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      Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease.

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          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.

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          Author and article information

          Journal
          Endocr Rev
          Endocrine reviews
          The Endocrine Society
          1945-7189
          0163-769X
          Oct 2009
          : 30
          : 6
          Affiliations
          [1 ] Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Ospedale Garibaldi-Nesima, 95122 Catania, Italy. belfiore@unicz.it
          Article
          er.2008-0047
          10.1210/er.2008-0047
          19752219
          e75e260e-60f5-40e4-b6b1-fe007cf6024d
          History

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