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  • 1
    Electronic Resource
    Electronic Resource
    A 973 valine to methionine mutation of the human insulin receptor: interaction with insulin-receptor substrate-1 and Shc in HEK 293 cells (1997)
    Springer
    Diabetologia 40 (1997), S. 1135-1140 
    Details
    ISSN: 1432-0428
    Keywords: Keywords NIDDM ; insulin receptor ; mutation ; hyperglycaemia ; substrate phosphorylation ; PI3-kinase.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A population-based study in the Netherlands has recently demonstrated that a mutation of the human insulin receptor (HIR-973 valine to methionine) is associated with hyperglycaemia and an increased prevalence of non-insulin-dependent diabetes mellitus (NIDDM). The aim of the present study was to assess whether this mutation leads to a functional alteration of the insulin receptor. We prepared the HIR-973 mutant by in vitro mutagenesis. This mutant was transiently overexpressed in HEK 293 cells either alone or together with insulin-receptor substrate-1 (IRS-1) or Shc. Insulin stimulated autophosphorylation, phosphorylation of the substrates IRS-1 and Shc as well as activation of phosphatidylinositol-3 (PI3)-kinase were studied. Autophosphorylation of HIR-973 and its susceptibility to hyperglycaemia induced inhibition was not different from HIR-wt. Human insulin receptor with a juxtamembrane deletion HIR-ΔJM which is known to impair HIR/IRS-1 interaction was used as control. While the HIR-ΔJM induces a reduced IRS-1 phosphorylation HIR-973 showed even a slightly increased ability to phosphorylate IRS-1 (n = 7, 115 % of control, p 〈 0.01). Shc phosphorylation was only mediated by HIR-wt and HIR-973 but not by HIR-ΔJM. Again a tendency to higher phosphorylation of Shc was seen with HIR-973 (n = 7, 109 % of control, NS). When PI3-kinase activity was measured in IRS-1 precipitates similar activity was found for HIR-wt and HIR-973 whereas PI3-kinase stimulation was reduced with HIR-ΔJM. In summary, the data suggest that HIR-973 does not impair the first steps of the insulin signalling cascade. It is therefore unlikely that this mutation may cause cellular insulin resistance. The close vicinity of this mutation to insulin receptor domains which are involved in IRS-1 and Shc binding may, however, alter the interaction of the insulin receptor with these substrates. This could explain the slightly increased insulin effect on tyrosine phosphorylation of these docking proteins. These characteristics of HIR-973 might have a compensatory function of impaired signal transduction further downstream of the signalling chain in this specific subgroup of NIDDM patients. [Diabetologia (1997) 40: 1135–1140]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250050798
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  • 2
    Electronic Resource
    Electronic Resource
    Protein kinase C isoforms α, δ and θ require insulin receptor substrate-1 to inhibit the tyrosine kinase activity of the insulin receptor in human kidney embryonic cells (HEK 293 cells) (1998)
    Springer
    Diabetologia 41 (1998), S. 833-838 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Insulin receptor ; insulin receptor substrate ; protein kinase C ; insulin resistance ; serine phosphorylation.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Protein kinase C (PKC) isoforms are potentially important as modulators of the insulin signalling chain and could be involved in the pathogenesis of cellular insulin resistance. We have previously shown that phorbol ester stimulated PKC β1 and β2 as well as tumor necrosis factor-α (TNFα) stimulated PKC ɛ inhibit human insulin receptor (HIR) signalling. There is increasing evidence that the insulin receptor substrate-1 (IRS-1) is involved in inhibitory signals in insulin receptor function. The aim of the present study was to elucidate the role of IRS-1 in the inhibitory effects of protein kinase C on human insulin receptor function. HIR, PKC isoforms (α, β1, β2, γ, δ, ɛ, η, θ and ζ) and IRS-1 were coexpressed in human embryonic kidney (HEK) 293 cells. PKCs were activated by preincubation with the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (CTPA) (10––7 mol/l) following insulin stimulation. While PKCs α, δ and θ were not inhibitory in HEK 293 cells which were transfected only with HIR and PKC, additional transfection of IRS-1 induced a strong inhibitory effect of these PKC isoforms being maximal for PKC θ (99 ± 1.8 % inhibition of insulin stimulated receptor autophosphorylation, n = 7, p 〈 0.001). No effect was seen with PKC γ, ɛ, ζ and η while the earlier observed insulin receptor kinase inhibition of PKC β2 was further augmented (91 ± 13 %, n = 7, p 〈 0.001 instead of 45 % without IRS-1). The strong inhibitory effect of PKC θ is accompanied by a molecular weight shift of IRS-1 (183 kDa vs 180 kDa) in the sodium dodecyl sulphate polyacrylamide gel. This can be reversed by alkaline phosphatase treatment of IRS-1 suggesting that this molecular weight shift is due to an increased phosphorylation of IRS-1 on serine or threonine residues. In summary, these data show that IRS-1 is involved in the inhibitory effect of the PKC isoforms α, β2, δ and θ and it is likely that this involves serine/threonine phosphorylation of IRS-1. [Diabetologia (1998) 41: 833–838]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250050995
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  • 3
    Electronic Resource
    Electronic Resource
    Subcellular distribution of GLUT 4 in the skeletal muscle of lean type 2 (non-insulin-dependent) diabetic patients in the basal state (1992)
    Springer
    Diabetologia 35 (1992), S. 456-463 
    Details
    ISSN: 1432-0428
    Keywords: Glucose transporter ; human skeletal muscle ; Type 2 diabetes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Insulin resistance of the skeletal muscle is a key feature of Type 2 (non-insulin-dependent) diabetes mellitus. To determine whether a decrease of glucose carrier proteins or an altered subcellular distribution of glucose transporters might contribute to the pathogenesis of the insulin resistant state, we measured glucose transporter numbers in membrane fractions of gastrocnemius muscle of 14 Type 2 diabetic patients and 16 non-diabetic control subjects under basal conditions. Cytochalasin-B binding and immunoblotting with antibodies against transporter-subtypes GLUT 1 and GLUT 4 were applied. The cytochalasin-B binding values (pmol binding sites/g muscle) found in a plasma membrane enriched fraction, high and low density membranes of both groups (diabetic patients and non-diabetic control subjects) suggested a reduced number of glucose transporters in the plasma membranes of the diabetic patients compared to the control subjects (diabetic patients: 1.47 ± 1.01, control subjects: 3.61 ± 2.29,p ≤ 0.003). There was no clear difference in cytochalasin-B binding sites in high and low density membranes of both groups (diabetic patients: high density membranes 3.76 ± 1.82, low density membranes: 1.67 ± 0.81; control subjects: high density membranes 5.09 ± 1.68, low density membranes 1.45 ± 0.90). By Western blotting analysis we determined the distribution of the glucose transporter sub-types GLUT 1 and GLUT 4 in the plasma membrane enriched fraction and low density membranes of seven patients of each group. In agreement with the cytochalasin-B binding data and despite a high variance within one group, the results show a clear decrease of GLUT 4 in the plasma membrane enriched fraction of diabetic patients compared to control subjects. In contrast, we found no difference in the distribution of GLUT 1 in diabetic patients and control subjects. In conclusion, despite a high variance of glucose transporter numbers in the skeletal muscle of different individuals fractionation of muscle samples clearly suggests that the number of GLUT 4 is reduced in the plasma membrane fraction of skeletal muscle of lean diabetic patients in the basal state.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02342444
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  • 4
    Electronic Resource
    Electronic Resource
    Leptin activates PI-3 kinase in C2C12 myotubes via janus kinase-2 (JAK-2) and insulin receptor substrate-2 (IRS-2) dependent pathways (1997)
    Springer
    Diabetologia 40 (1997), S. 1358-1362 
    Details
    ISSN: 1432-0428
    Keywords: Keywords leptin ; leptin receptor ; insulin receptor ; phosphatidylinositol kinase ; janus kinase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We have recently shown that leptin mimicks insulin effects on glucose transport and glycogen synthesis through a phosphatidylinositol-3 (PI) kinase dependent pathway in C2C12 myotubes. The aim of the present study was to identify the signalling path from the leptin receptor to the PI-3 kinase. We stimulated C2C12 myotubes with insulin (100 nmol/l, 5 min) or leptin (0.62 nmol/l, 10 min) and determined PI-3 kinase activity in immunoprecipitates with specific non-crossreacting antibodies against insulin-receptor substrate (IRS 1/IRS 2) and against janus kinase (JAK 1 and JAK 2). While insulin-stimulated PI-3 kinase activity is detected in IRS-1 and IRS-2 immunoprecipitates, leptin-stimulated PI-3 kinase activity is found only in IRS-2 immunoprecipitates, suggesting that the leptin signal to PI-3 kinase occurs via IRS-2 and not IRS-1. Leptin-, but not insulin-stimulated PI-3 kinase activity is also detected in immunoprecipitates with antibodies against JAK-2, but not JAK-1. The data suggest that JAK-2 and IRS-2 couple the leptin signalling pathway to the insulin signalling chain. Since we have also detected leptin-stimulated tyrosine phosphorylation of JAK-2 and IRS-2 in C2C12 myotubes it can be assumed that leptin activates JAK-2 which induces tyrosine phosphorylation of IRS-2 leading to activation of PI-3 kinase. As we could not detect the long leptin receptor isoform in C2C12 myotubes we conclude that this signalling pathway is activated by a short leptin receptor isoform. [Diabetologia (1997) 40: 1358–1362]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250050832
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  • 5
    Electronic Resource
    Electronic Resource
    TPA inhibits insulin stimulated PIP hydrolysis in fat cell membranes: Evidence for modulation of insulin dependent phospholipase C by proteinkinase C
    Amsterdam : Elsevier
    Biochemical and Biophysical Research Communications 172 (1990), S. 446-454 
    Details
    ISSN: 0006-291X
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Chemistry and Pharmacology , Physics
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1016/0006-291X(90)90693-H
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  • 6
    Electronic Resource
    Electronic Resource
    The phorbol ester TPA induces a translocation of the insulin sensitive glucose carrier (GLUT4) in fat cells
    Amsterdam : Elsevier
    Biochemical and Biophysical Research Communications 168 (1990), S. 1089-1094 
    Details
    ISSN: 0006-291X
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Chemistry and Pharmacology , Physics
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1016/0006-291X(90)91141-E
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  • 7
    Electronic Resource
    Electronic Resource
    Stimulation of phospholipase C activity by insulin is mediated by both isotypes of the human insulin receptor
    Amsterdam : Elsevier
    Biochemical and Biophysical Research Communications 181 (1991), S. 566-572 
    Details
    ISSN: 0006-291X
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Chemistry and Pharmacology , Physics
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1016/0006-291X(91)91227-4
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  • 8
    Electronic Resource
    Electronic Resource
    Catecholamines and tumour promoting phorbolesters inhibit insulin receptor kinase and induce insulin resistance in isolated human adipocytes (1987)
    Springer
    Diabetologia 30 (1987), S. 93-99 
    Details
    ISSN: 1432-0428
    Keywords: Insulin receptor kinase ; insulin resistance ; glucose transport ; catecholamines ; phorbolester
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The effect of the catecholamine isoprenaline (10−5mol/l) and of the tumour promoting phorbolester tetradecanoyl-β-phorbol acetate (10−9mol/l) on insulin stimulated 3-O-methyl-glucose transport was studied in freshly isolated human adipocytes. Both substances reduced the maximal responsiveness of the glucose transport system to insulin by approximately 50%. To test if this is caused by inhibition of the insulin receptor kinase the receptor from phorbolester and isoprenaline treated cells was solubilized, partially purified and its kinase activity studied in vitro. Insulin stimulated 32P-incorporation into the β-subunit of the insulin receptor of phorbolester or isoprenaline treated cells was reduced to 20–60% of the values found with receptor from control cells at insulin concentrations between 10−10mol/l and 10−7mol/l. This inhibition of kinase activity of receptor from phorbolester and isoprenaline treated cells was observed at nonsaturating adenosine triphosphate levels (5 μmol/l), and it could be overcome with higher concentrations of γ-32P-adenosine triphosphate in the phosphorylation assay. A Lineweaver Burk analysis of the insulin stimulated receptor phosphorylation revealed that the Michaelis constant for adenosine triphosphate of the receptor kinase from phorbolester and isoprenaline treated cells was increased to 〉100 μmol/l compared with 〈50 μmol/l for receptor from control cells. We conclude from the data that catecholamine and phorbolester treatment of human adipocytes modulates the kinase activity of the insulin receptor by increasing its Michaelis constant for adenosine-triphosphate, and propose that this modulation of receptor kinase is a mechanism that can contribute to the pathogenesis of insulin resistance in human fat cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00274578
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