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  • 1
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): Key words NIDDM ; Biguanides ; Combination therapy ; Insulin treatment
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/s005920070030
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  • 2
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): Sulphonylurea ; rat ; insulin binding ; insulin action ; extrapancreatic effect ; glycogen synthesis ; rat hepatocytes in primary culture
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00262222
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  • 3
    Digitale Medien
    Digitale Medien
    The insulin receptor: signalling mechanism and contribution to the pathogenesis of insulin resistance (1991)
    Springer
    Diabetologia 34 (1991), S. 848-861 
    Details
    ISSN: 1432-0428
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary The insulin receptor is a heterotetrameric structure consisting of two α-subunits of Mr135 kilodalton on the outside of the plasma membrane connected by disulphide bonds to β-subunits of Mr95 kilodalton which are transmembrane proteins. Insulin binding to the α-subunit induces conformational changes which are transduced to the β-subunit. This leads to the activation of a tyrosine kinase activity which is intrinsic to the cytoplasmatic domains of the β-subunit. Activation of the tyrosine kinase activity of the insulin receptor represents an essential step in the transduction of an insulin signal across the plasma membrane of target cells. Signal transduction on the post-kinase level is not yet understood in detail, possible mechanisms involve phosphorylation of substrate proteins at tyrosine residues, activation of serine kinases, the interaction with G-proteins, phospholipases and phosphatidylinositol kinases. Studies in multiple insulin-resistant cell models have demonstrated that an impaired response of the tyrosine kinase to insulin stimulation is one potential mechanism causing insulin resistance. An impairment of the insulin effect on tyrosine kinase activation in all major target tissues of insulin, in particular the skeletal muscle was demonstrated in Type 2 (non-insulin-dependent) diabetic patients. There is no evidence that the impaired tyrosine kinase response in the skeletal muscle is a primary defect, however, it is likely that this abnormality of insulin signal transduction contributes significantly to the pathogenesis of the insulin-resistant state in Type 2 diabetes.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00400192
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  • 4
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): Keywords Insulin resistance ; insulin receptor ; protein kinase C.
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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]
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/s001250050761
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  • 5
    Digitale Medien
    Digitale Medien
    The tumour necrosis factor alpha –238 G → A and –308 G → A promoter polymorphisms are not associated with insulin sensitivity and insulin secretion in young healthy relatives of Type II Diabetic patients (2000)
    Springer
    Diabetologia 43 (2000), S. 181-184 
    Details
    ISSN: 1432-0428
    Schlagwort(e): Keywords Insulin resistance, Type II diabetes, tumour necrosis factor-α, promotor polymorphisms, first-degree relatives.
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Aims/hypothesis. Tumour necrosis factor-α (TNF-α) is believed to influence skeletal muscle insulin resistance. Two G → A transitions in the promoter region of TNF- α at position –238 and –308 have been identified that could play a part in transcriptional regulation of the gene. Insulin resistance is an independent familial trait that predicts the development of Type II (non-insulin-dependent) diabetes mellitus. We investigated the influence on insulin sensitivity and insulin secretion of both polymorphisms in a cohort of young healthy relatives of patients with Type II diabetes.¶Methods. We examined 109 first-degree relatives of Caucasian patients with a history of Type II diabetes, who underwent extensive metabolical and anthropometrical phenotyping, and determined the TNF- α –238 and –308 G→ A promoter polymorphisms.¶Results. For the –238 polymorphism, 83 probands (76.1 %) were homozygous for the G-allele, 25 probands (22.9 %) were heterozygous and 1 proband (0.9 %) was homozygous for the A-allele. For the –308 polymorphism, 83 probands (76.1 %) were homozygous for the G-allele, 24 probands (22.0 %) were heterozygous and 2 probands (1.18 %) were homozygous for the A-allele. Probands with and without the polymorphism did not differ in insulin sensitivity (p = 0.78), insulin-concentrations and C-peptide concentrations in oral glucose tolerance tests (p 〉 0.05).¶Conclusions/interpretation. We could not detect an association between insulin sensitivity or insulin secretion and TNF- α promoter polymorphisms in our cohort. The polymorphisms occur at the same frequencies in probands with either low or high insulin sensitivity. [Diabetologia (2000) 43: 181–184]
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/s001250050027
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  • 6
    Digitale Medien
    Digitale Medien
    Serine residues 994 and 1023/25 are important for insulin receptor kinase inhibition by protein kinase C isoforms β2 and θ (2000)
    Springer
    Diabetologia 43 (2000), S. 443-449 
    Details
    ISSN: 1432-0428
    Schlagwort(e): Keywords Insulin receptor inhibition, tyrosine kinase activity, serine phosphorylation, protein kinase C.
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Aims/hypothesis. Inhibition of the signalling function of the human insulin receptor (HIR) is one of the principle mechanisms which induce cellular insulin resistance. It is speculated that serine residues in the insulin receptor β-subunit are involved in receptor inhibition either as inhibitory phosphorylation sites or as part of receptor domains which bind inhibitory proteins or tyrosine phosphatases. As reported earlier we prepared 16 serine to alanine point mutations of the HIR and found that serine to alanine mutants HIR-994 and HIR-1023/25 showed increased tyrosine autophosphorylation when expressed in human embryonic kidney (HEK) 293 cells. In this study we examined whether these mutant receptors have a different susceptibility to inhibition by serine kinases or an altered tyrosine kinase activity.¶Methods. Tyrosine kinase assay and transfection studies.¶Results. In an in vitro kinase assay using IRS-1 as a substrate we could detect a higher intrinsic tyrosine kinase activity of both receptor constructs. Additionally, a higher capacity to phosphorylate the adapter protein Shc in intact cells was seen. To test the inhibition by serine kinases, the receptor constructs were expressed in HEK 293 cells together with IRS-1 and protein kinase C isoforms β2 and θ. Phorbol ester stimulation of these cells reduced wild-type receptor autophosphorylation to 58 % or 55 % of the insulin simulated state, respectively. This inhibitory effect was not observed with HIR-994 and HIR-1023/25, although all other tested HIR mutants showed similar inhibition induced by protein kinase C.¶Conclusion/interpretation. The data suggest that the HIR-domain which contains the serine residues 994 and 1023/25 is important for the inhibitory effect of protein kinase C isoforms β2 and θ on insulin receptor autophosphorylation. [Diabetologia (2000) 43: 443–449]
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/s001250051327
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  • 7
    Digitale Medien
    Digitale Medien
    Insulin binding and action in antibody-induced diabetes in the rat (1982)
    Springer
    Diabetologia 23 (1982), S. 517-520 
    Details
    ISSN: 1432-0428
    Schlagwort(e): Insulin deficiency ; insulin receptor ; fat cells ; lipogenesis ; antibody-induced diabetes mellitus ; rat
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00254302
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  • 8
    Digitale Medien
    Digitale Medien
    Lack of a lipoprotein-induced insulin resistance in hepatoma cells in culture (1986)
    Springer
    Diabetologia 29 (1986), S. 457-461 
    Details
    ISSN: 1432-0428
    Schlagwort(e): Insulin resistance ; lipoproteins ; liver ; insulin binding ; insulin action ; hepatoma cells
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary A lipoprotein-induced resistance to the action of insulin has been postulated. To test this hypothesis, cultured ratderived hepatoma cells, designated FAO, and human-derived hepatoma cells, designated HEP-G2, were incubated for 20 h in the presence or absence of lipoproteins; specific 125I-insulin receptor binding and labeled glucose incorporation into glycogen were then measured. Very low density lipoproteins (d 〈 1.006 g/ml) in physiologic (0.5 mg/ml) or pathophysiologic (5 mg/ml) concentrations did not modify insulin receptor binding of FAO or HEP-G2 cells. This was true for very low density lipoproteins derived from normal human, diabetic human, and streptozotocin-diabetic rat plasma. Low density lipoproteins (d=,.019–1.063g/ml) isolated from normal human plasma similarly failed to modify insulin receptor binding. Concerning insulin action, the different very low density lipoprotein preparations did not modulate either basal or insulin-stimulated glucose incorporation into glycogen of the cells. Thus, very low density lipoproteins and low density lipoproteins did not induce insulin resistance in cultured hepatoma cells either at the insulin receptor level or at the post-receptor level.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00506539
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  • 9
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): Insulin receptor kinase ; insulin resistance ; glucose transport ; catecholamines ; phorbolester
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00274578
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  • 10
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): Glucose transporter ; human skeletal muscle ; Type 2 diabetes
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF02342444
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