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  • 11
    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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  • 12
    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: Key words 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+ AT Pase. The data suggest that skeletal muscle insulin resistance of obese Zucker rats is not associated with a lack of GLUT 4 translocation. [Diabetologia (1994) 37: 3–9]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250050064
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  • 13
    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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  • 14
    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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  • 15
    Electronic Resource
    Electronic Resource
    The PPARγ2 amino acid polymorphism Pro 12 Ala is prevalent in offspring of Type II diabetic patients and is associated to increased insulin sensitivity in a subgroup of obese subjects (1999)
    Springer
    Diabetologia 42 (1999), S. 758-762 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Insulin resistance ; Type II diabetes ; obesity ; peroxisome proliferator activated receptors ; Pro 12 Ala mutation.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aims/hypothesis. Recently a mutation in the coding sequence of the adipocyte specific isoform peroxisome proliferator-activated receptor γ2 (PPARγ2) was described, leading to the substitution of Proline to Alanine at codon 12. Mutations in PPARγ2 could have a role in people who are at increased risk for the development of obesity and Type II (non-insulin-dependent) diabetes mellitus. Methods. Non-diabetic first-degree relatives (n = 108) of subjects with Type II diabetes were characterized by oral glucose tolerance tests and euglycaemic hyperinsulinaemic glucose clamp to determine insulin sensitivity. Results. We found 75 (69 %) probands without the PPARγ ProAla12 substitution, 28 heterozygotes (26 %) and 5 (4 %) homozygotes. When the whole group was analysed for an association between the mutation and insulin sensitivity, no statistical significance could be shown. Only in the group with severe obesity more than 30 kg/m2, an association (p = 0.016) of the polymorphism with an increase in insulin sensitivity was found. Conclusion/interpretation. These observations suggest that the mutation in the PPARγ2 molecule may have a role in subgroups prone to the development of obesity and Type II diabetes. [Diabetologia (1999) 42: 758–762]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250051225
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  • 16
    Electronic Resource
    Electronic Resource
    Altered pattern of insulin receptor isotypes in skeletal muscle membranes of Type 2 (non-insulin-dependent) diabetic subjects (1993)
    Springer
    Diabetologia 36 (1993), S. 628-632 
    Details
    ISSN: 1432-0428
    Keywords: Insulin receptor isotypes ; Type 2 (non-insulin-dependent) diabetes mellitus ; insulin receptor antibody
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The human insulin receptor exists in two isoforms (HIR-A α-subunit 719 amino acids and HIR-B α-subunit 731 amino acids) which are generated by alternative splicing of a small exon and display distinct patterns of tissue-specific expression. Using the polymerase chain reaction we have recently shown that skeletal muscle of non-diabetic individuals contains predominantly mRNA encoding HIR-A while in skeletal muscle derived from subjects with Type 2 (non-insulin-dependent) diabetes mellitus similar amounts of each mRNA are expressed. We used a polyclonal antibody which discriminates between HIR-A and HIR-B to assess the isoform expression at the protein level. The antibody showed clearly distinct displacement of insulin binding in skeletal muscle membranes of non-diabetic subjects compared to Type 2 diabetic subjects (displacement of specific 125I-insulin binding: 13 non-diabetic subjects 70.0%±14.34, 12 Type 2 diabetic subjects 32.6%±17.45). A control antibody which does not discriminate between both isoforms showed similar displacement of 125I-insulin in membranes of non-diabetic and Type 2 diabetic subjects. These data suggest that the altered expression of receptor isotype mRNA in the skeletal muscle of Type 2 diabetic subjects leads to an altered receptor isoform pattern in the plasma membrane. While skeletal muscle membranes of non-diabetic subjects contain predominantly HIR-A, membranes of Type 2 diabetic subjects show an increased level of HIR-B in addition to HIR-A.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00404072
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  • 17
    Electronic Resource
    Electronic Resource
    Pathogenesis of Type 2 (non-insulin-dependent) diabetes mellitus: candidates for a signal transmitter defect causing insulin resistance of the skeletal muscle (1993)
    Springer
    Diabetologia 36 (1993), S. 176-182 
    Details
    ISSN: 1432-0428
    Keywords: Type 2 (non-insulin-dependent) diabetes mellitus ; insulin resistance ; insulin receptor ; phosphatases ; glycogen synthase ; glucose transporter
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Insulin resistance of skeletal muscle, liver and fat combined with an abnormality of insulin secretion characterizes Type 2 (non-insulin-dependent) diabetes mellitus. There is increasing evidence that the insulin resistance of the skeletal muscle plays a key role early in the development of Type 2 diabetes. As a consequence recent research efforts have focussed on the characterization of insulin signal transduction elements in the muscle which are candidates for a localization of a defect causing insulin resistance i.e. the insulin receptor, phosphatases related to insulin action, glycogen synthase and the glucose transporters. In this review we attempt to summarize present knowledge about abnormalities of these systems in skeletal muscle of Type 2 diabetic and pre-diabetic individuals. We try to classify abnormalities as secondary events or as candidates for putative primary molecular defects which might initiate the development of insulin resistance as early as in the “pre-diabetic” state.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00399946
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  • 18
    Electronic Resource
    Electronic Resource
    Lipolysis in skeletal muscle is rapidly regulated by low physiological doses of insulin (1999)
    Springer
    Diabetologia 42 (1999), S. 1171-1174 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Skeletal muscle ; adipose tissue ; intramyocellular lipids ; lipolysis ; insulin resistance.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aims/hypothesis. Both patients with Type II (non-insulin-dependent) diabetes mellitus and normoglycaemic, insulin resistant subjects were shown to have an increased lipid content in skeletal muscle, which correlates negatively with insulin sensitivity. Recently, it was shown that during a hyperinsulinaemic euglycaemic clamp interstitial glycerol was reduced not only in adipose tissue but also in skeletal muscle. To assess whether lipolysis of muscular lipids is also regulated by low physiological concentrations of insulin, we used the microdialysis technique in combination with a 3-step hyperinsulinaemic glucose clamp. Methods. Nineteen lean, healthy subjects (12 m/7 f) underwent a glucose clamp with various doses of insulin (GC I = 0.1, GC II = 0.25 and GC III = 1.0mU · kg–1· min–1). Two double lumen microdialysis catheters each were inserted in the paraumbilical subcutaneous adipose tissue and in skeletal muscle (tibialis anterior) to measure interstitial glycerol concentration (index of lipolysis) and ethanol outflow (index of tissue flow). Results. During the different steps of the glucose clamp, glycerol in adipose tissue was reduced to 81 ± 7 % (GC I), 55 ± 8 % (GC II) and 25 ± 5 % (GC III), respectively, of basal. In contrast, glycerol in skeletal muscle declined to 73 ± 5 % (GC I) and to 57 ± 6 % (GC II) but was not further reduced at GC III. Tissue flow was higher in the skeletal muscle and remained unchanged in both compartments throughout the experiment. Conclusion/interpretation. This study confirms the presence of glycerol release in skeletal muscle. Lipolysis in skeletal muscle and adipose tissue are suppressed similarly by minute and physiological increases in insulin but differently by supraphysiological increases. Inadequate suppression of intramuscular lipolysis resulting in increased availability of non-esterified fatty acids, could represent a potential mechanism involved in the pathogenesis of impaired glucose disposal, i. e. insulin resistance, in muscle. [Diabetologia (1999) 42: 1171–1174]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250051288
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  • 19
    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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  • 20
    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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