Abstract
The pathophysiology of type 2 diabetes includes two apparently distinct defects i.e. impaired insulin action at the level of muscle, fat and liver, and failure in β-cells secretory capacity. Insulin action is mediated by the insulin receptor, (IR) a member of the receptor tyrosine kinase family also including the type 1 Insulin-like Growth Factor I (IGF-I) receptor (IGF-IR) and the orphan receptor Insulin Receptor-Related Receptor (IRR). IR exists in two functionally distinct isoforms differing by the absence (Ex11-) or presence (Ex11+) of a 12 amino acid sequence in the COOH-terminus of the α-subunit due to alternative splicing of exon 11. In addition to forming homodimers, IR, IGF-IR and IRR can form hybrid receptors. IR / IGF-IR hybrids bind IGF-I, but not insulin, with high affinity, and function as IGF-IR homoreceptors rather than IR homoreceptors. The function of IRR is unknown and it does not transduce signals through IR / IRR hybrids. The generation of genetically engineered knockout mice with total or tissue -specific lack of IR has been instrumental in dissecting the pathophysiological role of IR not only in classical target tissues, such as muscle and liver, but also in non-classical target tissues, such as brain and pancreatic β-cells. Some, but not all, studies have reported that expression of the low-affinity Ex11+ isoform is increased in target tissues from type 2 diabetics, thus contributing to insulin resistance. There is evidence that abundance of IR / IGF-IR hybrid receptors is increased in insulin target tissues, where they might affect insulin sensitivity by sequestering IR in a less insulin-responsive form. This review will focus on the structural and functional heterogeneity of IR and related receptors, and will discuss the studies in knockout mice lacking IR. Finally, studies addressing the potential role of IR variant forms in the development of conditions of insulin resistance, such as obesity and type 2 diabetes mellitus will be reviewed.
Keywords: Type 2 diabetes,, obesity,, insulin resistance,, insulin receptor isoforms,, IGF-I receptor,, hybrid receptor.
Current Genomics
Title: Role of the Insulin Receptor Variant Forms in Human Metabolic Disorders
Volume: 4 Issue: 4
Author(s): Giorgio Sesti
Affiliation:
Keywords: Type 2 diabetes,, obesity,, insulin resistance,, insulin receptor isoforms,, IGF-I receptor,, hybrid receptor.
Abstract: The pathophysiology of type 2 diabetes includes two apparently distinct defects i.e. impaired insulin action at the level of muscle, fat and liver, and failure in β-cells secretory capacity. Insulin action is mediated by the insulin receptor, (IR) a member of the receptor tyrosine kinase family also including the type 1 Insulin-like Growth Factor I (IGF-I) receptor (IGF-IR) and the orphan receptor Insulin Receptor-Related Receptor (IRR). IR exists in two functionally distinct isoforms differing by the absence (Ex11-) or presence (Ex11+) of a 12 amino acid sequence in the COOH-terminus of the α-subunit due to alternative splicing of exon 11. In addition to forming homodimers, IR, IGF-IR and IRR can form hybrid receptors. IR / IGF-IR hybrids bind IGF-I, but not insulin, with high affinity, and function as IGF-IR homoreceptors rather than IR homoreceptors. The function of IRR is unknown and it does not transduce signals through IR / IRR hybrids. The generation of genetically engineered knockout mice with total or tissue -specific lack of IR has been instrumental in dissecting the pathophysiological role of IR not only in classical target tissues, such as muscle and liver, but also in non-classical target tissues, such as brain and pancreatic β-cells. Some, but not all, studies have reported that expression of the low-affinity Ex11+ isoform is increased in target tissues from type 2 diabetics, thus contributing to insulin resistance. There is evidence that abundance of IR / IGF-IR hybrid receptors is increased in insulin target tissues, where they might affect insulin sensitivity by sequestering IR in a less insulin-responsive form. This review will focus on the structural and functional heterogeneity of IR and related receptors, and will discuss the studies in knockout mice lacking IR. Finally, studies addressing the potential role of IR variant forms in the development of conditions of insulin resistance, such as obesity and type 2 diabetes mellitus will be reviewed.
Export Options
About this article
Cite this article as:
Sesti Giorgio, Role of the Insulin Receptor Variant Forms in Human Metabolic Disorders, Current Genomics 2003; 4 (4) . https://dx.doi.org/10.2174/1389202033490376
DOI https://dx.doi.org/10.2174/1389202033490376 |
Print ISSN 1389-2029 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5488 |
Call for Papers in Thematic Issues
Advanced Computational Algorithms and Artificial Intelligence in Clinical Pharmacogenomics
In the era of personalized medicine, understanding the relationship between genetics and drug response is crucial. This issue delves into innovative methodologies, leveraging deep computational analysis and artificial intelligence, to enhance the field of Clinical Pharmacogenomics. The interdisciplinary approach harnesses the power of advanced high-throughput genotyping technologies, sophisticated computational analysis, ...read more
Applications of Single-cell Sequencing Technology in Reproductive Medicine
Single cell sequencing (SCS) technology utilizes individual cells' genetic material to sequence their genome, transcriptome, and epigenetics at the molecular level. It offers insights into cell heterogeneity and enables the study of limited biological materials. Since its recognition as a valuable technique in 2011, single cell sequencing has yielded numerous ...read more
Big Data in Cancer Research
Cancer is a significant threat to human life and health, remaining a highly aggressive killer. It is a leading cause of death worldwide and represents a crucial medical issue for humanity. However, in the past decade, the effectiveness of new synthetic anticancer agents has not matched the current clinical speculation. ...read more
Current Genomics in Cardiovascular Research
Cardiovascular diseases are the main cause of death in the world, in recent years we have had important advances in the interaction between cardiovascular disease and genomics. In this Research Topic, we intend for researchers to present their results with a focus on basic, translational and clinical investigations associated with ...read more
Related Journals
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Extraction, Structure and Bioactivities of the Polysaccharides from Fructus corni
Recent Patents on Food, Nutrition & Agriculture Structure-Function Relationships of PEDF
Current Molecular Medicine Correlation between Serum 25 hydroxy vitamin D level and plasminogen activator inhibitor 1 in type 2 diabetic patients
Endocrine, Metabolic & Immune Disorders - Drug Targets The Putative Impact of Metabolic Health on Default Mode Network Activity and Functional Connectivity in Neuropsychiatric Disorders
CNS & Neurological Disorders - Drug Targets Flavonoids: Cellular and Molecular Mechanism of Action in Glucose Homeostasis
Mini-Reviews in Medicinal Chemistry Insulin Therapy for Improving Cardiac Surgical Outcomes
Current Drug Targets Targeting Chromatin Remodeling to Prevent Cardiovascular Disease in Diabetes
Current Pharmaceutical Biotechnology Pericyte: Potential Target for Hemorrhagic Stroke Prevention and Treatment
Current Drug Delivery Evaluation of Blood Pressure Control using a New Arterial Stiffness Parameter, Cardio-ankle Vascular Index (CAVI)
Current Hypertension Reviews Subject Index To Volume 12
Current Pharmaceutical Design Incretin-Based Therapy of Type 2 Diabetes Mellitus
Current Protein & Peptide Science Novel Swellable/Expandable Gastroretentive Floating Films of Gliclazide Folded in Capsule Shell for the Effective Management of Diabetes Mellitus: Formulation Development, Optimization and In Vitro Evaluation
Current Drug Therapy Endothelial Progenitor Cells as Potential Drug Targets
Current Drug Targets - Cardiovascular & Hematological Disorders The Role of Fibrate Treatment in Dyslipidemia: An Overview
Current Pharmaceutical Design Transplantation of Genetically Modified Haematopoietic Stem Cells to Induce Antigen-Specific Tolerance as a Cure for Autoimmune Diseases
Current Stem Cell Research & Therapy The Crosstalk Between Insulin and Renin-Angiotensin-Aldosterone Signaling Systems and its Effect on Glucose Metabolism and Diabetes Prevention
Current Vascular Pharmacology Effect of Adding Proprioceptive Exercise to Balance Training in Older Adults with Diabetes: A Systematic Review
Current Diabetes Reviews Lipid-Lowering Therapy in HIV-Infected Patients: Relationship with Antiretroviral Agents and Impact of Substance-Related Disorders
Current Vascular Pharmacology Nonalcoholic Fatty Liver Disease In Children: Recent Practice Guidelines, Where Do They Take Us?
Current Pediatric Reviews The Role of Glycoprotein IIb/IIIa Inhibitors- A Promise Not Kept?
Current Cardiology Reviews