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.

Diabetes and cancer are two heterogeneous, multifactorial, severe, and chronic diseases. Because of their frequency, reciprocal influences -even minor influences -may have a major impact. Epidemiological studies clearly indicate that the risk of several types of cancer (including pancreas, liver, breast, colorectal, urinary tract, and female reproductive organs) is increased in diabetic patients. Mortality is also moderately increased. Several confounding factors, having general or site-specific relevance, make it difficult to accurately assess cancer risk in diabetic patients. These factors include diabetes duration, varying levels of metabolic control, different drugs used for therapy, and the possible presence of chronic complications. Hyperinsulinemia most likely favors cancer in diabetic patients as insulin is a growth factor with pre-eminent metabolic but also mitogenic effects, and its action in malignant cells is favored by mechanisms acting at both the receptor and post-receptor level. Obesity, hyperglycemia, and increased oxidative stress may also contribute to increased cancer risk in diabetes. While anti-diabetic drugs have a minor influence on cancer risk (except perhaps the biguanide metformin that apparently reduces the risk), drugs used to treat cancer may either cause diabetes or worsen a pre-existing diabetes. In addition to the well-known diabetogenic effect of glucocorticoids and anti-androgens, an increasing number of targeted anti-cancer molecules may interfere with glucose metabolism acting at different levels on the signaling substrates shared by IGF-I and insulin receptors. In conclusion, diabetes and cancer have a complex relationship that requires more clinical attention and better-designed studies.

Insulin-like growth factor II (IGF-II) is a peptide growth factor that is homologous to both insulin-like growth factor I (IGF-I) and insulin and plays an important role in embryonic development and carcinogenesis. IGF-II is believed to mediate its cellular signaling via the transmembrane tyrosine kinase type 1 insulin-like growth factor receptor (IGF-I-R), which is also the receptor for IGF-I. Earlier studies with both cultured cells and transgenic mice, however, have suggested that in the embryo the insulin receptor (IR) may also be a receptor for IGF-II. In most cells and tissues, IR binds IGF-II with relatively low affinity. The IR is expressed in two isoforms (IR-A and IR-B) differing by 12 amino acids due to the alternative splicing of exon 11. In the present study we found that IR-A but not IR-B bound IGF-II with an affinity close to that of insulin. Moreover, IGF-II bound to IR-A with an affinity equal to that of IGF-II binding to the IGF-I-R. Activation of IR-A by insulin led primarily to metabolic effects, whereas activation of IR-A by IGF-II led primarily to mitogenic effects. These differences in the biological effects of IR-A when activated by either IGF-II or insulin were associated with differential recruitment and activation of intracellular substrates. IR-A was preferentially expressed in fetal cells such as fetal fibroblasts, muscle, liver and kidney and had a relatively increased proportion of isoform A. IR-A expression was also increased in several tumors including those of the breast and colon. These data indicate, therefore, that there are two receptors for IGF-II, both IGF-I-R and IR-A. Further, they suggest that interaction of IGF-II with IR-A may play a role both in fetal growth and cancer biology.

The insulin receptor (IR)1 and the insulin-like growth factor (IGF) I receptor (IGF-IR) are tetrameric glycoproteins composed of two extracellular ␣-and two transmembrane ␤-subunits linked by disulfide bonds. Each ␣-subunit, containing the ligand-binding site, is ϳ130 kDa, whereas each ␤-subunit, containing the tyrosine kinase domain, is ϳ95-97 kDa. These receptors share Ͼ50% overall amino acid sequence homology and 84% homology in the tyrosine kinase domains. After ligand binding, activated receptors recruit and phosphorylate docking proteins, including the insulin receptor substrate-1 family proteins Gab1 and Shc (1-5), leading to the activation of many intracellular mediators, including phosphatidylinositol 3-kinase, Akt, and ERK1/2, involved in the regulation of cell metabolism, proliferation, and survival. Although both the IR and IGF-IR similarly activate major signaling pathways, subtle differences exist in the recruitment of certain docking proteins and intracellular mediators between the two receptors (6 -9). These differences are the basis for the predominant metabolic effect elicited by IR activation and the predominant mitogenic, transforming, and anti-apoptotic effect elicited by IGF-IR activation (10 -13). According to the classical view, insulin binds with high affinity to the IR (100-fold higher than to the IGF-IR), whereas both insulin-like growth factors (IGF-I and IGF-II) bind to the IGF-IR (with 100-fold higher affinity than to the IR).Given the high degree of homology, the insulin and IGF-I half-receptors (composed of one ␣-and one ␤-subunit) can heterodimerize, leading to the formation of insulin/IGF-I hybrid receptors (Hybrid-Rs) (14 -16). In many tissues, Hybrid-Rs are the most represented receptor subtype (17). Hybrid-Rs may also be overexpressed in a variety of human malignancies as a result of both IR and IGF-IR overexpression (18 -21). However, the biological role of these Hybrid-Rs is still unclear. Functional studies have indicated that Hybrid-Rs behave more like IGF-IRs than IRs because they bind to and are activated by IGF-I with an affinity similar to that of the typical IGF-IR. In contrast, Hybrid-R activation in response to insulin occurs with much lower affinity (22, 23). Hybrid-Rs are therefore believed to provide additional binding sites to IGF-I and to increase cell sensitivity to this growth factor (17-19). These studies have not, however, taken into account the different IR isoform contribution to Hybrid-R formation and function.The human IR exists in two isoforms (IR-A and IR-B), gen-* This work was supported in part by grants from the Associazione Italiana per la Ricerca sul Cancro and Ministero dell'Università e della Ricerca Scientifica e Tecnologica (1999Tecnologica ( , 2001. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.¶ Recipient of a fellowship from the Fondazione Giuseppe Alazio per l...

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Aims/hypothesis Five insulin analogues, with modified insulin-like molecular structures, are currently approved for treating diabetic patients. They activate cell signalling and biological responses via insulin receptor isoforms (IR-A and IR-B), each having specific characteristics for eliciting cell responses. The molecular and biological effects of these analogues on receptor isoforms in comparison to native insulin are not well defined, and their effects on the IGF1 receptor (IGF1R) are controversial. The characterisation of these effects was the aim of the present study. Methods Short-acting (insulin lispro [B28Lys,B29Pro human insulin], insulin aspart [B28Asp human insulin], insulin glulisine [B3Lys,B29Glu human insulin]) and long-acting (insulin glargine [A21Gly,B31Arg,B32Arg human insulin], insulin detemir [B29Lys(ε-tetradecanoyl),desB30 human insulin]) insulin analogues were studied in three engineered cell models (R − , IGF1R-deprived mouse fibroblasts transfected with either only human IR-A or IR-B or IGF1R). Receptor binding and phosphorylation, AKT and extracellular signal-regulated kinase (ERK) activation, cell proliferation and colony formation were evaluated after exposing the cells to each analogue and were compared with insulin, IGF1 and the carcinogenic analogue B10Asp.Results All short-acting insulin analogues produced molecular and biological effects similar but not identical to those of insulin. Relative to insulin, long-acting analogues more strongly activated the ERK pathway via both IR-A and IGF1R as well as increased cell proliferation. At the concentration tested, no analogue (except B10Asp via IR-A) had increased transforming activity. Conclusions/interpretation Cell models that permit comparisons of the activity of insulin to that of insulin analogues via each receptor individually indicate that only minor differences exist between insulin and short-acting analogues. By contrast, long-acting analogues activate the mitogenic signalling pathway more effectively than insulin and cause increased cell proliferation.

In this study, we show that androgens up-regulate insulin-like growth factor