1-20 of 1472 Search Results for

irs-2-insulin-receptor-substrate-2

Follow your search
Access your saved searches in your account

Would you like to receive an alert when new items match your search?
Close Modal
Sort by
Meeting Abstracts
Journal: Diabetes
Diabetes 1999;48(3):640–642
Published: 01 March 1999
...A Bektas; J H Warram; M F White; A S Krolewski; A Doria We investigated whether variability at the insulin receptor substrate (IRS)-2 locus plays a role in the etiology of early-onset autosomal dominant type 2 diabetes. By means of radiation hybrid mapping, we placed the human IRS-2 gene on 13q...
Images
Proposed model for mechanisms regulating β-cell mass in type <span class="search-highlight">2</span> diabetes. Be...
Published: 01 December 2005
FIG. 4. Proposed model for mechanisms regulating β-cell mass in type 2 diabetes. Before onset of diabetes, insulin resistance may lead to transient postprandial hyperglycemic excursions. Other factors modulating β-cell mass may include dyslipidemia, leptin, and cytokines. Genetic predisposition to... More
Images
Two possible scenarios for pathogenesis of diabetes. <em>A</em>: In...
Published: 01 February 2002
FIG. 6. Two possible scenarios for pathogenesis of diabetes. A: Independent causality for insulin resistance and β-cell dysregulation. Both genetic predisposition and environmental factors may induce insulin resistance and simultaneously lead to inability of the β-cells to compensate adequately for insulin resistance. In most cases, both defects will be necessary and sufficient for final conversion to diabetes. Genes for diabetes have not yet been clearly defined. B: Diabetes seen as dysfunction of the closed-loop relationship between insulin resistance and insulin secretory response. All signals relating secretion and action have not been defined; thus, it is not yet clear why β-cells upregulate their function when faced with insulin resistance. Diabetes may result from failure of appropriate signaling between insulin-sensitive and insulin-secreting cells. IRS-2, insulin receptor substrate 2. FIG. 6. Two possible scenarios for pathogenesis of diabetes. A: Independent causality for insulin resistance and β-cell dysregulation. Both genetic predisposition and environmental factors may induce insulin resistance and simultaneously lead to inability of the β-cells to compensate adequately for insulin resistance. In most cases, both defects will be necessary and sufficient for final conversion to diabetes. Genes for diabetes have not yet been clearly defined. B: Diabetes seen as dysfunction of the closed-loop relationship between insulin resistance and insulin secretory response. All signals relating secretion and action have not been defined; thus, it is not yet clear why β-cells upregulate their function when faced with insulin resistance. Diabetes may result from failure of appropriate signaling between insulin-sensitive and insulin-secreting cells. IRS-2, insulin receptor substrate 2. More
Images
Proposed interaction of Cav-1 and eNOS in the pathogenesis of endothelial d...
Published: 14 October 2015
Figure 1 Proposed interaction of Cav-1 and eNOS in the pathogenesis of endothelial dysfunction. IRS-1/2, insulin receptor substrate 1/2. Figure 1. Proposed interaction of Cav-1 and eNOS in the pathogenesis of endothelial dysfunction. IRS-1/2, insulin receptor substrate 1/2. More
Images
PKR is at the confluence of inflammatory and metabolic signals. Infectious ...
Published: 16 January 2014
Figure 1 PKR is at the confluence of inflammatory and metabolic signals. Infectious agents (virus) and nutrients (fatty acids) can activate PKR, which, in turn, directly and indirectly activate inflammatory activity. Inflammatory activity can be triggered by the direct action of PKR on JNK or indi... More
Images
A schematic representation of the proposed molecular pathways whereby APPL1...
Published: 17 October 2011
FIG. 8. A schematic representation of the proposed molecular pathways whereby APPL1 enhances insulin-evoked Akt-dependent NO production and blocks insulin-induced ERK1/2-dependent ET-1 expression in endothelial cells. IRS, insulin receptor substrate; MEK1/2, mitogen-activated protein kinase kinase... More
Images
Enhanced Nrf2 activity induces earlier onset of <span class="search-highlight">IR</span> in Lep<em><sup>ob/ob</sup></em>...
Published: 15 November 2012
FIG. 2. Enhanced Nrf2 activity induces earlier onset of IR in Lepob/ob mice. Blood glucose concentration during glucose tolerance test (A) and insulin tolerance test (B) assay from 6-week-old mice (black squares, OB mice; gray squares, OBKeap1-KD mice; n = 5 to 6) is shown. C: Gene expression in SKM (n = 5 to 6). Immunoblot analysis of ser473-phospholylated-Akt (p-Akt), total-Akt (Akt) (D), and Glut4 (E) in SKM of 6-week-old mice is shown. $P < 0.05, Keap1-KD mice compared with WT mice; #P < 0.05, OB mice compared with WT mice; *P < 0.05, OBKeap1-KD mice compared with OB mice. Insr, insulin receptor; Irs, insulin receptor substrate; PGC, peroxisome proliferator–activated receptor γ coactivator; wk, weeks. FIG. 2. Enhanced Nrf2 activity induces earlier onset of IR in Lepob/ob mice. Blood glucose concentration during glucose tolerance test (A) and insulin tolerance test (B) assay from 6-week-old mice (black squares, OB mice; gray squares, OBKeap1-KD mice; n = 5 to 6) is shown. C: Gene expression in SKM (n = 5 to 6). Immunoblot analysis of ser473-phospholylated-Akt (p-Akt), total-Akt (Akt) (D), and Glut4 (E) in SKM of 6-week-old mice is shown. $P < 0.05, Keap1-KD mice compared with WT mice; #P < 0.05, OB mice compared with WT mice; *P < 0.05, OBKeap1-KD mice compared with OB mice. Insr, insulin receptor; Irs, insulin receptor substrate; PGC, peroxisome proliferator–activated receptor γ coactivator; wk, weeks. More
Images
Decreased activity of LARG caused by the Tyr1306Cys substitution is associa...
Published: 01 May 2006
FIG. 2. Decreased activity of LARG caused by the Tyr1306Cys substitution is associated with higher skeletal muscle insulin sensitivity in Pima Indians. Rho proteins cycle between an inactive GDP-bound and an active GTP-bound state that is under the regulation of GEFs and GTPase-activating proteins... More
Images
Feedback inhibition of <span class="search-highlight">IRS</span> signaling cascade pathways. Once <span class="search-highlight">insulin</span> has act...
Published: 14 June 2013
FIG. 2. Feedback inhibition of IRS signaling cascade pathways. Once insulin has activated IRS signal transduction pathways in cells, after a period of time there are internal physiological feedback inhibition signals (indicated by red arrows) that ensure that the “insulin signal” is not chronically sustained. Under hyperinsulinemic conditions, this feedback results in chronic desensitization of IRS signal transduction and contributes to the insulin-resistant state. Downstream activation of extracellular signal–regulated kinases-1 and -2 (Erk-1/2) (as described in Fig. 1 ) can lead to Erk-1/2 protein kinase–mediated serine phosphorylation (pS) of IRS-1/2, which results in dissociation of the insulin receptor and IRS-1/2 interaction together with IRS-1/2 degradation. This is one route of delayed feedback inhibition of insulin signaling. 3-Phosphoinositide-dependent protein kinase-1 (PDK1) activation can result in downstream activation atypical protein kinase-C (PKC) isoforms, such as PKCζ, which can also serine phosphorylate (pS) IRS-1/2 to promote their degradation, representing another route of delayed feedback inhibition for insulin signal transduction. In contrast, protein kinase-B (PKB; also known as Akt) can serine phosphorylate IRS-1/2 at alternative sites to stabilize IRS-1/2 tyrosine phosphorylation state and thus enhance downstream signaling. However, PKB-mediated phosphorylation activation of some of its other substrates can have a more dominant-negative feedback effect on IRS signaling. Both target of rapamycin complex-1 (TORC1) and p70 S6-ribosomal kinase (p70S6K) (the latter amplified by PDK1 phosphorylation) can serine phosphorylate IRS-1/2 to promote their degradation, which then dampens IRS signaling. This denotes a third route for delayed feedback inhibition of insulin signaling. A fourth route may be via the Src-homology domain–tyrosine phosphatase-2 (SHP2), which upon binding to certain phosphotyrosine residues on IRS-1/2 becomes activated and can then remove phosphate from phosphotyrosines on IRS-1/2, thus dampening downstream signaling. FoxO1 and -3a have been shown to be critical factors for driving IRS-2 expression under basal conditions, especially FoxO3a in β-cells ( 15 ). But when IRS signaling is triggered by insulin, FoxO1/3a transcriptional activity is inactivated, resulting in another route of temporal feedback inhibition by decreasing IRS-2 expression. Several of these IRS signaling feedback mechanisms have indeed been shown to be present in pancreatic β-cells ( 2 – 4 , 15 , 16 ). Another consideration for feedback inhibition of insulin action is that when insulin binds to its receptor, the insulin/insulin receptor complex is internalized into the cell where it dissociates in an endosomal compartment, allowing the “free” insulin receptor to return to the surface ( 18 , 19 ). When insulin levels are high, this cycle is biased toward there being minimal insulin receptors on the surface of the cell with the majority being internalized, and acts as an additional physiological mechanism to prevent prolonged activation of IRS signal transduction by insulin. Under chronic hyperinsulinemia, insulin receptor internalization makes a contribution to insulin resistance. This long-term hyperinsulinemia also leads to downregulation of insulin receptor gene expression by a mechanism not yet well defined. FIG. 2. Feedback inhibition of IRS signaling cascade pathways. Once insulin has activated IRS signal transduction pathways in cells, after a period of time there are internal physiological feedback inhibition signals (indicated by red arrows) that ensure that the “insulin signal” is not chronically sustained. Under hyperinsulinemic conditions, this feedback results in chronic desensitization of IRS signal transduction and contributes to the insulin-resistant state. Downstream activation of extracellular signal–regulated kinases-1 and -2 (Erk-1/2) (as described in Fig. 1) can lead to Erk-1/2 protein kinase–mediated serine phosphorylation (pS) of IRS-1/2, which results in dissociation of the insulin receptor and IRS-1/2 interaction together with IRS-1/2 degradation. This is one route of delayed feedback inhibition of insulin signaling. 3-Phosphoinositide-dependent protein kinase-1 (PDK1) activation can result in downstream activation atypical protein kinase-C (PKC) isoforms, such as PKCζ, which can also serine phosphorylate (pS) IRS-1/2 to promote their degradation, representing another route of delayed feedback inhibition for insulin signal transduction. In contrast, protein kinase-B (PKB; also known as Akt) can serine phosphorylate IRS-1/2 at alternative sites to stabilize IRS-1/2 tyrosine phosphorylation state and thus enhance downstream signaling. However, PKB-mediated phosphorylation activation of some of its other substrates can have a more dominant-negative feedback effect on IRS signaling. Both target of rapamycin complex-1 (TORC1) and p70 S6-ribosomal kinase (p70S6K) (the latter amplified by PDK1 phosphorylation) can serine phosphorylate IRS-1/2 to promote their degradation, which then dampens IRS signaling. This denotes a third route for delayed feedback inhibition of insulin signaling. A fourth route may be via the Src-homology domain–tyrosine phosphatase-2 (SHP2), which upon binding to certain phosphotyrosine residues on IRS-1/2 becomes activated and can then remove phosphate from phosphotyrosines on IRS-1/2, thus dampening downstream signaling. FoxO1 and -3a have been shown to be critical factors for driving IRS-2 expression under basal conditions, especially FoxO3a in β-cells (15). But when IRS signaling is triggered by insulin, FoxO1/3a transcriptional activity is inactivated, resulting in another route of temporal feedback inhibition by decreasing IRS-2 expression. Several of these IRS signaling feedback mechanisms have indeed been shown to be present in pancreatic β-cells (2–4,15,16). Another consideration for feedback inhibition of insulin action is that when insulin binds to its receptor, the insulin/insulin receptor complex is internalized into the cell where it dissociates in an endosomal compartment, allowing the “free” insulin receptor to return to the surface (18,19). When insulin levels are high, this cycle is biased toward there being minimal insulin receptors on the surface of the cell with the majority being internalized, and acts as an additional physiological mechanism to prevent prolonged activation of IRS signal transduction by insulin. Under chronic hyperinsulinemia, insulin receptor internalization makes a contribution to insulin resistance. This long-term hyperinsulinemia also leads to downregulation of insulin receptor gene expression by a mechanism not yet well defined. More
Images
Overview of the major stimuli resulting in <span class="search-highlight">insulin</span> resistance. Multiple fac...
Published: 17 January 2013
FIG. 1. Overview of the major stimuli resulting in insulin resistance. Multiple factors including reduced mitochondrial content and/or function may predispose certain individuals to intramyocellular lipid accumulation and insulin resistance. IMCL promotes the production of diacylglycerol, activati... More
Images
Proposed signaling of TNF-α− and leptin-induced EL upregulation in primary ...
Published: 16 September 2011
FIG. 5. Proposed signaling of TNF-α− and leptin-induced EL upregulation in primary placental ECs. TNF receptor (TNFR) can induce NF-κB–related gene expression via TNF receptor type 1–associated death domain protein (TRADD) and receptor-interacting serine/threonine-protein kinase (RIP), as well as via TNF receptor–associated factor 2 (TRAF2)/NF-κB–inducing kinase (NIK) ( 47 ). Extracellular signal–related kinase (ERK)-1/2 can be activated by TNF receptor via MAP kinase activating death domain (MADD) ( 48 ) or via TNF receptor-associated factor 2 ( 49 ). The leptin receptor (LEPR) can induce ERK1/2 activation via protein tyrosine phosphatase, non-receptor type 11 (SHP2)/growth factor receptor-bound protein 2 (GRB2) and/or NF-κB–related gene expression by insulin receptor substrate (IRS)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) signaling ( 50 ). Inhibition of ERK1/2 signaling by UO126 had no effect on TNF-α− and leptin-induced upregulation of the EL gene (LIPG) expression, whereas the NF-κB inhibitor BAY completely abolished TNF-α−induced EL upregulation. BAY only in part (not significantly) block leptin-induced EL upregulation in primary placental ECs, suggesting that another pathway is involved. FIG. 5. Proposed signaling of TNF-α− and leptin-induced EL upregulation in primary placental ECs. TNF receptor (TNFR) can induce NF-κB–related gene expression via TNF receptor type 1–associated death domain protein (TRADD) and receptor-interacting serine/threonine-protein kinase (RIP), as well as via TNF receptor–associated factor 2 (TRAF2)/NF-κB–inducing kinase (NIK) (47). Extracellular signal–related kinase (ERK)-1/2 can be activated by TNF receptor via MAP kinase activating death domain (MADD) (48) or via TNF receptor-associated factor 2 (49). The leptin receptor (LEPR) can induce ERK1/2 activation via protein tyrosine phosphatase, non-receptor type 11 (SHP2)/growth factor receptor-bound protein 2 (GRB2) and/or NF-κB–related gene expression by insulin receptor substrate (IRS)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) signaling (50). Inhibition of ERK1/2 signaling by UO126 had no effect on TNF-α− and leptin-induced upregulation of the EL gene (LIPG) expression, whereas the NF-κB inhibitor BAY completely abolished TNF-α−induced EL upregulation. BAY only in part (not significantly) block leptin-induced EL upregulation in primary placental ECs, suggesting that another pathway is involved. More
Images
<em>Upper panel</em>: Summary of the pathway by which <span class="search-highlight">insulin</span> binds...
Published: 16 October 2012
FIG. 3. Upper panel: Summary of the pathway by which insulin binds to and activates its receptor, thereby enhancing signaling through the phosphatidylinositol-3 kinase (PI-3-K) Akt pathway to phosphorylate endothelial NOS (eNOS) and increase its enzymatic activity, augmenting the production of NO. NO can readily diffuse to nearby smooth muscle cells (SMCs) and act both to increase the production of cyclic GMP and to directly nitrosylate specific proteins to promote smooth muscle relaxation. Lower panel: Effect of this relaxation on resistance and terminal arterioles is illustrated. Relaxing the former can increase overall blood flow, while relaxing the latter increases the number of capillaries perfused within the tissue (indicated by the increased numbers of red capillaries in the right panel) at any one time. It should be noted that this is a dynamic process, and because of flowmotion, the particular capillaries that are perfused at any time will vary over time scales from 2 to 40 s. IRS, insulin receptor substrate. FIG. 3. Upper panel: Summary of the pathway by which insulin binds to and activates its receptor, thereby enhancing signaling through the phosphatidylinositol-3 kinase (PI-3-K) Akt pathway to phosphorylate endothelial NOS (eNOS) and increase its enzymatic activity, augmenting the production of NO. NO can readily diffuse to nearby smooth muscle cells (SMCs) and act both to increase the production of cyclic GMP and to directly nitrosylate specific proteins to promote smooth muscle relaxation. Lower panel: Effect of this relaxation on resistance and terminal arterioles is illustrated. Relaxing the former can increase overall blood flow, while relaxing the latter increases the number of capillaries perfused within the tissue (indicated by the increased numbers of red capillaries in the right panel) at any one time. It should be noted that this is a dynamic process, and because of flowmotion, the particular capillaries that are perfused at any time will vary over time scales from 2 to 40 s. IRS, insulin receptor substrate. More
Images
<span class="search-highlight">Insulin</span> sensitivity in butyrate-treated mice. <em>A</em>: Fasting g...
Published: 14 April 2009
FIG. 2. Insulin sensitivity in butyrate-treated mice. A: Fasting glucose. Tail vein blood was used for glucose assay after 16 h fasting during the period of high-fat diet feeding. B: Fasting insulin. The insulin level was determined at 16 weeks on high-fat diet in fasting condition with a Lincoplex kit (MADPK model). C: Intraperitoneal insulin tolerance in butyrate-treated mice. Intraperitoneal insulin tolerance testing was performed at 12 weeks on high-fat diet (at 16 weeks of age). In AC, data are the means ± SE (n = 9). *P < 0.05, **P < 0.001 by Student's t test. D: HOMA-IR. After an overnight fast, blood glucose and insulin were measured and used to determine insulin sensitivity through HOMA-IR (IR = fasting insulin mU/ml × fasting glucose mg/dl ÷ 405). Values are the means ± SE (n = 8 mice). **P < 0.001. E: Insulin signaling. The gastrocnemius muscle was isolated after insulin (0.75 units/kg) injection in mice for 30 min and used to prepare the whole-cell lysate for immunoblot. The mice on high-fat diet for 13 weeks were used in the signaling assay. F: Signal quantification. The blot signal in E was quantified and presented after normalization with protein loading. **P < 0.001 (n = 2). IRS, insulin receptor substrate. FIG. 2. Insulin sensitivity in butyrate-treated mice. A: Fasting glucose. Tail vein blood was used for glucose assay after 16 h fasting during the period of high-fat diet feeding. B: Fasting insulin. The insulin level was determined at 16 weeks on high-fat diet in fasting condition with a Lincoplex kit (MADPK model). C: Intraperitoneal insulin tolerance in butyrate-treated mice. Intraperitoneal insulin tolerance testing was performed at 12 weeks on high-fat diet (at 16 weeks of age). In A–C, data are the means ± SE (n = 9). *P < 0.05, **P < 0.001 by Student's t test. D: HOMA-IR. After an overnight fast, blood glucose and insulin were measured and used to determine insulin sensitivity through HOMA-IR (IR = fasting insulin mU/ml × fasting glucose mg/dl ÷ 405). Values are the means ± SE (n = 8 mice). **P < 0.001. E: Insulin signaling. The gastrocnemius muscle was isolated after insulin (0.75 units/kg) injection in mice for 30 min and used to prepare the whole-cell lysate for immunoblot. The mice on high-fat diet for 13 weeks were used in the signaling assay. F: Signal quantification. The blot signal in E was quantified and presented after normalization with protein loading. **P < 0.001 (n = 2). IRS, insulin receptor substrate. More
Images
Activation of the <span class="search-highlight">IRS</span> signaling cascade pathways. A peptide ligand such as ...
Published: 14 June 2013
FIG. 1. Activation of the IRS signaling cascade pathways. A peptide ligand such as insulin or insulin-like growth factor-1 (IGF-1) binds to its receptor, activating the intrinsic tyrosine kinase activity of that receptor that then tyrosine phosphorylates (pY) adaptor molecules such as IRS-1 or -2. Other receptor tyrosine kinases, or receptors that activate tyrosine kinases such as Janus kinase (JAK), can also activate IRS signaling. This leads to activation of two major signaling cascades, the Ras-Raf-mitogen-activated protein kinase (MAPK) pathway (orange) and the phosphatidylinositol-3′-kinase (PI3’K)/protein kinase-B (PKB; also known as Akt) signaling pathway (green). For the Ras-Raf-MAPK pathway, growth factor receptor–bound protein-2 (Grb2)/son of sevenless (SOS) protein complex binds to specific phosphorylated tyrosines on IRS-1/2, activating the GTP/GDP exchange activity of SOS, which loads p21Ras (Ras) with GTP to activate Ras, leading to phosphorylation of the serine/threonine protein kinase Raf-1, which then phosphorylates the mitogen-activated protein kinase kinase (MEK1), which is then activated to phosphorylate the extracellular signal–regulated kinases-1 and -2 (Erk-1/2). Phospho-activated Erk-1/2 can then directly (or indirectly via phospho-activation of other kinases such as p90 ribosomal serine kinase [p90RSK]) serine/threonine phosphorylate certain transcription factors, such as cFos and E-twenty-six–like transcription factor 1 (Elk-1), to upregulate gene transcription. Phospho-activated Erk-1/2 can also phosphorylate MAPK–interacting kinase (Mnk) 1 and 2, leading to phosphorylation activation of the eukaryotic initiation factor-4e (eIF4e) in a complex also containing eIF4a and eIF4G to increase general protein synthesis at the level initiation phase of translational control. For the PI3’K/PKB signaling pathway, the p85 regulatory subunit of PI3’K docks to other specific phosphorylated tyrosine sites on IRS-1/2 that then activates its p110 catalytic activity. This catalyzes the phosphorylation of phosphatidylinositol-4, 5-bisphophaste [PI(4,5)P2] to phosphatidylinositol-3, 4, 5-trisphophaste [PI(3,4,5)P3], which then activates 3-phosphoinositide dependent protein kinase-1 (PDK1). PDK1 then threonine (pT) phosphorylates PKB for PKB activation, which can be amplified by serine phosphorylation (pS) of PKB by the target of rapamycin complex-2 (TORC2; which includes the protein kinase, mammalian target of rapamycin [mTOR] and associated proteins rictor and mLST8). PKB has a plethora of serine/threonine phosphorylation substrates. PKB-mediated phosphorylation of the tuberous sclerosis protein-1/2 complex (TSC1/2) inhibits its GTPase activating protein activity to then load the Ras homolog enriched in brain (Rheb) protein with GTP (RhebGTP), leading to activation of the TORC1 (which includes mTOR and associated proteins raptor and mLST8). TORC1 can then serine/threonine phosphorylate a series of substrates. This includes the eIF4e-binding protein-1 (4e-BP1) that releases it from eIF4e binding, enabling eIF4e to associate with eIF4a and eIF4G in a complex with Mnk, where Mnk then phosphorylates eIF4e to increase rates of protein synthesis translation. This also shows how the Ras/Raf/Erk and PI3’K/PKB signaling pathways can coordinate to give a tight translational control of protein synthesis. TORC1 can also phosphorylate and subsequently activate p70 S6-ribosomal kinase (p70S6K), which can lead to an increase in the elongation phase of protein synthesis translation. PDK1 can threonine phosphorylate p70S6K to amplify this effect. TORC1 also phosphorylates Unc-51–like kinases-1/2 (ULK-1/2; also known as autophagy gene-1), which results in inhibition of autophagy. Among PKB’s other phosphorylation substrates are proteins involved in the apoptotic process such as Bcl-antagonist of cell death (BAD) and X-linked inhibitor of apoptosis protein (XIAP), outlining a mechanism whereby PKB is antiapoptotic. PKB phosphorylation of the transcription factors FoxO1 and FoxO3a causes their removal from the nucleus and promotes their degradation, causing an inhibition of FoxO1/3a-mediated transcription. Phosphorylation of glycogen synthase kinase-3 (GSK3) by PKB inhibits GSK3 activity, resulting in increased glycogen deposition and cell growth. Under certain circumstances, PKB can also influence increases in cell growth by phosphorylating the cell-cycle inhibitor proteins p21 cyclin-dependent kinase inhibitor-1 (p21CIP) and p27 cyclin-dependent-kinase inhibitor (p27KIP). PKB can also phosphorylate-inhibit phosphodiesterase-3b (PDE3b) to elevate intracellular cAMP ([cAMP]i) levels. Many of these IRS signaling elements have been shown to be expressed and active and play important roles in pancreatic β-cells in terms of certain functions, growth, and survival (rev. in 2 – 4 ), and these are indicated by a yellow highlighted halo. FIG. 1. Activation of the IRS signaling cascade pathways. A peptide ligand such as insulin or insulin-like growth factor-1 (IGF-1) binds to its receptor, activating the intrinsic tyrosine kinase activity of that receptor that then tyrosine phosphorylates (pY) adaptor molecules such as IRS-1 or -2. Other receptor tyrosine kinases, or receptors that activate tyrosine kinases such as Janus kinase (JAK), can also activate IRS signaling. This leads to activation of two major signaling cascades, the Ras-Raf-mitogen-activated protein kinase (MAPK) pathway (orange) and the phosphatidylinositol-3′-kinase (PI3’K)/protein kinase-B (PKB; also known as Akt) signaling pathway (green). For the Ras-Raf-MAPK pathway, growth factor receptor–bound protein-2 (Grb2)/son of sevenless (SOS) protein complex binds to specific phosphorylated tyrosines on IRS-1/2, activating the GTP/GDP exchange activity of SOS, which loads p21Ras (Ras) with GTP to activate Ras, leading to phosphorylation of the serine/threonine protein kinase Raf-1, which then phosphorylates the mitogen-activated protein kinase kinase (MEK1), which is then activated to phosphorylate the extracellular signal–regulated kinases-1 and -2 (Erk-1/2). Phospho-activated Erk-1/2 can then directly (or indirectly via phospho-activation of other kinases such as p90 ribosomal serine kinase [p90RSK]) serine/threonine phosphorylate certain transcription factors, such as cFos and E-twenty-six–like transcription factor 1 (Elk-1), to upregulate gene transcription. Phospho-activated Erk-1/2 can also phosphorylate MAPK–interacting kinase (Mnk) 1 and 2, leading to phosphorylation activation of the eukaryotic initiation factor-4e (eIF4e) in a complex also containing eIF4a and eIF4G to increase general protein synthesis at the level initiation phase of translational control. For the PI3’K/PKB signaling pathway, the p85 regulatory subunit of PI3’K docks to other specific phosphorylated tyrosine sites on IRS-1/2 that then activates its p110 catalytic activity. This catalyzes the phosphorylation of phosphatidylinositol-4, 5-bisphophaste [PI(4,5)P2] to phosphatidylinositol-3, 4, 5-trisphophaste [PI(3,4,5)P3], which then activates 3-phosphoinositide dependent protein kinase-1 (PDK1). PDK1 then threonine (pT) phosphorylates PKB for PKB activation, which can be amplified by serine phosphorylation (pS) of PKB by the target of rapamycin complex-2 (TORC2; which includes the protein kinase, mammalian target of rapamycin [mTOR] and associated proteins rictor and mLST8). PKB has a plethora of serine/threonine phosphorylation substrates. PKB-mediated phosphorylation of the tuberous sclerosis protein-1/2 complex (TSC1/2) inhibits its GTPase activating protein activity to then load the Ras homolog enriched in brain (Rheb) protein with GTP (RhebGTP), leading to activation of the TORC1 (which includes mTOR and associated proteins raptor and mLST8). TORC1 can then serine/threonine phosphorylate a series of substrates. This includes the eIF4e-binding protein-1 (4e-BP1) that releases it from eIF4e binding, enabling eIF4e to associate with eIF4a and eIF4G in a complex with Mnk, where Mnk then phosphorylates eIF4e to increase rates of protein synthesis translation. This also shows how the Ras/Raf/Erk and PI3’K/PKB signaling pathways can coordinate to give a tight translational control of protein synthesis. TORC1 can also phosphorylate and subsequently activate p70 S6-ribosomal kinase (p70S6K), which can lead to an increase in the elongation phase of protein synthesis translation. PDK1 can threonine phosphorylate p70S6K to amplify this effect. TORC1 also phosphorylates Unc-51–like kinases-1/2 (ULK-1/2; also known as autophagy gene-1), which results in inhibition of autophagy. Among PKB’s other phosphorylation substrates are proteins involved in the apoptotic process such as Bcl-antagonist of cell death (BAD) and X-linked inhibitor of apoptosis protein (XIAP), outlining a mechanism whereby PKB is antiapoptotic. PKB phosphorylation of the transcription factors FoxO1 and FoxO3a causes their removal from the nucleus and promotes their degradation, causing an inhibition of FoxO1/3a-mediated transcription. Phosphorylation of glycogen synthase kinase-3 (GSK3) by PKB inhibits GSK3 activity, resulting in increased glycogen deposition and cell growth. Under certain circumstances, PKB can also influence increases in cell growth by phosphorylating the cell-cycle inhibitor proteins p21 cyclin-dependent kinase inhibitor-1 (p21CIP) and p27 cyclin-dependent-kinase inhibitor (p27KIP). PKB can also phosphorylate-inhibit phosphodiesterase-3b (PDE3b) to elevate intracellular cAMP ([cAMP]i) levels. Many of these IRS signaling elements have been shown to be expressed and active and play important roles in pancreatic β-cells in terms of certain functions, growth, and survival (rev. in 2–4), and these are indicated by a yellow highlighted halo. More
Images
Schematic of proposed effects of IGFBP1 on vascular endothelial cells. IGFB...
Published: 14 March 2012
FIG. 7. Schematic of proposed effects of IGFBP1 on vascular endothelial cells. IGFBP1 forms high-affinity complexes with circulating IGFs in the circulation (1) and confers dynamic regulation of IGF-I activity at the type 1 IGF receptor (2). IGF-I acts in a similar manner to insulin in endothelial... More
Journal Articles
Journal: Diabetes
Diabetes 2008;57(4):967–979
Published: 01 April 2008
... was blocked by inhibition of adenylyl cyclase/cAMP/protein kinase A (PKA), PI 3-kinase/Akt, and ERK1/2 signaling. Moreover, obestatin upregulated GLP-1R mRNA and insulin receptor substrate-2 (IRS-2) expression and phosphorylation. The GLP-1R antagonist exendin-(9-39) reduced obestatin effect on β-cell...
Images
Potential mechanisms of <span class="search-highlight">insulin</span>-mediated neuronal signaling in the control ...
Published: 17 August 2012
FIG. 1. Potential mechanisms of insulin-mediated neuronal signaling in the control of food intake. 1) An increase in insulin-mediated glucose uptake ( 16 ) raises the ATP/ADP ratio, closes KATP channels, depolarizes the plasma membrane, increases Ca2+ entry through voltage-gated channels, and subsequently increases neuronal activity. 2) Direct stimulatory effect on KATP channels ( 17 ). 3) Increased PI3 kinase activity enhancing leptin signaling. 4) Increased transcription of POMC and reduced transcription of NPY genes. IRS, insulin receptor substrate; ATP/ADP, adenosine triphosphate to adenosine diphosphate ratio; K, potassium; POMC, pro-opiomelanocortin; NPY, neuropeptide Y; AgRP, agouti-related peptide; GABA, γ-aminobutyric acid; a-MSH, α-melanocyte–stimulatory hormone; FOXO1, forkhead box protein O1; STAT3, signal transducer and activator of transcription 3; JAK2, Janus kinase 2; PI3K, phosphoinositide 3-kinase. Adapted from ref. 15. FIG. 1. Potential mechanisms of insulin-mediated neuronal signaling in the control of food intake. 1) An increase in insulin-mediated glucose uptake (16) raises the ATP/ADP ratio, closes KATP channels, depolarizes the plasma membrane, increases Ca2+ entry through voltage-gated channels, and subsequently increases neuronal activity. 2) Direct stimulatory effect on KATP channels (17). 3) Increased PI3 kinase activity enhancing leptin signaling. 4) Increased transcription of POMC and reduced transcription of NPY genes. IRS, insulin receptor substrate; ATP/ADP, adenosine triphosphate to adenosine diphosphate ratio; K, potassium; POMC, pro-opiomelanocortin; NPY, neuropeptide Y; AgRP, agouti-related peptide; GABA, γ-aminobutyric acid; a-MSH, α-melanocyte–stimulatory hormone; FOXO1, forkhead box protein O1; STAT3, signal transducer and activator of transcription 3; JAK2, Janus kinase 2; PI3K, phosphoinositide 3-kinase. Adapted from ref. 15. More
Meeting Abstracts
Journal: Diabetes
Diabetes 1999;48(4):801–812
Published: 01 April 1999
..., diabetic rats were characterized by multiple insulin signaling abnormalities in skeletal muscle, which included 1) increased insulin-stimulated tyrosine phosphorylation of the insulin receptor beta-subunit and insulin receptor substrates IRS-1 and IRS-2, 2) increased substrate tyrosine phosphorylation...
Meeting Abstracts
Journal: Diabetes
Diabetes 2018;67(Supplement_1):513-P
Published: 01 July 2018
...SAMY L. HABIB Insulin resistance is a major risk for development of type 2 diabetes. Several genes involved in regulation of insulin receptor substrate 1 (IRS1) and lead to chronic diabetes. Our RNA sequence data from kidney of diabetic mice show a new candidate gene involved in the regulation...
Journal Articles
Journal: Diabetes
Diabetes 1998;47(2):179–185
Published: 01 February 1998
... with englitazone for 48 h or with insulin for 10 or 30 min, or both, and 2-deoxy-D-[3H]glucose (2DG) uptake and lipogenesis (from [14C]glucose) were measured. Tyrosine phosphorylation of the insulin receptor (IR), insulin receptor substrates 1 and 2 (IRS-1 and IRS-2), and pp60...