Diabetic Patients: A Systematic Review and Meta-analysis

“…Hyperinsulinemia adversely affects prognosis in cancer patients (3,(7)(8)(9)(10)(11) and is an independent risk factor for several types of neoplasms, thus explaining the obesity-cancer association (12). Insulin can promote tumorigenesis through a direct effect on epithelial tissues acting on the insulin/insulin-like growth factor family of receptors (13), or indirectly by affecting the levels of other modulators, such as insulin-like growth factors, sex hormones, and adipokines (14,15). Recent evidence indicates that the abnormally high proliferative activity of premalignant and malignant cells requires high levels of nutrients to meet the increased demands for energy consumption and protein biosynthesis (16).…”

Differential effects of IGF-I, IGF-II and insulin in human preadipocytes and adipocytes – Role of insulin and IGF-I receptors

“…It should be noted that the IR exists in two isoforms due to alternative splicing of the IR gene. Isoform B contains the 12 amino acids encoded by the exon that has been spliced off in isoform A. IGF-II has a higher affinity for IR-A than for IR-B (Belfiore et al, 2009). In adipose tissue both IR-A and IR-B are present (Sesti et al, 1995).…”