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  • 1
    ISSN: 1432-0428
    Keywords: Anti-insulin receptor antibodies ; insulin-like effects ; insulin resistance ; skeletal muscle ; insulin receptor ; insulin binding ; insulin action ; glucose transport ; glycolysis ; glycogen synthesis ; obese mice
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Autoantibodies against the insulin receptor are found in the serum of some patients with severe insulin resistance. The effects of one of these sera on insulin binding and on glucose transport and metabolism were investigated in the isolated mouse soleus muscle. Preincubation of muscles with the patient's serum resulted in an inhibition of subsequent125I-insulin binding (half-maximal effect at 1∶500 dilution) and in a two to three-fold stimulation of glucose transport and metabolism (half-maximal effect at 1∶2000 dilution). The insulin-like effects were blocked by anti-human IgG, but not by antiinsulin antibodies. The magnitude of the serum effects on 2-deoxyglucose uptake and glycolysis was similar to that of insulin, but the effect on glycogen synthesis was smaller than that of insulin. It is suggested that the patient's serum and insulin promote glucose transport and glycolysis through a common pathway, but act differently on glycogen synthesis.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-0428
    Keywords: Human fibroblasts ; insulin receptors ; glycogen synthase ; Type 1 diabetes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 125I-Insulin binding and insulin stimulation of glycogen synthase were examined in fibroblasts cultured from nine Type 1 (insulin-dependent) diabetic patients with age of onset of 〈42 years. In all cases specific insulin binding was qualitatively and quantitatively normal. Total 125I-insulin binding was elevated in cells from three patients with early onset diabetes (two with onset before age 1 year) due to an increase in ‘non-specific’ binding. When the ability of insulin to stimulate the conversion of the glucose-6-phosphate dependent to the glucose-6-phosphate independent form of glycogen synthase was measured, all cell lines responded, albeit to differing degrees. In general, the response of cells from diabetic donors was more variable than that of control fibroblasts. A slightly lower level of cellular glycogen was evident in the cells of the diabetic patients, and this was mirrored in slightly higher levels of the independent form of the enzyme. The average maximal level of the independent form of the enzyme also was higher in the diabetic patients' cells. Fibroblasts from one of the patients with very early onset diabetes had glycogen synthase levels that were markedly lower than in any other cell line examined. In summary, fibroblasts cultured from Type 1 diabetic patients do not show major defects in either insulin binding or action. A suggestion of subtle differences in the cells from the diabetic patients, particularly those with very early onset, is evident, however. Whether these are secondary to some primary genetic defect or represent some selection during culture remains to be determined.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-0428
    Keywords: Insulin receptors ; acanthosis nigricans ; insulin resistance ; insulin receptor autoantibodies ; Type A patients ; Type B patients ; negative cooperativity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary This report analyzes the in vitro characteristics of 125I-insulin binding to the monocytes of nine patients with the syndromes of acanthosis nigricans and insulin resistance. The 3 Type A patients (without demonstrable autoantibodies to the insulin receptor) had decreased binding of insulin due to a decreased concentration of receptors. In these patients the residual receptors demonstrated normal dissociation kinetics, negative cooperativity, and were blocked by anti-receptor antibodies in a manner similar to normal cells. In contrast, monocytes from the 6 Type B patients (with circulating anti-receptor autoantibodies) had decreased binding of insulin due to a decrease in receptor affinity. Insulin binding to monocytes of Type B patients demonstrated accelerated rates of dissociation with no evidence of cooperative interactions among insulin receptors. When coupled with previous data, the present studies further suggest that different mechanisms account for the defects in insulin binding and insulin resistance observed in these patients.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-0428
    Keywords: 123I-Insulin ; Zucker rats ; receptors ; scintillation scanning ; computer analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Imaging and quantitative analysis of insulin-receptor interaction was studied in vivo in lean and obese Zucker rats, using a recently developed technique in which purified Tyr A14 123I-monoiodoinsulin is intravenously injected and the tracer followed by scintillation scanning. The obese rats were 72% overweight, had near normal blood glucose concentrations and an 11-fold increase in plasma insulin concentration. In both groups of rats, the tracer was rapidly taken up by the liver (by a receptor mediated mechanism) and the kidneys (by a non-receptor mediated process). Past this maximum, radioactivity decreased in both organs as 123I-insulin was degraded and free 123I-iodide was released into the plasma compartment. Heart radioactivity (i.e. blood pool) mirrored that of the liver and kidneys. The rapid initial decrease of blood radioactivity was concomitant with liver and kidney uptake of 123I-insulin. Release of free iodide from these organs induced a slow secondary rise of blood radioactivity followed by a final decline corresponding to clearance of plasma iodide, mainly by urinary excretion. Liver radioactivity profiles of lean and obese rats were parallel. When expressed per g weight, liver radioactivity was significantly decreased in obese rats. However, due to hepatomegaly in obese rats, total liver radioactivity was significantly higher in homozygous fa/fa rats than in lean littermates. Furthermore, if the marked hyperinsulinaemia of the obese rats is taken into account, total bound insulin was enhanced in the liver of fa/fa rats whatever reference is used, either g weight or total liver. The kidney profile of radioactivity of both rats was not significantly different. In conclusion: (1) obese rats are insulin resistant as near normal glycaemia is achieved at the price of a marked hyperinsulinaemia; (2) liver uptake of insulin is enhanced in obese rats, and (3) the insulin resistance syndrome of fa/fa rats is not due to a decrease in liver insulin receptor number and/or affinity but rather to as yet unknown event(s) subsequent to receptor binding.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-0428
    Keywords: Insulin antibodies ; insulin structure ; evolution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In the present study, we attempted to define possible subpopulations of antibodies which theoretically could be directed against evolutionarily conserved regions of the insulin molecule in sera from insulin-treated diabetic patients using a variety of labelled and unlabelled insulins which differ widely in structure but are very similar in functional properties. Ten high titre human insulin antisera from patients treated with mixed beef-pork insulin were examined. All sera were found to bind 125I-pork insulin better than labelled chicken insulin which bound better than labelled fish insulin. Detailed studies were conducted with four of the antisera using the pork and fish tracers. With two of the antisera, a subpopulation of antibody could be detected with 125I-fish insulin which had similar affinity for both fish and pork insulin, but reacted much less well with guinea pig insulin and the desoctapeptide derivative of porcine insulin. Based on the known properties of these four insulins, the data provide suggestive evidence consistent with the hypothesis that there are subpopulations of antibodies recognizing regions on the insulin molecule that are well conserved, possibly the region involved in the formation of insulin dimers or receptor binding.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-0428
    Keywords: Keywords Insulin receptor substrate-1 (IRS-1) ; non-insulin-dependent diabetes mellitus ; genetics ; single-stranded conformation polymorphisms ; insulin resistance ; polymorphism.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Since the insulin receptor substrate-1 (IRS-1) is the major substrate of the insulin receptor tyrosine kinase and has been shown to activate phosphatidylinositol (PI) 3-kinase and promote GLUT4 translocation, the IRS-1 gene is a potential candidate for development of non-insulin-dependent diabetes mellitus (NIDDM). In this study, we have identified IRS-1 gene polymorphisms, evaluated their frequencies in Japanese subjects, and analysed the contribution of these polymorphisms to the development of NIDDM. The entire coding region of the IRS-1 gene of 94 subjects (47 NIDDM and 47 control subjects) was screened by polymerase chain reaction-single stranded conformation polymorphism (PCR-SSCP) analysis. Seven SSCP polymorphisms were identified. These corresponded to two previously identified polymorphisms [Gly971→Arg (GGG→AGG) and Ala804 (GCA→GCG)] as well as five novel polymorphisms [Pro190→Arg (CCC→CGC), Met209→Thr (ATG→ACG), Ser809→Phe (TCT→TTT), Leu142 (CTT→CTC), and Gly625 (GGC→GGT)]. Although the prevalence of each of these polymorphisms was not statistically different between NIDDM and control subjects, the prevalence of the four IRS-1 polymorphisms with an amino acid substitution together was significantly higher in NIDDM than in control subjects (23.4 vs 8.5 %, p 〈 0.05), and two substitutions (Met209→Thr and Ser809→Phe) were found only in NIDDM patients. Equilibrium glucose infusion rates during a euglycaemic clamp in NIDDM and control subjects with the IRS-1 polymorphisms decreased by 29.5 and 22.0 %, respectively on the average when compared to those in comparable groups without polymorphisms, although they were not statistically significant. Thus, IRS-1 polymorphisms may contribute in part to the insulin resistance and development of NIDDM in Japanese subjects; however, they do not account for the major part of the decrease in insulin-stimulated glucose uptake which is observed in subjects with clinically apparent NIDDM. [Diabetologia (1996) 39: 600–608]
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-0428
    Keywords: Glycogen phosphorylase ; muscle ; gene expression ; insulin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Glycogen phosphorylase regulates the breakdown of glycogen into glucose, but as previous studies have demonstrated, the control of glycogen metabolism becomes deregulated in diabetes mellitus. Messenger RNA levels encoding several different proteins are altered in skeletal muscle biopsies of patients with insulin-dependent and non-insulin-dependent diabetes. The possible alteration of expression of the gene encoding the skeletal muscle isoform of glycogen phosphorylase during diabetes has not previously been investigated. We examined the effect of streptozotocin-induced diabetes and insulin treatment on glycogen phosphorylase mRNA in rat skeletal muscle; glycogen phosphorylase mRNA levels were elevated in diabetic rat muscle tissue, but were partially suppressed in diabetic rat muscle following insulin treatment. To distinguish between the effects of insulin and counter-regulatory hormones on glycogen phosphorylase mRNA levels, we employed differentiating rat L6 myoblasts in culture. Insulin stimulated the accumulation of glycogen phosphorylase mRNA as determined by Northern blot analysis. Moreover, insulin and dibutyryl cAMP stimulated expression of a transiently transfected chloramphenicol acetyl transferase reporter gene under the control of the muscle glycogen phosphorylase promoter in differentiating myotubes in culture, suggesting that the effects of insulin and counter-regulatory hormones on glycogen phosphorylase mRNA are at the level of transcription. These results suggest that insulin and epinephrine may participate in the induction of the glycogen phosphorylase gene during myogenesis; moreover, activation of this gene in muscle tissue may be a contributing factor in impaired glycogen storage during uncontrolled diabetes.
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Springer
    Diabetologia 40 (1997), S. B3 
    ISSN: 1432-0428
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    Diabetologia 35 (1992), S. 109-115 
    ISSN: 1432-0428
    Keywords: Membrane lipids ; insulin receptors ; insulin action ; tyrosine phosphorylation ; pp 185
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary To study the role of membrane lipids in signal transduction by the insulin receptor, we have studied the effect of phospholipase C (Clostridium perfringens) and a phosphatidylinositol-specific phospholipase (Staphylococcus aureus) on insulin binding, a function of the α-subunit, and tyrosine kinase activity, a function of the β-subunit in IM-9 lymphocytes and NIH 3T3 fibroblasts transfected with the human insulin receptor. Treatment of the cells with phospholipase C at concentrations up to 3.4 U/ml did not affect specific insulin binding, but reduced insulin-stimulated receptor phosphorylation by 50%. This effect of phospholipase C was observed within 10 min of treatment and occurred with no change in the basal level of phosphorylation. Pre-treatment of cells with insulin for 5 min prior to enzyme addition prevented any change in kinase activity. Insulin-stimulated phosphorylation of pp 185, the presumed endogenous substrate for the insulin receptor kinase, was also reduced following phospholipase C treatment, with an almost complete loss of insulin stimulation after exposure of cells to enzyme at concentrations as low as 0.6 U/ml. In contrast to these effects of phospholipase C on intact cells, receptor autophosphorylation was not affected in insulin receptors purified on wheat germ agglutinin-agarose from phospholipase C treated cells. Likewise, the phospholipase C effect was reduced by the addition of phosphatidylcholine, but not by the addition of the protease inhibitors, aprotinin and phenylmethylsulfonyl fluoride, to the incubation indicating its dependence on phospholipid hydrolysis. Treatment of cells with the phosphatidylinositol-specific phospholipase C did not affect any of the parameters studied. These data suggest that the phospholipid environment in the plasma membrane is an important modulator of transmembrane signalling within the insulin receptor heterotetramer and at the level of substrate phosphorylation.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1432-0428
    Keywords: Hyperinsulinaemic glucose clamp ; skeletal muscle ; liver ; insulin receptors ; tyrosine kinase ; insulin resistance ; β-subunit C-terminus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We have studied autophosphorylation and tyrosine kinase activity of the insulin receptor purified from liver and muscle of fasted rats before and after infusion of insulin (100 mU/h) during a 2.5 h glucose clamp. Recovery of insulin receptors and insulin binding to the solubilised receptors was unaffected by the glucose clamp. Autophosphorylation of the insulin receptor β subunit was increased in liver receptors prepared from rats at the end of the glucose clamp compared to rats in the basal state both in the absence of insulin in vitro (109% increase, p〈0.001) and after in vitro stimulation with 10−7 mol/l insulin (clamped vs fasted; 96% increase, p〈0.001). Insulin (10−7 mol/l) stimulated autophosphorylation was also increased in muscle receptor preparations from clamped rats compared with rats in the basal state (58% increase, p〈0.05). In both liver and muscle receptors, the clamp increased the amount of [32P]-phosphate incorporated into the β subunit without changing the sensitivity of the insulin stimulation. HPLC analysis of the tryptic phosphopeptides derived from the β subunit after insulin stimulated autophosphorylation of liver receptors revealed an increase of 32P in all phosphorylation sites without any change in the overall pattern. Tyrosine kinase activity of liver and muscle insulin receptors from clamped rats was also increased approximately twofold (p〈0.05) when analysed using a synthetic substrate (poly Glu4 Tyr1). Our results support the notion that the insulin receptor exists in an active and inactive form, and that elevated plasma insulin concentrations increases the proportion of active receptors.
    Type of Medium: Electronic Resource
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