Mechanisms of Muscle Insulin Resistance in Obese Individuals

2001 ◽  
Vol 11 (s1) ◽  
pp. S64-S70 ◽  
Author(s):  
G. Lynis Dohm
Keyword(s):  
Insulin Resistance ◽  
Tyrosine Kinase ◽  
Insulin Receptor ◽  
Kinase Activity ◽  
Insulin Receptors ◽  
Published Data ◽  
Tyrosine Kinase Activity ◽  
Insulin Signal Transduction ◽  
Insulin Resistant ◽  
Obese Subjects

We previously reported that insulin resistance in skeletal muscle of obese individuals was associated with decreases in insulin signal transduction and tyrosine kinase activity of the insulin receptor. Herein is reviewed the recently published data supporting the hypothesis that protein kinase C (PKC) phosphorylates the insulin receptor on serine/threonine residues to decrease tyrosine kinase activity and cause insulin resistance. Treatment of insulin receptors from obese subjects with alkaline phosphatase restored tyrosine kinase activity, suggesting that the reduced activity was a result of hyperphosphorylation of the receptor. Incubating human muscle fiber strips with PKC inhibitors restored insulin action in muscle of obese patients, while activating PKC with a phorbol ester caused insulin resistance in muscle from lean control patients. The beta isoform of PKC was elevated in muscle of obese, insulin-resistant patients. These data are consistent with the hypothesis that elevated PKC activity may cause insulin resistance by phosphorylating the insulin receptor to decrease tyrosine kinase activity.

High-fat feeding induces tissue-specific alteration in proportion of activated insulin receptors in rats

1990 ◽  
Vol 122 (3) ◽  
pp. 361-368 ◽  
Author(s):  
Karoly Nagy ◽  
Joseph Levy ◽  
George Grunberger
Keyword(s):  
Insulin Resistance ◽  
Tyrosine Kinase ◽  
Insulin Receptor ◽  
Kinase Activity ◽  
Insulin Receptors ◽  
Β Subunit ◽  
High Fat ◽  
Tyrosine Kinase Activity ◽  
Tissue Specific ◽  
Fat Feeding

Abstract High dietary fat intake causes glucose intolerance and insulin resistance in man and in laboratory rats. We studied possible mechanisms of this insulin resistance in rat kidney, muscle and liver. In high-fat fed rats the body weight, plasma insulin concentration, plasma glucose levels, and serum triglyceride concentration were significantly higher than in the control rats. 125I-insulin binding to kidney basolateral membrane insulin receptors from high-fat fed rats was lower than in control rats. Basal as well as insulin-stimulated tyrosine kinase activity per insulin receptor was higher in the highfat fed group, accompanied by increased autophosphorylation of the β-subunit of the receptor and higher proportion of tyrosine-phosphorylated insulin receptors. In contrast, both in the skeletal muscle and the liver the insulin-stimulated tyrosine kinase activity per insulin receptor was significantly lower in high-fat fed animals, accompanied by diminished autophosphorylation of the β-subunit of the receptor and lower proportion of tyrosinephosphorylated receptors. Our results indicate tissue-specific alterations in transmembrane signaling induced by high-fat feeding in target tissues for insulin which in turn might contribute to the observed insulin resistance.

scholarly journals Insulin receptor desensitization correlates with attenuation of tyrosine kinase activity, but not of receptor endocytosis

1987 ◽  
Vol 245 (2) ◽  
pp. 357-364 ◽  
Author(s):  
A D Blake ◽  
N S Hayes ◽  
E E Slater ◽  
C D Strader
Keyword(s):  
Tyrosine Kinase ◽  
Insulin Receptor ◽  
Receptor Tyrosine Kinase ◽  
Kinase Activity ◽  
Glycogen Synthesis ◽  
Insulin Receptors ◽  
Beta Subunit ◽  
Tyrosine Kinase Activity ◽  
Down Regulation ◽  
Receptor Endocytosis

A model of insulin-receptor down-regulation and desensitization has been developed and described. In this model, both insulin-receptor down-regulation and functional desensitization are induced in the human HepG2 cell line by a 16 h exposure of the cells to 0.1 microM-insulin. Insulin-receptor affinity is unchanged, but receptor number is decreased by 50%, as determined both by 125I-insulin binding and by protein immunoblotting with an antibody to the beta-subunit of the receptor. This down-regulation is accompanied by a disproportionate loss of insulin-stimulated glycogen synthesis, yielding a population of cell-surface insulin receptors which bind insulin normally but which are unable to mediate insulin-stimulated glycogen synthesis within the cell. Upon binding of insulin, the desensitized receptors are internalized rapidly, with characteristics indistinguishable from those of control cells. In contrast, this desensitization is accompanied by a loss of the insulin-sensitive tyrosine kinase activity of insulin receptors isolated from these cells. Receptors isolated from control cells show a 5-25-fold enhancement of autophosphorylation of the beta-subunit by insulin; this insulin-responsive autophosphorylation is severely attenuated after desensitization to a maximum of 0-2-fold stimulation by insulin. Likewise, the receptor-mediated phosphorylation of exogenous angiotensin II, which is stimulated 2-10-fold by insulin in receptors from control cells, is completely unresponsive to insulin in desensitized cells. These data provide evidence that the insulin-receptor tyrosine kinase activity correlates with insulin stimulation of an intracellular metabolic event. The data suggest that receptor endocytosis is not sufficient to mediate insulin's effects, and thereby argue for a role of the receptor tyrosine kinase activity in the mediation of insulin action.

IRS-1-Mediated Inhibition of Insulin Receptor Tyrosine Kinase Activity in TNF-alpha- and Obesity-Induced Insulin Resistance

Science ◽  
1996 ◽  
Vol 271 (5249) ◽  
pp. 665-670 ◽  
Author(s):  
G k. S. Hotamisligil ◽  
P. Peraldi ◽  
A. Budavari ◽  
R. Ellis ◽  
M. F. White ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Tyrosine Kinase ◽  
Insulin Receptor ◽  
Receptor Tyrosine Kinase ◽  
Kinase Activity ◽  
Tnf Alpha ◽  
Tyrosine Kinase Activity ◽  
Insulin Receptor Tyrosine Kinase

Increased insulin receptor number and insulin responsiveness in a chicken hepatoma cell line

1994 ◽  
Vol 140 (1) ◽  
pp. 119-124 ◽  
Author(s):  
M Taouis ◽  
M Derouet ◽  
J P Caffin ◽  
J Simon
Keyword(s):  
Tyrosine Kinase ◽  
Insulin Receptor ◽  
Kinase Activity ◽  
Hepatoma Cell ◽  
Insulin Receptors ◽  
Hepatoma Cell Line ◽  
Tyrosine Kinase Activity ◽  
Receptor Number ◽  
Insulin Responsiveness ◽  
Lmh Cells

Abstract Insulin receptor number and insulin responsiveness were compared in a chicken hepatoma cell line (LMH) and in normal chicken hepatocyte (cHep) cells cultured in the same conditions. LMH cells expressed two- to threefold more insulin receptors than cHep cells, without significant changes in affinity. The tyrosine kinase activity of solubilized and lectin (lentil+wheat germ agglutinin; WGA)-purified LMH receptors was higher than that of cHep receptors. The ATP hydrolytic activity previously observed in WGA-purified receptors from chicken liver membranes was also present in WGA-purified receptors from cultured cHep cells. This unidentified membrane-associated ATPase was absent from LMH membrane-solubilized material and therefore from WGA-purified LMH insulin receptors. Finally, LMH cells incorporated at least tenfold more amino isobutyric acid than cHep cells in the absence of insulin and were more responsive to insulin. The enhanced basal amino acid transport of LMH cells was most probably the consequence of their proliferative activity. The enhanced insulin responsiveness of LMH cells can be accounted for, at least in part, by one or several of the modifications presently demonstrated in LMH cells when compared with normal cultured hepatocytes: increased insulin receptor number and tyrosine kinase activity and possibly the loss of the membrane-associated ATPase. Journal of Endocrinology (1994) 140, 119–124

scholarly journals Effect of cyclic AMP-dependent protein kinase on insulin receptor tyrosine kinase activity

1987 ◽  
Vol 245 (1) ◽  
pp. 19-26 ◽  
Author(s):  
J F Tanti ◽  
T Grémeaux ◽  
N Rochet ◽  
E Van Obberghen ◽  
Y Le Marchand-Brustel
Keyword(s):  
Protein Kinase ◽  
Cyclic Amp ◽  
Tyrosine Kinase ◽  
Insulin Receptor ◽  
Kinase Activity ◽  
Insulin Receptors ◽  
Catalytic Subunit ◽  
Tyrosine Kinase Activity ◽  
Dependent Protein Kinase ◽  
Dependent Protein

To explain the insulin resistance induced by catecholamines, we studied the tyrosine kinase activity of insulin receptors in a state characterized by elevated noradrenaline concentrations in vivo, i.e. cold-acclimation. Insulin receptors were partially purified from brown adipose tissue of 3-week- or 48 h-cold-acclimated mice. Insulin-stimulated receptor autophosphorylation and tyrosine kinase activity of insulin receptors prepared from cold-acclimated mice were decreased. Since the effect of noradrenaline is mediated by cyclic AMP and cyclic AMP-dependent protein kinase, we tested the effect of the purified catalytic subunit of this enzyme on insulin receptors purified by wheat-germ agglutinin chromatography. The catalytic subunit had no effect on basal phosphorylation, but completely inhibited the insulin-stimulated receptor phosphorylation. Similarly, receptor kinase activity towards exogenous substrates such as histone or a tyrosine-containing copolymer was abolished. This inhibitory effect was observed with receptors prepared from brown adipose tissue, isolated hepatocytes and skeletal muscle. The same results were obtained on epidermal-growth-factor receptors. Further, the catalytic subunit exerted a comparable effect on the phosphorylation of highly purified insulin receptors. To explain this inhibition, we were able to rule out the following phenomena: a change in insulin binding, a change in the Km of the enzyme for ATP, activation of a phosphatase activity present in the insulin-receptor preparation, depletion of ATP, and phosphorylation of a serine residue of the receptor. These results suggest that the alteration in the insulin-receptor tyrosine kinase activity induced by cyclic AMP-dependent protein kinase could contribute to the insulin resistance produced by catecholamines.

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