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  • 1
    Electronic Resource
    Electronic Resource
    Normal insulin receptor tyrosine kinase activity and glucose transporter (GLUT 4) levels in the skeletal muscle of hyperinsulinaemic hypertensive rats (1992)
    Springer
    Diabetologia 35 (1992), S. 712-718 
    Details
    ISSN: 1432-0428
    Keywords: Spontaneous hypertensive rat ; insulin receptor kinase ; glucose transporter
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The spontaneous hypertensive rat is an animal model characterized by a syndrome of hypertension, insulin resistance and hyperinsulinaemia. To elucidate whether in analogy to other insulin resistant animal models an inactivity of the insulin receptor kinase or an alteration of the glucose transporter (GLUT 4) level in the skeletal muscle might contribute to the pathogenesis of insulin resistance we determined insulin receptor kinase activity and GLUT 4 level in the hindlimbs of spontaneous hypertensive rats and normotensive control rats. Normotensive normoinsulinaemic Lewis and Wistar rats were used as insulin sensitive controls, obese Zucker rats were used as an insulin resistant control with known reduced skeletal muscle insulin receptor kinase activity. Binding of 125I-insulin, crosslinking of 125I-B26-insulin, autophosphorylation in vitro with 32P-ATP and phosphorylation of the synthetic substrate Poly (Glu 4: Tyr 1) were performed after partial purification of solubilized receptors on wheat germ agglutinin columns. GLUT 4 levels were determined by Western blotting of subcellular muscle membranes. Insulin receptors from spontaneous hypertensive rats compared to those from Lewis and Wistar rats showed no difference of the binding characteristics or the in vitro auto- and substrate phosphorylation activity of the receptor, while in the Zucker rats the earlier described insulin receptor kinase defect was clearly evident. Western blots of subcellular muscle membrane fractions with antibodies against GLUT 4 revealed no difference in transporter levels. These data suggest that insulin resistance in spontaneous hypertensive rats is caused neither by an insulin receptor inactivity nor by a decreased number of glucose transporters in the skeletal muscle.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00429089
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  • 2
    Electronic Resource
    Electronic Resource
    Modulation of insulin receptor signalling: significance of altered receptor isoform patterns and mechanism of hyperglycaemia-induced receptor modulation (1994)
    Springer
    Diabetologia 37 (1994), S. S149 
    Details
    ISSN: 1432-0428
    Keywords: Insulin receptor ; skeletal muscle ; proteinkinase C ; non-insulin-dependent diabetes mellitus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Insulin resistance of the skeletal muscle plays a key role in the development of the metabolic endocrine syndrome and its further progression to non-insulin dependent diabetes (NIDDM). Available data suggest that insulin resistance is caused by an impaired signal from the insulin receptor to the glucose transport system and to glycogen synthase. The impaired response of the insulin receptor tyrosine kinase which is found in NIDDM appears to contribute to the pathogenesis of the signalling defect. The reduced kinase activation is not caused by mutations within the insulin receptor gene. We investigated two potential mechanisms that might be relevant for the abnormal function of the insulin receptor in NIDDM, i.e. changes in the expression of the receptor isoforms and the effect of hyperglycaemia on insulin receptor tyrosine kinase activity. The insulin receptor is expressed in two different isoforms (HIRA and HIR-B). We found that HIR-B expression in the skeletal muscle is increased in NIDDM. However, the characterisation of the functional properties of HIR-A and HIR-B revealed no difference in their tyrosine kinase activity in vivo. The increased expression of HIR-B might represent a compensatory event. In contrast, hyperglycaemia might directly inhibit insulin-receptor function. We have found that in rat-1 fibroblasts which overexpressing human insulin receptor an inhibition of the tyrosine kinase activity of the receptor may be induced by high glucose levels. This appears to be mediated through activation of certain protein kinase C isoforms which form stable complexes with the insulin receptor and modulate the tyrosine kinase activity of the insulin receptor through serine phosphorylation of the receptor beta subunit. This mechanism might also be relevant in human skeletal muscle and contribute to the pathogenesis of insulin resistance.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00400838
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  • 3
    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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  • 4
    Electronic Resource
    Electronic Resource
    Leptin stimulates glucose transport and glycogen synthesis in C2C12 myotubes: evidence for a PI3-kinase mediated effect (1997)
    Springer
    Diabetologia 40 (1997), S. 606-609 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Leptin ; phosphatidylinositol-3 kinase ; insulin signalling.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary It was recently shown that leptin impairs insulin signalling, i. e. insulin receptor autophosphorylation and insulin-receptor substrate (IRS)-1 phosphorylation in rat-1 fibroblasts, NIH3T3 cells and HepG2 cells. To evaluate whether leptin might impair the effects of insulin in muscle tissue we studied the interaction of insulin and leptin in a muscle cell system, i. e. C2C12 myotubes. Preincubation of C2C12 cells with leptin (1–500 ng/ml) did not significantly affect insulin stimulated glucose transport and glycogen synthesis (1.8 to 2 fold stimulation); however, leptin by itself (1 ng/ml) was able to mimic approximately 80–90 % of the insulin effect on glucose transport and glycogen synthesis. Both glucose transport as well as glycogen synthesis were inhibited by the phosphatidylinositol-3 (PI3)-kinase inhibitor wortmannin and the protein kinase C inhibitor H7 while no effect was observed with the S6-kinase inhibitor rapamycin. We determined whether the effect of leptin occurs through activation of IRS-1 and PI3-kinase. Leptin did not stimulate PI3-kinase activity in IRS-1 immunoprecipitates; however, PI3-kinase activation could be demonstrated in p85α immunoprecipitates (3.04 ± 1.5 fold of basal). In summary the data provide the first evidence for a positive crosstalk between the signalling chain of the insulin receptor and the leptin receptor. Leptin mimics in C2C12 myotubes insulin effects on glucose transport and glycogen synthesis most likely through activation of PI3-kinase. This effect of leptin occurs independently of IRS-1 activation in C2C12 cells. [Diabetologia (1997) 40: 606–609]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250050722
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  • 5
    Electronic Resource
    Electronic Resource
    Protein kinase C isoforms β 1 and β 2 inhibit the tyrosine kinase activity of the insulin receptor (1997)
    Springer
    Diabetologia 40 (1997), S. 863-866 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Insulin resistance ; insulin receptor ; protein kinase C.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Downregulation of insulin receptor tyrosine kinase (IRK) activity yields to impaired insulin signalling and contributes to the pathogenesis of cellular insulin resistance. Activation of protein kinase C (PKC) by different agents is associated with an inhibition of IRK activity in various cell types. There is evidence that this effect on IRK activity might be mediated through phosphorylation of specific serine residues of the insulin receptor β -subunit. Neither the domains of the IRK where inhibiting serine phosphorylation occurs nor the PKC isoform responsible for IRK inhibition have been identified. PKC consists of a family of at least 12 isoforms. The aim of the present study was to determine which PKC isoform might be capable of IRK inhibition. The human insulin receptor and the PKC isoforms α, β 1, β 2, γ , δ , ɛ , η , θ and ζ were overexpressed in human embryo kidney fibroblasts (HEK 293 cells) in order to answer this question. PKCs were activated by preincubation with the phorbolester (TPA) (10−7 mol/l) following insulin stimulation of the cells. When the IRK was coexpressed with the PKC isoforms β 1 and β 2, a 50 ± 15.7 and 45 ± 10.1 % inhibition of tyrosine autophosphorylation of IRK was observed while coexpression with the other isoforms did not significantly modify IRK autophosphorylation. The data suggest that the PKC isoforms β 1 and β 2 might be candidates for insulin receptor inhibition. [Diabetologia (1997) 40: 863–866]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250050761
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  • 6
    Electronic Resource
    Electronic Resource
    Insulin binding and action in antibody-induced diabetes in the rat (1982)
    Springer
    Diabetologia 23 (1982), S. 517-520 
    Details
    ISSN: 1432-0428
    Keywords: Insulin deficiency ; insulin receptor ; fat cells ; lipogenesis ; antibody-induced diabetes mellitus ; rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The influence of antibody-induced insulin deficiency in rats on the insulin binding and insulin sensitivity of adipocytes was studied. Rats were injected intraperitoneally with an insulin antibody preparation; the development of hyperglycaemia was followed and the animals were sacrificed 3 and 5 h after antibody injection. Up to 3 h, no significant change of insulin binding or sensitivity of the adipocytes occurred. At 5 h, cells of antibody-treated rats showed an approximately 40% increased binding capacity compared with untreated rats. The increased binding capacity was accompanied by an approximate two-fold increased sensitivity of the insulin effect on lipogenesis from glucose in these cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00254302
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  • 7
    Electronic Resource
    Electronic Resource
    Extrapancreatic action of the sulphonylurea gliquidone: post-receptor effect on insulin-stimulated glycogen synthesis in rat hepatocytes in primary culture (1984)
    Springer
    Diabetologia 26 (1984), S. 462-465 
    Details
    ISSN: 1432-0428
    Keywords: Sulphonylurea ; rat ; insulin binding ; insulin action ; extrapancreatic effect ; glycogen synthesis ; rat hepatocytes in primary culture
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The effects of a sulphonylurea, gliquidone, on insulin binding and the insulin induced rate of glycogen synthesis, were studied in rat hepatocytes in primary culture. Hepatocytes were cultured for 48 h. During the second 24 h of this period, the hepatocytes were incubated with or without gliquidone (5 mg/l). The binding of 125I-insulin and the insulin stimulation of glycogen synthesis from 14C-glucose were measured. Gliquidone influenced neither insulin binding nor the basal rate of glycogen synthesis, but it did enhance the effect of insulin on glycogen synthesis. Responsiveness was increased by gliquidone at all insulin concentrations used (10–10,000 mU/l); at 1000 mil/l the drug increased glycogen synthesis from 310 to 430% above the basal rate. Half-maximal stimulation was reached in control cells at an insulin concentration of 95 mU/l and in gliquidone-treated cells at 94 mU/l, which indicates unchanged insulin sensitivity. Based on these experiments with cultured rat hepatocytes it appears that the extrapancreatic action of gliquidone is not mediated by an effect on insulin binding.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00262222
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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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  • 9
    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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  • 10
    Electronic Resource
    Electronic Resource
    Insulin-induced translocation of GLUT 4 in skeletal muscle of insulin-resistant Zucker rats (1994)
    Springer
    Diabetologia 37 (1994), S. 3-9 
    Details
    ISSN: 1432-0428
    Keywords: Zucker rats ; skeletal muscle ; insulin resistance ; glucose transporter (GLUT 1 and GLUT 4) ; GLUT 4 translocation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The genetically obese Zucker rat (fa/fa) is an animal model with severe insulin resistance of the skeletal muscle. We investigated whether a defect of insulin-dependent glucose transporter (GLUT 4) translocation might contribute to the pathogenesis of the insulin-resistant state. fa/fa rats, lean controls (Fa/Fa) as well as normal Wistar rats were injected intraperitoneally with insulin and were killed after 2 or 20 min, respectively. Subcellular fractions were prepared from-hind-limb skeletal muscle and were characterized by determination of marker-enzyme activities and immunoblotting applying antibodies against α1 Na+/K+ AT Pase. The relative amounts of GLUT 1 and GLUT 4 were determined in the fractions by immunoblotting with the respective antibodies. Insulin induced an approximately two-fold increase of GLUT 4 in a plasma membrane and transverse tubule enriched fraction and a decrease in the low density enriched membrane fraction in all three groups of rats. There was a high individual variation in GLUT 4 translocation efficiency within the groups. However, no statistically significant difference was noted between the groups. No effect of insulin was detectable on the distribution of GLUT 1 or α1 Na+K+ ATPase. The data suggest that skeletal muscle insulin resistance of obese Zucker rats is not associated with a lack of GLUT 4 translocation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00428770
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