Effect of benzyl succinate on insulin receptor function and insulin action in skeletal muscle: Further evidence for a lack of spare high-affinity insulin receptors

1993 ◽  
Vol 91 (1-2) ◽  
pp. 29-33 ◽  
Author(s):  
A. Gumà ◽  
F. Viñals ◽  
M. Camps ◽  
M. Lizarbe ◽  
C. Mora ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Receptor ◽  
Insulin Action ◽  
Insulin Receptors ◽  
Receptor Function ◽  
High Affinity

Insulin receptor kinase is hyperresponsive in adipocytes of young obese Zucker rats

1987 ◽  
Vol 252 (2) ◽  
pp. E273-E278 ◽  
Author(s):  
A. Debant ◽  
M. Guerre-Millo ◽  
Y. Le Marchand-Brustel ◽  
P. Freychet ◽  
M. Lavau ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Receptor ◽  
Insulin Action ◽  
Kinase Activity ◽  
Insulin Receptors ◽  
Zucker Rats ◽  
Receptor Kinase ◽  
Insulin Receptor Tyrosine Kinase ◽  
Obese Zucker Rats ◽  
Insulin Receptor Kinase

Thirty-day-old obese Zucker rats have hyperresponsive adipose tissue, whereas their skeletal muscle normally responds to insulin in vitro. To further substantiate the role of insulin receptor tyrosine kinase in insulin action, we have studied the kinase activity of receptors obtained from adipocytes and skeletal muscle of these young obese Zucker rats. Insulin receptors, partially purified by wheat germ agglutinin agarose chromatography from plasma membranes of isolated adipocytes or from skeletal muscles, were studied in a cell-free system for auto-phosphorylation and for their ability to phosphorylate a synthetic glutamate-tyrosine copolymer. For an identical amount of receptors, the insulin stimulatory action on its beta-subunit receptor phosphorylation was markedly augmented in preparations from hyperresponsive adipocytes of obese animals compared with lean rats. Basal phosphorylation of adipocyte insulin receptors was nearly identical in lean and obese animals. Similarly the capacity of adipocyte insulin receptors to catalyze the phosphorylation of the synthetic substrate in response to insulin was increased. By contrast, the kinase activity of insulin receptors prepared from normally insulin-responsive skeletal muscle was similar in preparations of lean and obese rats. These results show that a state of hyperresponsiveness to insulin is correlated with a parallel increase of insulin receptor kinase activity suggesting an important role for this activity in insulin action.

Effect of exercise on insulin receptor binding and kinase activity in skeletal muscle

1989 ◽  
Vol 256 (1) ◽  
pp. E138-E144 ◽  
Author(s):  
J. L. Treadway ◽  
D. E. James ◽  
E. Burcel ◽  
N. B. Ruderman
Keyword(s):  
Skeletal Muscle ◽  
Insulin Receptor ◽  
Insulin Action ◽  
White Muscle ◽  
Kinase Activity ◽  
Polyacrylamide Gel Electrophoresis ◽  
Sodium Dodecyl ◽  
Insulin Receptors ◽  
Insulin Binding ◽  
Similar Data

Insulin action in skeletal muscle is markedly enhanced for several hours after an acute bout of exercise. The purpose of this study was to examine the possible involvement of the intrinsic tyrosine kinase activity of the insulin receptor in mediating these effects. Red and white muscles were removed from rats either at rest or following a treadmill run (45 min at 18 m/min), and insulin receptors were isolated in partially purified form. Basal and insulin-stimulated receptor kinase activity was higher in red than in white muscle, in agreement with previous studies (J. Biol. Chem. 261: 14939-14944, 1986). There was no effect of exercise on insulin binding, basal and insulin-stimulated receptor autophosphorylation, or basal and insulin-stimulated exogenous kinase activity, in either red or white muscle. Similar data were obtained when phosphatase inhibitors were used during receptor isolation. The structure of insulin receptors isolated from the muscle of exercised and control rats was similar as judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of affinity cross-linked insulin receptors. We conclude that enhanced insulin action in muscle during the postexercise state is not related to increased kinase activity of the insulin receptor.

Differential effects of acute hypertriglyceridemia on insulin action and insulin receptor autophosphorylation

1996 ◽  
Vol 270 (3) ◽  
pp. E424-E429 ◽  
Author(s):  
B. Gumbiner ◽  
J. F. Mucha ◽  
J. E. Lindstrom ◽  
I. Rekhi ◽  
J. N. Livingston
Keyword(s):  
Skeletal Muscle ◽  
Insulin Receptor ◽  
Insulin Action ◽  
Insulin Receptors ◽  
Plasma Free Fatty Acid ◽  
High Plasma ◽  
Insulin Signal Transduction ◽  
A Site ◽  
Muscle Biopsies

Experimentally induced hypertriglyceridemia (HTG) and high plasma free fatty acid (FFA) levels impair in vivo insulin action. To determine if this is a consequence of impaired in vivo insulin receptor autophosphorylation and related to defective receptor signaling, hyperinsulinemic euglycemic clamps, indirect calorimetry, and skeletal muscle biopsies were performed in nine healthy subjects. In vivo insulin action was determined from the glucose infusion rate (GINF) and glucose oxidation (Glcox) during 40 and 120 mU/m2 /min clamps with (HTG clamp) and without (control clamp) a triglyceride emulsion infusion. The percentage of receptors autophosphorylated in vivo was determined by 125I-labeled insulin tracer binding in skeletal muscle immunoprecipitates of insulin receptors and phosphorylated receptors. Compared with the control clamps, plasma triglycerides and FFA increased four- and twofold, whereas GINF and Glcox decreased 15 and 35%, respectively, during the HTG clamps (all P<0.05). However, the percentages of receptors phosphorylated after the 40 and 120 mU/m2/min HTG clamps (9.2 +/- 1.5 and 21.1 +/- 2.6%, respectively) were similar to the control clamps (9.0 +/- 0.6 and 18.6 +/- 2.2%, respectively). These results indicate that, if impaired insulin signal transduction is a mechanism by which HTG and FFA impair insulin action, it occurs at a site downstream from insulin receptor autophosphorylation.

Activity of insulin receptor kinase and glycogen synthase in skeletal muscle from patients with chronic renal failure

1989 ◽  
Vol 121 (5) ◽  
pp. 744-750 ◽  
Author(s):  
Jens F. Bak ◽  
Ole Schmitz ◽  
Søren S. Sørensen ◽  
Jens Frøkjær ◽  
Torben Kjær ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Renal Failure ◽  
Chronic Renal Failure ◽  
Insulin Receptor ◽  
Glycogen Synthase ◽  
Insulin Receptors ◽  
Receptor Function ◽  
Uremic Patients ◽  
Glycogen Synthase Activity

Abstract. To examine subcellular mechanisms behind the pathogenesis of peripheral insulin resistance in chronic uremic patients, insulin receptor function and glycogen synthase activity were studied in biopsies of skeletal muscle obtained during renal transplant surgery in 9 non-diabetic uremic patients. The results were compared with values obtained in an age- and sex-matched group of subjects with normal renal function, undergoing surgery for urological or gynecological diseases. The recovery of solubilized, wheat germ agglutinin-purified insulin receptors from skeletal muscle was increased among the uremic patients: 49.3 ± 6.1 vs 31.4 ± 2.8 fmol/100 mg muscle in healthy controls (p < 0.03). Basal as well as insulin-stimulated kinase activities of the insulin receptors, expressed as phosphorylation of the synthetic peptide poly(Glu-Tyr(4:1)) were similar. In addition, the maximal activity of the glycogen synthase was enhanced in uremic muscle: 26.6 ± 2.8 vs 19.5 ± 1.8 nmol · (mg protein)−1 · min−1 (p < 0.05), whereas the half-maximal activation constant for glucose-6-phosphate was identical in the two groups. Likewise, the muscle glycogen concentrations were similar in the uremic patients and the normal controls. In conclusion, our data suggest that neither impaired insulin receptor function nor a reduced maximal glycogen synthase activity of skeletal muscle are involved in the pathogenesis of the insulin resistance of patients with chronic renal failure.

scholarly journals Evidence for the lack of spare high-affinity insulin receptors in skeletal muscle

1992 ◽  
Vol 285 (3) ◽  
pp. 993-999 ◽  
Author(s):  
M Camps ◽  
A Gumà ◽  
F Viñals ◽  
X Testar ◽  
M Palacín ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Tyrosine Kinase ◽  
Dose Response ◽  
Receptor Tyrosine Kinase ◽  
Insulin Action ◽  
Response Curve ◽  
Kinase Activity ◽  
Insulin Receptors ◽  
Insulin Concentration ◽  
High Affinity

In this study, the relationship between the concentration of extracellular insulin, insulin binding and insulin action was evaluated in skeletal muscle. Initially we investigated the dose-response relationship of insulin action using three different experimental models that are responsive to insulin, i.e. the isolated perfused rat hindquarter, incubated strips of soleus muscle, and insulin receptors partially affinity-purified from skeletal muscle. We selected as insulin-sensitive parameters glucose uptake in the perfused hindquarter, lactate production in the incubated muscle preparation, and tyrosine receptor kinase activity in the purified receptor preparation. Our results showed that the dose-response curves obtained in the perfused hindquarter and in the incubated muscle were superimposable. In contrast, the dose-response curve for insulin-stimulated receptor tyrosine kinase activity in partially purified receptors was displaced to the left compared with the curves obtained in the perfused hindquarter and in the incubated muscle. The differences between the dose-response curve for receptor tyrosine kinase and those for glucose uptake and lactate production were not explained by a substantial insulin concentration gradient between medium and interstitial space. Thus the medium/interstitial insulin concentration ratio, when assayed in the incubated intact muscle at 5 degrees C, was close to 1. We also compared the dose-response curve of insulin-stimulated receptor tyrosine kinase with the pattern of insulin-binding-site occupancy. The curve of insulin-stimulated receptor kinase activity fitted closely with the occupancy of high-affinity binding sites. In summary, assuming that the estimation of the medium/interstitial insulin concentration ratio obtained at 5 degrees C reflects the actual ratio under more physiological conditions, our results suggest that maximal insulin action is obtained in skeletal muscle at insulin concentrations which do allow full occupancy of high-affinity binding sites. Therefore our data provide evidence for a lack of spare high-affinity insulin receptors in skeletal muscle.

Insulin action and resistance in obesity and noninsulin-dependent type II diabetes mellitus

1982 ◽  
Vol 243 (1) ◽  
pp. E15-E30 ◽  
Author(s):  
J. M. Olefsky ◽  
O. G. Kolterman ◽  
J. A. Scarlett
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Insulin Receptor ◽  
Insulin Action ◽  
Insulin Receptors ◽  
Tissue Level ◽  
Dependent Diabetes Mellitus ◽  
Target Tissue ◽  
Severe Insulin Resistance ◽  
Glucose Clamp Technique

Resistance to the action of insulin can result from a variety of causes, including the formation of abnormal insulin or proinsulin molecules, the presence of circulating antagonists to insulin or the insulin receptor, or defects in insulin action at the target tissue level. Defects of the latter type are characteristic of obesity and of noninsulin-dependent diabetes mellitus. Analysis of the nature of the insulin resistance in those disorders has been investigated in intact subjects with the use of the euglycemic glucose clamp technique, and both insulin receptors and insulin-mediated glucose metabolism have been studied in adipocytes and monocytes from affected individuals. In both conditions, the cause of insulin resistance is heterogeneous. In some, insulin resistance appears to be due to a defect in the insulin receptor, whereas others have a defect both in the receptor and at the postreceptor level. In both groups, more severe insulin resistance is due to the postreceptor lesion and is correctable with appropriate therapy.

scholarly journals Interplay and Effects of Temporal Changes in the Phosphorylation State of Serine-302, -307, and -318 of Insulin Receptor Substrate-1 on Insulin Action in Skeletal Muscle Cells

2008 ◽  
Vol 22 (12) ◽  
pp. 2729-2740 ◽  
Author(s):  
Cora Weigert ◽  
Matthias Kron ◽  
Hubert Kalbacher ◽  
Ann Kathrin Pohl ◽  
Heike Runge ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Insulin Receptor ◽  
Insulin Action ◽  
Muscle Cells ◽  
Skeletal Muscle Cells ◽  
Insulin Signal ◽  
Kinase C ◽  
Phosphorylation Pattern

Abstract Transduction of the insulin signal is mediated by multisite Tyr and Ser/Thr phosphorylation of the insulin receptor substrates (IRSs). Previous studies on the function of single-site phosphorylation, particularly phosphorylation of Ser-302, -307, and -318 of IRS-1, showed attenuating as well as enhancing effects on insulin action. In this study we investigated a possible cross talk of these opposedly acting serine residues in insulin-stimulated skeletal muscle cells by monitoring phosphorylation kinetics, and applying loss of function, gain of function, and combination mutants of IRS-1. The phosphorylation at Ser-302 was rapid and transient, followed first by Ser-318 phosphorylation and later by phosphorylation of Ser-307, which remained elevated for 120 min. Mutation of Ser-302 to alanine clearly reduced the subsequent protein kinase C-ζ-mediated Ser-318 phosphorylation. The Ser-307 phosphorylation was independent of Ser-302 and/or Ser-318 phosphorylation status. The functional consequences of these phosphorylation patterns were studied by the expression of IRS-1 mutants. The E302A307E318 mutant simulating the early phosphorylation pattern resulted in a significant increase in Akt and glycogen synthase kinase 3 phosphorylation. Furthermore, glucose uptake was enhanced. Because the down-regulation of the insulin signal was not affected, this phosphorylation pattern seems to be involved in the enhancement but not in the termination of the insulin signal. This enhancing effect was completely absent when Ser-302 was unphosphorylated and Ser-307 was phosphorylated as simulated by the A302E307E318 mutant. Phospho-Ser-318, sequentially phosphorylated at least by protein kinase C-ζ and a mammalian target of rapamycin/raptor-dependent kinase, was part of the positive as well as of the subsequent negative phosphorylation pattern. Thus we conclude that insulin stimulation temporally generates different phosphorylation statuses of the same residues that exert different functions in insulin signaling.

Effects of hyperinsulinemia and hyperglycemia on insulin receptor function and glycogen synthase activation in skeletal muscle of normal man

Metabolism ◽  
1991 ◽  
Vol 40 (8) ◽  
pp. 830-835 ◽  
Author(s):  
Jens Friss Bak ◽  
Niels Møller ◽  
Ole Schmitz ◽  
Erik A. Richter ◽  
Oluf Pedersen
Keyword(s):  
Skeletal Muscle ◽  
Insulin Receptor ◽  
Glycogen Synthase ◽  
Receptor Function ◽  
Normal Man

Decreased muscle insulin receptor kinase correlates with insulin resistance in normoglycemic Pima Indians

1997 ◽  
Vol 273 (2) ◽  
pp. E276-E283 ◽  
Author(s):  
J. F. Youngren ◽  
I. D. Goldfine ◽  
R. E. Pratley
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Body Fat ◽  
Insulin Action ◽  
Enzyme Linked Immunosorbent Assay ◽  
Percent Body Fat ◽  
Receptor Function ◽  
Pima Indians ◽  
Insulin Receptor Tyrosine Kinase

Defects in insulin receptor tyrosine kinase activity are present in insulin-resistant non-insulin-dependent diabetes mellitus patients and certain nondiabetic individuals, both lean and obese. However, the relationship between insulin receptor function, insulin action, and obesity is unclear. To address this issue, we have employed a new and highly sensitive enzyme-linked immunosorbent assay to measure in vitro insulin-stimulated autophosphorylation of immunocaptured muscle insulin receptors in a group of 25 normoglycemic Pima Indians. Insulin action, determined during two-step euglycemic insulin clamps, varied widely in these subjects. Maximal in vitro insulin stimulation of insulin receptor autophosphorylation strongly correlated with both low (Mlow)- and high (Mhigh)-dose insulin-stimulated glucose disposal (r = 0.62 and 0.51, P < 0.002 and 0.011, respectively). Insulin receptor autophosphorylation was inversely related to percent body fat (r = -0.52, P < 0.009). After control for percent body fat, receptor autophosphorylation remained correlated with Mlow (partial r = 0.49, P < 0.025). These data therefore suggest that defects in insulin receptor function are major contributors to insulin resistance in both lean and obese normoglycemic Pima Indians.

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