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...

The insulin receptor (IR) gene undergoes differential splicing that generates two IR isoforms, IR-A and IR-B. The physiological roles of IR isoforms are incompletely understood and appear to be determined by their different binding affinities for insulin-like growth factors (IGFs), particularly for IGF-2. Predominant roles of IR-A in prenatal growth and development and of IR-B in metabolic regulation are well established. However, emerging evidence indicates that the differential expression of IR isoforms may also help explain the diversification of insulin and IGF signaling and actions in various organs and tissues by involving not only different ligand-binding affinities but also different membrane partitioning and trafficking and possibly different abilities to interact with a variety of molecular partners. Of note, dysregulation of the IR-A/IR-B ratio is associated with insulin resistance, aging, and increased proliferative activity of normal and neoplastic tissues and appears to sustain detrimental effects. This review discusses novel information that has generated remarkable progress in our understanding of the physiology of IR isoforms and their role in disease. We also focus on novel IR ligands and modulators that should now be considered as an important strategy for better and safer treatment of diabetes and cancer and possibly other IR-related diseases.

While recent research on transgender populations has demonstrated high rates of experiencing violence, there has been little research attention to the mental health implications of these experiences. This study utilized data collected from the Virginia Transgender Health Initiative Survey (THIS) of transgender people (individuals who described their gender identity as different from their sex assigned at birth) collected from 2005-2006. Current study analyses were limited to two subgroups: trans women (n = 179) and trans men (n = 92). We hypothesized that, as in the general population, exposure to physical and sexual violence would be related to suicidal ideation, suicide attempts, and substance abuse. Both trans women and trans men in this sample were at high risk for physical and sexual violence, as well as suicidal ideation and suicide attempt. Logistic regression analyses indicated that among both trans women and trans men, those who had endured physical and/or sexual violence were significantly more likely than those who had not had such experiences to report a history of suicide attempt and multiple suicide attempts. In addition, among trans men, history of physical and sexual violence were each related to alcohol abuse. Among trans women, history of sexual violence was related to alcohol abuse and illicit substance use. Patterns of violence against transgender people were identified and are discussed, including frequent gender-related motivation for violence, low prevalence of reporting violence to police, and variety of perpetrators of violence. Clinical implications and recommendations are provided.

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