Insulin Receptor - Drugbank
ATP binding / GTP binding / insulin binding / insulin receptor substrate binding / insulin-activated receptor activity / insulin-like growth factor I binding / insulin-like growth factor II binding / insulin-like growth factor receptor binding / phosphatidylinositol 3-kinase binding / protein tyrosine kinase activity / PTB domain binding / receptor signaling protein tyrosine kinase activity activation of MAPK activity / activation of protein kinase activity / activation of protein kinase B activity / adrenal gland development / carbohydrate metabolic process / cellular response to growth factor stimulus / cellular response to insulin stimulus / epidermis development / exocrine pancreas development / G-protein coupled receptor signaling pathway / glucose homeostasis / heart morphogenesis / insulin receptor signaling pathway / male gonad development / male sex determination / peptidyl-tyrosine autophosphorylation / peptidyl-tyrosine phosphorylation / positive regulation of cell migration / positive regulation of cell proliferation / positive regulation of developmental growth / positive regulation of DNA replication / positive regulation of glucose import / positive regulation of glycogen biosynthetic process / positive regulation of glycolytic process / positive regulation of MAPK cascade / positive regulation of meiotic cell cycle / positive regulation of mitotic nuclear division / positive regulation of nitric oxide biosynthetic process / positive regulation of protein kinase B signaling / positive regulation of protein phosphorylation / positive regulation of respiratory burst / positive regulation of transcription, DNA-templated / protein autophosphorylation / protein heterotetramerization / regulation of embryonic development / regulation of female gonad developmen Continue reading >>
- Effects of Insulin Plus Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs) in Treating Type 1 Diabetes Mellitus: A Systematic Review and Meta-Analysis
- Relative effectiveness of insulin pump treatment over multiple daily injections and structured education during flexible intensive insulin treatment for type 1 diabetes: cluster randomised trial (REPOSE)
- Calculating Insulin Dose
Insulin Receptors
areas on the outer part of a cell that allow the cell to bind with insulin in the blood. When the cell and insulin bind, the cell can take glucose from the blood and use it for energy. Insularity Insularly Insulary Insulate Insulated Insulated wire insulating material Insulating stool insulating tape Insulation Insulator insulin insulin adjustment insulin pen insulin pump insulin reaction -- insulin receptors -- insulin resistance insulin shock insulin shock therapy insulin shock treatment insulin-dependent diabetes mellitus insulin-dependent diabetes mellitus (IDDM) insulinoma Insulite Insulous Insulse Insulsity Insult Insultable Insultation insulted Insulter Continue reading >>
Expression And Function Of The Insulin Receptor Substrate Proteins In Cancer
Abstract The Insulin Receptor Substrate (IRS) proteins are cytoplasmic adaptor proteins that function as essential signaling intermediates downstream of activated cell surface receptors, many of which have been implicated in cancer. The IRS proteins do not contain any intrinsic kinase activity, but rather serve as scaffolds to organize signaling complexes and initiate intracellular signaling pathways. As common intermediates of multiple receptors that can influence tumor progression, the IRS proteins are positioned to play a pivotal role in regulating the response of tumor cells to many different microenvironmental stimuli. Limited studies on IRS expression in human tumors and studies on IRS function in human tumor cell lines and in mouse models have provided clues to the potential function of these adaptor proteins in human cancer. A general theme arises from these studies; IRS-1 and IRS-4 are most often associated with tumor growth and proliferation and IRS-2 is most often associated with tumor motility and invasion. In this review, we discuss the mechanisms by which IRS expression and function are regulated and how the IRS proteins contribute to tumor initiation and progression. Introduction The Insulin Receptor Substrate (IRS) proteins are a family of cytoplasmic adaptor proteins that were first identified for their role in insulin signaling. The first family member to be identified, IRS-1, was initially characterized as a 185 kD phosphoprotein that was detected in anti-phosphotyrosine immunoblots in response to insulin stimulation [1]. IRS-2 was discovered as an alternative insulin receptor substrate, initially named 4PS, in insulin-stimulated cells derived from Irs-1 -/- mice [2]. IRS-1 and IRS-2 are ubiquitously expressed and are the primary mediators of insulin- Continue reading >>
- Early-onset and classical forms of type 2 diabetes show impaired expression of genes involved in muscle branched-chain amino acids metabolism
- Effects of Insulin Plus Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs) in Treating Type 1 Diabetes Mellitus: A Systematic Review and Meta-Analysis
- Defective, Infectious Proteins Linked to Type 2 Diabetes
Structure And Function Of The Insulin Receptor
INTRODUCTION Insulin initiates its cellular responses by binding to its cellular receptor, a transmembrane, multi-subunit glycoprotein that contains insulin-stimulated tyrosine kinase activity [1]. The cellular content of insulin receptors is variable, with the highest level of expression in cells that are most responsive to insulin for glucose, lipid, and protein metabolism, especially adipose, skeletal muscle, and liver. Initially identified over 25 years ago [2], the insulin receptor cDNA was cloned in 1985 [3,4]. Crystal structures of its protein tyrosine and of its extracellular domains were determined in 1994 [5] and 2006 [6], respectively. Since insulin has profound importance in metabolic control, studies of its receptor protein have been the subject of intense investigation [7]. EXPRESSION AND SUBUNIT STRUCTURE Receptor gene and mRNA — The insulin receptor gene maps to human chromosome 19 and spans more than 150 kilobases (kb) [8]. The 22 exons of the receptor gene are transcribed into several mRNA species ranging from 4.2 to 9.5 kb in length due to variation in their 3'-untranslated regions [9]. Exon 11, which encodes a 12 amino acid segment localized to the C-terminus of the α-subunit, is subject to tissue-specific alternative splicing in a pattern conserved between humans and lower mammals (figure 1) [10-12]. The abundance of receptor mRNA and protein are up-regulated by differentiation of adipocyte and muscle precursor cells as they acquire an insulin-sensitive phenotype [13]. In some cells, exposure to insulin reduces receptor mRNA abundance, which may play a role in regulation of receptor number in vivo [14,15]. In rare cases of severe insulin resistance due to mutations in the receptor gene, extreme reduction in receptor abundance has been shown [16]. Continue reading >>
- Effects of Insulin Plus Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs) in Treating Type 1 Diabetes Mellitus: A Systematic Review and Meta-Analysis
- Identification of novel biomarkers to monitor β-cell function and enable early detection of type 2 diabetes risk
- How Diabetes Affects Sexual Function
Hypoglycemia Associated With Antibodies To The Insulin Receptor
Abstract Antibodies to the insulin receptor are insulinomimetic in vitro, although they generally induce insulin resistance in vivo. We report the novel case of a patient who presented with fasting hypoglycemia as the sole manifestation of autoantibodies to the insulin receptor. Prednisone therapy (120 mg per day) produced a rise in fasting glucose to more than 100 mg per deciliter (6 mmol per liter) within 48 hours, although there was no detectable change in the titer of antireceptor antibodies. After 10 weeks of therapy, the titer of antireceptor antibodies had fallen approximately 100-fold, and prednisone could be discontinued without recurrence of hypoglycemia. This case demonstrates that antireceptor antibodies must be considered in the differential diagnosis of hypoglycemia, especially in patients with other manifestations of autoimmunity. (N Engl J Med. 1982; 307:1422–6.) Presented in part at the 39th annual meeting of the American Federation for Clinical Research, May 8, 1982. We are indebted to Dr. Jesse Roth for valuable discussions and to Ms. Laurie Tuchman for assistance in preparing the manuscript. Note added in proof: Since submission of this manuscript, Rossetti et al. have described a similar patient with hypoglycemia resulting from autoantibodies to the insulin receptor.24 From the Diabetes Branch, National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, and the Department of Medicine, University of Alabama, Birmingham. Address reprint requests to Dr. Taylor at Bldg. 10, Rm. 8S–243, National Institutes of Health, Bethesda, MD 20205. Continue reading >>
Why Are There No Small Molecule Drugs Targeting The Insulin Receptor?
This is an interesting question! There has been research in the area, with known small molecule insulin mimetics (including L-783,281 ; TE-17411 ; VOSO4 ; vanadate). One patent in 2002 specifically describes an insulin-mimetic pump (held by William Van Antwerp, US Patent 6,461,331). And here's a list of known insulin receptor agonists: National Drug File - Insulin Receptor Agonists - Terms Toxicity appears to have been a problem for vanadium compounds [role of cellula...] and while there's work on minimizing it without changing efficacy, it seems not to have gotten popular enough to risk going through clinical trials. That might be one factor, but surely people have done better! In a fit of wild conjecture: perhaps insulin mimetics are at risk of unintentionally binding to insulin-like growth factor receptor, occasionally linked to cancer [The insulin-like growth factor system and cancer.]. That definitely doesn't rule out an insulin mimetic, but it could be a reason drug developers are wary. ... let's see what more experienced voices have to add. Continue reading >>
- Gut molecule that blocks ‘hunger hormone’ may spur new treatments for diabetes, anorexia
- Effects of Insulin Plus Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs) in Treating Type 1 Diabetes Mellitus: A Systematic Review and Meta-Analysis
- Why there’s been a dangerous diabetes spike around the globe
Differential Endocytosis And Signaling Dynamics Of Insulin Receptor Variants Ir-a And Ir-b
Insulin signaling comprises a complex cascade of events, playing a key role in the regulation of glucose metabolism and cellular growth. Impaired response to insulin is the hallmark of diabetes, whereas upregulated insulin activity occurs in many cancers. Two splice variants of the insulin receptor (IR) exist in mammals: IR-A, lacking exon 11, and full-length IR-B. Although considerable biochemical data exist on insulin binding and downstream signaling, little is known about the dynamics of the IR itself. We created functional IR transgenes fused with visible fluorescent proteins for use in combination with biotinamido-caproyl insulin and streptavidin quantum dots. Using confocal and structured illumination microscopy, we visualized the endocytosis of both isoforms in living and fixed cells and demonstrated a higher rate of endocytosis of IR-A than IR-B. These differences correlated with higher and sustained activation of IR-A in response to insulin and with distinctive ERK1/2 activation profiles and gene transcription regulation. In addition, cells expressing IR-B showed higher AKT phosphorylation after insulin stimulation than cells expressing IR-A. Taken together, these results suggest that IR signaling is dependent on localization; internalized IRs regulate mitogenic activity, whereas metabolic balance signaling occurs at the cell membrane. Insulin signaling comprises a complex cascade of events, playing a key role in the regulation of glucose metabolism and in cellular growth. Impaired response to insulin is the hallmark of diabetes, whereas upregulated insulin activity occurs in many cancers (Papa et al., 1993; Bailyes et al., 1997; Pandini et al., 1999; Saltiel and Kahn, 2001; Pandini et al., 2002). Insulin binds to specific receptors at the cell surface, trigger Continue reading >>
- Researchers identify gene variants linked to both type 2 diabetes and CHD risk
- Differential Weight Loss Effects on Type 2 Diabetes Remission Among Adults
- Effects of Insulin Plus Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs) in Treating Type 1 Diabetes Mellitus: A Systematic Review and Meta-Analysis
Insulin Receptor Signaling And Glucagon-like Peptide 1 Effects On Pancreatic Beta Cells
Abstract Glucagon-like peptide-1 (GLP-1) is a potent gluco-incretin hormone, which plays a central role on pancreatic beta cell proliferation, survival and insulin secreting activity and whose analogs are used for treating hyperglycemia in type 2 diabetes mellitus. Notably, abnormal insulin signaling affects all the above-mentioned aspects on pancreatic beta cells. The aim of our study was to investigate whether the protective effects of GLP1-1 on beta cells are affected by altered insulin receptor signaling. To this end, several effects of GLP-1 were studied in INS-1E rat beta cells transfected either with an inhibitor of insulin receptor function (i.e., the Ectonucleotide Pyrophosphatase Phosphodiesterase 1, ENPP1), or with insulin receptor small interfering RNA, as well as in control cells. Crucial experiments were carried out also in a second cell line, namely the βTC-1 mouse beta cells. Our data indicate that in insulin secreting beta cells in which either ENPP1 was up-regulated or insulin receptor was down-regulated, GLP-1 positive effects on several pancreatic beta cell activities, including glucose-induced insulin secretion, cell proliferation and cell survival, were strongly reduced. Further studies are needed to understand whether such a scenario occurs also in humans and, if so, if it plays a role of clinical relevance in diabetic patients with poor responsiveness to GLP-1 related treatments. Figures Citation: Caporarello N, Parrino C, Trischitta V, Frittitta L (2017) Insulin receptor signaling and glucagon-like peptide 1 effects on pancreatic beta cells. PLoS ONE 12(8): e0181190. Editor: Claudia Miele, Consiglio Nazionale delle Ricerche, ITALY Received: February 7, 2017; Accepted: June 26, 2017; Published: August 2, 2017 Copyright: © 2017 Caporarello et al Continue reading >>
Insulin Receptor And Type 2 Diabetes
Part 2 of two animations about type 2 diabetes. This animation describes the role of the insulin receptor in type 2 diabetes. It focuses on the recent discovery of how the hormone insulin actually binds to the receptor on the surface of cells, as determined by Professor Mike Lawrence's laboratory at the Walter and Eliza Hall Institute. Insulin binds to the receptor protein on the cell surface and instructs the cell to take up glucose from the blood for use as an energy source. In type 2 diabetes, we believe that insulin binds to the receptor normally, but the signal is not sent into the cell, the cells do not take up glucose and the resulting high blood glucose levels cause organ damage over time. Understanding how insulin interacts with its receptor is fundamental to the development of novel insulin for the treatment of diabetes. Maja Divjak, 2015 Continue reading >>
- Effects of Insulin Plus Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs) in Treating Type 1 Diabetes Mellitus: A Systematic Review and Meta-Analysis
- Relative contribution of type 1 and type 2 diabetes loci to the genetic etiology of adult-onset, non-insulin-requiring autoimmune diabetes
- Relative effectiveness of insulin pump treatment over multiple daily injections and structured education during flexible intensive insulin treatment for type 1 diabetes: cluster randomised trial (REPOSE)
Physiologic Effects Of Insulin
Stand on a streetcorner and ask people if they know what insulin is, and many will reply, "Doesn't it have something to do with blood sugar?" Indeed, that is correct, but such a response is a bit like saying "Mozart? Wasn't he some kind of a musician?" Insulin is a key player in the control of intermediary metabolism, and the big picture is that it organizes the use of fuels for either storage or oxidation. Through these activities, insulin has profound effects on both carbohydrate and lipid metabolism, and significant influences on protein and mineral metabolism. Consequently, derangements in insulin signalling have widespread and devastating effects on many organs and tissues. The Insulin Receptor and Mechanism of Action Like the receptors for other protein hormones, the receptor for insulin is embedded in the plasma membrane. The insulin receptor is composed of two alpha subunits and two beta subunits linked by disulfide bonds. The alpha chains are entirely extracellular and house insulin binding domains, while the linked beta chains penetrate through the plasma membrane. The insulin receptor is a tyrosine kinase. In other words, it functions as an enzyme that transfers phosphate groups from ATP to tyrosine residues on intracellular target proteins. Binding of insulin to the alpha subunits causes the beta subunits to phosphorylate themselves (autophosphorylation), thus activating the catalytic activity of the receptor. The activated receptor then phosphorylates a number of intracellular proteins, which in turn alters their activity, thereby generating a biological response. Several intracellular proteins have been identified as phosphorylation substrates for the insulin receptor, the best-studied of which is insulin receptor substrate 1 or IRS-1. When IRS-1 is activa Continue reading >>
Insr - Insulin Receptor Precursor - Homo Sapiens (human) - Insr Gene & Protein
This subsection describes interesting single amino acid sites on the sequence that are not defined in any other subsection. This subsection can be displayed in different sections (Function, PTM / Processing, Pathology and Biotech) according to its content.More...Sitei This subsection of the Function section describes the interaction between a single amino acid and another chemical entity. Priority is given to the annotation of physiological ligands.More...Binding sitei Manual validated information which has been generated by the UniProtKB automatic annotation system. More Manual assertion according to rulesi Manually curated information for which there is published experimental evidence. More Manual assertion based on experiment ini Cited for: X-RAY CRYSTALLOGRAPHY (1.65 ANGSTROMS) OF 1005-1310 IN COMPLEX WITH ATP AND IRS2, CATALYTIC ACTIVITY, PHOSPHORYLATION AT TYR-1185; TYR-1189 AND TYR-1190, INTERACTION WITH IRS2. This subsection of the Function section describes the interaction between a single amino acid and another chemical entity. Priority is given to the annotation of physiological ligands.More...Binding sitei Manual validated information which has been generated by the UniProtKB automatic annotation system. More Manual assertion according to rulesi Manually curated information for which there is published experimental evidence. More Manual assertion based on experiment ini Cited for: X-RAY CRYSTALLOGRAPHY (1.65 ANGSTROMS) OF 1005-1310 IN COMPLEX WITH ATP AND IRS2, CATALYTIC ACTIVITY, PHOSPHORYLATION AT TYR-1185; TYR-1189 AND TYR-1190, INTERACTION WITH IRS2. This subsection of the Function section is used for enzymes and indicates the residues directly involved in catalysis.More...Active sitei Manually curated information for which there is published experiment Continue reading >>
The Insulin Receptor And Its Cellular Targets1
The pleiotropic actions of insulin are mediated by a single receptor tyrosine kinase. Structure/function relationships of the insulin receptor have been conclusively established, and the early steps of insulin signaling are known in some detail. A generally accepted paradigm is that insulin receptors, acting through insulin receptor substrates, stimulate the lipid kinase activity of phosphatidylinositol 3-kinase. The rapid rise in Tris-phosphorylated inositol (PIP3) that ensues triggers a cascade of PIP3-dependent serine/threonine kinases. Among the latter, Akt (a product of the akt protooncogene) and atypical protein kinase C isoforms are thought to be involved in insulin regulation of glucose transport and oxidation; glycogen, lipid, and protein synthesis; and modulation of gene expression. The presence of multiple insulin-regulated, PIP3-dependent kinases is consistent with the possibility that different pathways are required to regulate different biological actions of insulin. Additional work remains to be performed to understand the distal components of insulin signaling. Moreover, there exists substantial evidence for insulin receptor substrate- and/or phosphatidylinositol 3-kinase-independent pathways of insulin action. The ultimate goal of these investigations is to provide clues to the pathogenesis and treatment of the insulin resistant state that is characteristic of type 2 diabetes. The prevalence of obesity in children and adults is increasing worldwide. This demonstrates that the primary cause of obesity lies in environmental and behavioral changes rather than in genetic modifications. Among the environmental influences on body weight regulation, the percentage of fat energy of the everyday diet plays an important role. In many low-income countries, the per Continue reading >>
- Cellular markers of aging could reveal how insulin-producing cells begin to fail in type 2 diabetes
- Pancreatic cancer and diabetes – a cellular case of chicken and egg
- Effects of Insulin Plus Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs) in Treating Type 1 Diabetes Mellitus: A Systematic Review and Meta-Analysis
Reduced Expression Of Insulin Receptors In The Kidneys Of Insulin-resistant Rats
Abstract Insulin resistance is accompanied by hyperinsulinemia and activation of the renin-angiotensin system, both of which are associated with hypertension. Because the kidney plays a major role in the regulation of blood pressure, we studied the regulation of insulin receptor expression in the kidney during states of insulin resistance. Using two rat models of insulin resistance, Western blot analysis demonstrated a significant reduction in the expression of insulin receptor subunits in the kidney compared to lean control rats. Treatment of insulin resistance in Zucker rats with the insulin-sensitizing drug rosiglitazone partially restored renal insulin receptor levels. Conversely, treatment with the angiotensin II type 1 receptor (AT1) antagonist candesartan increased renal insulin receptor expression compared to untreated rats. Streptozotocin-induced hyperglycemia, which results from hypoinsulinemia, reduced expression of renal insulin receptors. Hyperinsulinemia induced by insulin infusion, however, did not produce a similar effect. In conclusion, insulin receptors are downregulated in the kidneys of insulin resistant rats, possibly mediated by hyperglycemia and angiotensin II. RESULTS An outline of the study designs is provided in Figure 1. Peptide-blocking experiments confirmed the specificity of the commercial IR antibodies used in this study (Figure 2). The binding of the IR-α and IR-β antibodies was completely inhibited in the presence of their respective peptides (Ab+P), whereas the specific bands corresponding to the expected size for IR-α (125 kD) and IR-β (95 kD) were observed in the absence of blocking peptides (Ab). Figure 2. Specificity of insulin receptor antibodies (IR-α and IR-β). For peptide-blocking tests, equal amounts of protein from whole Continue reading >>
The Insulin Receptor And Its Signal Transduction Network
Go to: 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. Go to: INTRODUCTION Insulin is an a Continue reading >>
- International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #59: Mechanisms of insulin signal transduction Part 3 of 8
- NIHR Signal Insulin pumps not much better than multiple injections for intensive control of type 1 diabetes
- Effects of Insulin Plus Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs) in Treating Type 1 Diabetes Mellitus: A Systematic Review and Meta-Analysis
Insulin Receptors
Insulin Receptors are areas on the outer part of a cell that allow the cell to join or bind with insulin that is in the blood. When the cell and insulin bind together, the cell can take glucose (sugar) from the blood and use it for energy. Phe 25B is the active site of insulin. Insulin makes contact with the insulin receptor in a hydrophobic pocket. This causes the C-terminus of the B chain to separate from the N-terminus of the A chain. This allows for more binding and reactions to occur. Although insulin stimulates a vast array of responses in its target tissues skeletal muscle, adipose tissue and the liver, they all appear to be initiated by an interaction between insulin and a protein receptor located on the cell membranes of these tissues. The insulin receptor protein can only be found on these tissues, which explains the specificity of the action. When insulin binds it induces a conformational change within the receptor, known as oligomerization, which leads to autophosphorylation of specific tyrosine residues in the cytoplasmic domains of the receptors. Insulin Receptor To view the insulin receptor in cartoon form Continue reading >>
