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  • 1
    Electronic Resource
    Electronic Resource
    Intensive insulin therapy combined with metformin in obese type 2 diabetec patients (2000)
    Springer
    Acta diabetologica 37 (2000), S. 13-18 
    Details
    ISSN: 1432-5233
    Keywords: Key words NIDDM ; Biguanides ; Combination therapy ; Insulin treatment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Unlike other pharmacological therapies used in obese type 2 diabetic patients, metformin has been shown to improve glycemic control with lower insulin levels and not to involve weight gain. We therefore examined the effect of adjunct metformin in 13 severely obese type 2 diabetic patients (BMI 39.3 ± 3.9 kg/m2) in suboptimal glycemic control pretreated with intensified insulin therapy. Patients were randomly assigned to either metformin or placebo treatment (double-blind) for 10 weeks and after a 2 week washout period received the opposite treatment, respectively, for 10 additional weeks. HbA1c decreased comparably during placebo (from 8.1 ± 0.4 to 7.6 ± 0.3%) and metformin (from 8.5 ± 0.4 to 7.4 ± 0.3%, p = 0.29 vs. placebo). Changes in fasting glucose levels were also not different between placebo (from 9.3 ± 0.7 to 9.5 ± 0.7 mM) and metformin (from 10.3 ± 0.5 to 9.5 ± 0.6 mM, p = 0.44 vs. placebo) Total exogenous insulin requirements decreased from 53 ± 10 to 35 ± 7 units during metformin treatment (p = 0.11). Metformin had no effect on body weight and serum triglycerides but marginally decreased serum cholesterol levels (from 239 ± 18 to 211 ± 14 mg/dl, p = 0.005, p = 0.08 vs. placebo). During the oral glucose tolerance test no differences were observed in the areas under the curve for glucose and insulin while that for C-peptide showed a tendency to increase during metformin administration. We conclude that addition of metformin to insulin treatment in severely obese type 2 diabetic patient improves glycemia but no hyperinsulinemia in comparison to intensive insulin therapy alone. With adjunct metformin, ∼30% less exogenous insulin is required. With respect to glycemia and lipids, adjunct metformin can be a reasonable treatment alternative in selective obese patients with type 2 diabetes already on intensive insulin therapy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s005920070030
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  • 2
    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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  • 3
    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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  • 4
    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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  • 5
    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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