The Insulin Receptor and Its Signal Transduction Network
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De Meyts P
The Insulin Receptor and Its Signal Transduction Network
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- PubMed ID
- 27512793 [ View in PubMed]
- Abstract
Insulin is an anabolic peptide hormone secreted by the b cells of the pancreas acting through a receptor located in the membrane of target cells - major ones being liver (where it promotes glucose storage into glycogen and decreases glucose output), as well as skeletal muscle and fat (where it stimulates glucose transport through translocation of GLUT4), but also b cells, brain cells and in fact most cells, where it has pleiotropic effects. The receptor belongs to the receptor tyrosine kinase superfamily and has orthologues in all metazoans. The structure of the unbound extracellular domain ("apo-receptor") has been solved. Insulin binds to two distinct sites on each a subunit of the receptor, crosslinking the two receptor halves to create high affinity. The structure of the site 1 interface has also been solved, as well as the structure of the inactive and activated tyrosine kinase, revealing the activation by phosphorylation of an autoinhibitory loop. The receptor activates a complex intracellular signaling network through IRS proteins and the canonical PI3K and ERK cascades. Overall and tissue-specific targeted gene disruption in mice has explored the role of many of the signaling proteins in creating the type 2 diabetes phenotype, with some surprising results. Insulin signaling in the liver and b cell is emerging as the major determinant in preventing type 2 diabetes, through the integrative role of molecules like IRS2 and FOXO, preventing b cell dedifferentiation. The emerging new biology of diabetes opens novel therapeutic opportunities for the 442 million type 2 diabetics worldwide. For complete coverage of this and all related areas of Endocrinology, please visit our FREE on-line web-textbook, www.endotext.org.
DrugBank Data that Cites this Article
- Drugs
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Insulin argine Insulin receptor Protein Humans YesAgonistDetails Insulin aspart Insulin receptor Protein Humans YesAgonistDetails Insulin beef Insulin receptor Protein Humans YesAgonistDetails Insulin defalan (bovine) Insulin receptor Protein Humans YesAgonistDetails Insulin defalan (porcine) Insulin receptor Protein Humans YesAgonistDetails Insulin degludec Insulin receptor Protein Humans YesAgonistDetails Insulin glulisine Insulin receptor Protein Humans YesAgonistDetails Insulin human Insulin receptor Protein Humans YesAgonistDetails Insulin lispro Insulin receptor Protein Humans YesAgonistDetails Insulin peglispro Insulin receptor Protein Humans UnknownNot Available Details Insulin tregopil Insulin receptor Protein Humans YesAgonistDetails