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.

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.

In vivo insulin mimetic effects of pV compounds: role for tissue targeting in determining potency

1995 ◽  
Vol 268 (1) ◽  
pp. E60-E66 ◽  
Author(s):  
A. P. Bevan ◽  
J. W. Burgess ◽  
J. F. Yale ◽  
P. G. Drake ◽  
D. Lachance ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Receptor ◽  
Glycogen Synthesis ◽  
Insulin Receptors ◽  
Receptor Kinase ◽  
Rat Diaphragm ◽  
Insulin Mimetic ◽  
Integrated Response ◽  
Insulin Receptor Kinase

Peroxovanadium (pV) compounds activate the insulin receptor kinase in hepatocytes and inhibit the dephosphorylation of insulin receptors in hepatic endosomes with highly correlated potencies (Posner, B. I., R. Faure, J. W. Burgess, A. P. Bevan, D. Lachance, G. Zhang-Sun, J. B. Ng, D. A. Hall, B. S. Lum, and A. Shaver J. Biol. Chem. 269: 4596–4604, 1994). After intravenous administration, K2[VO(O2)2(picolinato)].2H2O [bpV(pic)], VO(O2) (picolinato) (H2O)2 [mpV(pic)], K[VO(O2)2(picolinato)].3H2O [bpV(phen)], and K[VO(O2)2(4,7-dimethyl-1,10-phenanthroline)].1/2H2O [bpV(Me2phen)] produced 50% of their maximal hypoglycemic effect at doses of 0.04, 0.04, 0.32, and 0.65 mumol/100 g body wt, respectively. In contrast, their potencies as inhibitors of dephosphorylation were bpV(pic) = bpV(phen) > mpV(pic) = bpV(Me2phen). bpV(pic) stimulated [14C]glucose incorporation into rat diaphragm glycogen in vivo, and its effect was dose dependent, synergistic with insulin, and evident in other skeletal muscles. In contrast, bpV(phen) displayed no effect on glycogen synthesis in skeletal muscle. mpV(pic) stimulated and bpV(Me2phen) had no effect on glycogen synthesis in the diaphragm. bpV(pic) augmented rat diaphragm insulin receptor kinase 2.2-fold with a time-integrated response 70% that of insulin. In contrast, the effect of bpV(phen) was delayed and much reduced. Thus, the in vivo potencies of pV compounds reflect differing capacities to act on skeletal muscle. The ancillary ligand within the pV complex may target one tissue in preference to another.

Insulin receptor binding and kinase activity in liver and skeletal muscles of lactating goats

1992 ◽  
Vol 262 (5) ◽  
pp. E561-E568 ◽  
Author(s):  
M. Balage ◽  
C. Sornet ◽  
J. Grizard
Keyword(s):  
Insulin Receptor ◽  
Skeletal Muscles ◽  
Insulin Action ◽  
Kinase Activity ◽  
Insulin Receptors ◽  
Insulin Binding ◽  
Insulin Receptor Tyrosine Kinase ◽  
Lactating Goats ◽  
A Minor

Lactation in goats has been shown to modify in vivo insulin action. [Debras, E., J. Grizard, E. Aina, S. Tesseraud, C. Champredon, and M. Arnal. Am. J. Physiol. 256 (Endocrinol. Metab. 19): E295-E302, 1989]. To further elucidate the mechanism of insulin action, we studied insulin binding and insulin receptor tyrosine kinase activity in solubilized and partially purified receptor preparations from liver and skeletal muscles (longissimus dorsi, tensor fascia lata, diaphragm, and masseter) from lactating and nonlactating goats. Lactation did not alter insulin receptors in the various skeletal muscles and had a minor influence on liver receptors (where only a 20% increase in receptor number was visible, P less than 0.05). Insulin-stimulated autophosphorylation and the kinase activity against polyglutamyltyrosine (4:1) were not significantly modified in skeletal muscle receptor preparations from lactating goats when compared with nonlactating animals. They tended to decrease in liver preparations, but not significantly. Thus the changes in insulin action in vivo during lactation in goats were not related to modifications in insulin kinase activity but were probably localized at a postreceptor level.

scholarly journals Endothelial insulin receptors differentially control insulin signaling kinetics in peripheral tissues and brain of mice

2017 ◽  
Vol 114 (40) ◽  
pp. E8478-E8487 ◽  
Author(s):  
Masahiro Konishi ◽  
Masaji Sakaguchi ◽  
Samuel M. Lockhart ◽  
Weikang Cai ◽  
Mengyao Ella Li ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Endothelial Cells ◽  
Food Intake ◽  
Insulin Signaling ◽  
Insulin Action ◽  
Insulin Receptors ◽  
Brain Regions ◽  
Peripheral Tissues ◽  
Systemic Insulin Resistance

Insulin receptors (IRs) on endothelial cells may have a role in the regulation of transport of circulating insulin to its target tissues; however, how this impacts on insulin action in vivo is unclear. Using mice with endothelial-specific inactivation of the IR gene (EndoIRKO), we find that in response to systemic insulin stimulation, loss of endothelial IRs caused delayed onset of insulin signaling in skeletal muscle, brown fat, hypothalamus, hippocampus, and prefrontal cortex but not in liver or olfactory bulb. At the level of the brain, the delay of insulin signaling was associated with decreased levels of hypothalamic proopiomelanocortin, leading to increased food intake and obesity accompanied with hyperinsulinemia and hyperleptinemia. The loss of endothelial IRs also resulted in a delay in the acute hypoglycemic effect of systemic insulin administration and impaired glucose tolerance. In high-fat diet-treated mice, knockout of the endothelial IRs accelerated development of systemic insulin resistance but not food intake and obesity. Thus, IRs on endothelial cells have an important role in transendothelial insulin delivery in vivo which differentially regulates the kinetics of insulin signaling and insulin action in peripheral target tissues and different brain regions. Loss of this function predisposes animals to systemic insulin resistance, overeating, and obesity.

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.

A malonyl-CoA fuel-sensing mechanism in muscle: effects of insulin, glucose, and denervation

1995 ◽  
Vol 269 (2) ◽  
pp. E283-E289 ◽  
Author(s):  
A. K. Saha ◽  
T. G. Kurowski ◽  
N. B. Ruderman
Keyword(s):  
Skeletal Muscle ◽  
Plasma Insulin ◽  
Contractile Activity ◽  
High Plasma ◽  
Muscle Contractions ◽  
Glucose Levels ◽  
Malonyl Coa ◽  
Ad Libitum ◽  
Sciatic Nerve Stimulation

Increases in the concentration of malonyl-CoA in skeletal muscle have been observed in the KKAy mouse, an obese rodent with high plasma insulin and glucose levels [Saha et al. Am. J. Physiol. 267 (Endocrinol. Metab. 30): E95-E101, 1994]. To assess whether insulin and glucose directly regulate malonyl-CoA in muscle, soleus muscles from young rats were incubated with insulin and glucose at various concentrations, and their content of malonyl-CoA was determined. In addition, the effect on malonyl-CoA of denervation and electrically induced muscle contractions was assessed. The concentration of malonyl-CoA in the soleus, taken directly from a rat fed ad libitum, was 2.0 +/- 0.2 nmol/g. In muscles incubated for 20 min in a medium devoid of added insulin and glucose, the concentration was decreased to 0.8 +/- 0.2 nmol/g. When the medium contained 0.5, 7.5, or 30 mM glucose, malonyl-CoA levels were 1.3 +/- 0.1, 1.8 +/- 0.1, or 2.4 +/- 0.2 nmol/g, respectively, in the absence of insulin and 1.7 +/- 0.1, 4.6 +/- 0.3, or 5.5 +/- 0.6 nmol/g in its presence (10 mU/ml). Compared with its level in a control muscle, the concentration of malonyl-CoA was increased threefold in the soleus 6-8 h after denervation and remained twofold higher for > or = 48 h. In contrast, muscle contractions induced by sciatic nerve stimulation, in vivo, acutely decreased the concentration of malonyl-CoA by 30-35%. The results indicate that insulin and glucose, and probably contractile activity, regulate the concentration of malonyl-CoA in muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

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