Mechanisms by Which Insulin and Muscle Contraction Stimulate Glucose Transport

1997 ◽  
Vol 22 (6) ◽  
pp. 519-530 ◽  
Author(s):  
Ronald N. Cortright ◽  
G. Lynis Dohm
Keyword(s):  
Insulin Receptor ◽  
Glucose Uptake ◽  
Glucose Transport ◽  
Initial Step ◽  
Insulin Binding ◽  
Channel Blockers ◽  
Receptor Kinase ◽  
Increase Insulin Sensitivity ◽  
Key Words Insulin ◽  
Insulin Receptor Kinase

Insulin binding to its receptor activates a tyrosine kinase that initiates a cascade of signaling events, the initial step being the tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1). Subsequent IRS-1 association and activation of phosphatidylinositiol 3-kinase (PI 3-kinase) is believed to be involved in the events leading to the translocation of glucose transporters (GLUT4) to the plasma membrane resulting in uptake of glucose into the cell. Muscle contractions increase insulin sensitivity, but also stimulate muscle glucose uptake independent of insulin. The contraction signaling pathway is distinct from the insulin pathway because the effect of insulin and contractions on glucose uptake are additive, and contractions do not increase insulin receptor kinase or PI 3-kinase activity. In contrast, studies indicating that contractions cause the translocation of GLUT4 and that both contractions and insulin-stimulated glucose transport can be blocked by calcium channel blockers suggest that the two pathways may converge. However, the possibility that two distinct GLUT4 pools may be targeted, one by insulin the other by contractions, indicates that additional research is needed to better define the mechanisms by which glucose transport is stimulated in muscle. Key words: insulin signaling, exercise

Effect of a high-fat-sucrose diet on in vivo insulin receptor kinase activation

1990 ◽  
Vol 259 (1) ◽  
pp. E111-E116 ◽  
Author(s):  
J. J. Boyd ◽  
I. Contreras ◽  
M. Kern ◽  
E. B. Tapscott ◽  
D. L. Downes ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Glucose Uptake ◽  
Kinase Activity ◽  
Insulin Binding ◽  
Receptor Kinase ◽  
High Fat ◽  
Glucose Injection ◽  
Insulin Receptor Kinase

Insulin-stimulated glucose uptake into muscle is depressed by high-fat-sucrose (HFS) feeding of rats. To investigate the mechanism of this insulin resistance, the in vivo activation of the insulin receptor kinase in liver and muscle of control and HFS-fed rats was determined. Rats were injected with glucose and insulin and killed 0, 5, 15, and 30 min after injection. Insulin binding was not changed in partially purified receptors from muscle of HFS rats. In control rats insulin receptor kinase activity was maximally stimulated threefold in liver at 5 min and fourfold in muscle at 15 min after insulin-glucose injection. The insulin-stimulated tyrosine kinase activity of receptors isolated from the liver of rats fed the HFS diet was decreased by 30% in comparison with the controls. In contrast, receptors isolated from muscle did not show any difference in basal or insulin-stimulated kinase activity between HFS-fed and control rats. Decreased in vivo activation of the insulin receptor kinase may be at least partially responsible for insulin resistance in liver. Because insulin binding and insulin stimulation of receptor kinase were normal in muscle of HFS-fed animals, it is concluded that the insulin resistance of glucose uptake into muscle is caused by a defect distal to the insulin receptor.

scholarly journals The inhibition of insulin action and glucose metabolism by porcine growth hormone in porcine adipocytes is not the result of any decrease in insulin binding or insulin receptor kinase activity

1990 ◽  
Vol 266 (1) ◽  
pp. 107-113 ◽  
Author(s):  
K A Magri ◽  
M Adamo ◽  
D Leroith ◽  
T D Etherton
Keyword(s):  
Insulin Receptor ◽  
Glucose Transport ◽  
Kinase Activity ◽  
Insulin Binding ◽  
Transport Rate ◽  
Receptor Kinase ◽  
Insulin Responsiveness ◽  
Porcine Adipocytes ◽  
Insulin Receptor Kinase ◽  
Insulin Receptor Kinase Activity

The present study was undertaken to determine the effects of porcine growth hormone (pGH) on glucose transport, to establish which lipogenic enzymes were affected by pGH, and to determine if changes in insulin binding or insulin receptor kinase activity contributed to the diminished insulin responsiveness of adipocytes from pigs treated with pGH. Pigs were treated with pGH daily (70 micrograms/kg body wt.) for 7 days. pGH treatment reduced the basal (non-insulin-stimulated) glucose transport rate by 62% and the insulin-stimulated transport rate by 47%. The decline in glucose transport rate was paralleled by a 64% decrease in fatty acid synthesis. The reduction in the lipogenic rate was associated with a marked decline in the activity of several lipogenic enzymes: glucose-6-phosphate dehydrogenase (50% decrease), 6-phosphogluconate dehydrogenase (11% decrease), malic enzyme (62% decrease) and fatty acid synthase (activity not detectable after pGH treatment). The pGH-dependent decline in insulin responsiveness was not associated with any change in the binding of insulin to intact adipocytes or to plasma membrane preparations. The insulin-stimulated tyrosine kinase activity of the wheat-germ agglutinin-purified receptors from pGH-treated adipocytes was not different from that in control adipocytes, except when high concentrations of insulin were employed. These findings establish that pGH elicits a number of metabolic effects in porcine adipocytes which collectively diminish the rate of lipid synthesis, and thereby contribute to the decrease in lipid deposition observed in pGH-treated pigs. Furthermore, the pGH-dependent impairment in insulin action appears to be mediated at some location distal to the receptor kinase step or in other signal pathway(s) which mediate the biological effects of insulin that are not dependent on activation of insulin receptor tyrosine kinase activity.

scholarly journals Insulin receptor function is inhibited by guanosine 5′-[γ-thio]triphosphate (GTP[S])

1990 ◽  
Vol 270 (2) ◽  
pp. 401-407 ◽  
Author(s):  
H W Davis ◽  
J M McDonald
Keyword(s):  
Insulin Receptor ◽  
G Proteins ◽  
Plasma Membranes ◽  
Insulin Receptors ◽  
Insulin Binding ◽  
Peptide Sequence ◽  
Receptor Kinase ◽  
Receptor Function ◽  
Gtp Binding ◽  
Insulin Receptor Kinase

The regulatory role of GTP-binding proteins (G-proteins) in insulin receptor function was investigated using isolated insulin receptors and plasma membranes from rat adipocytes. Treatment of isolated insulin receptors with 1 mM-guanosine 5′-[gamma-thio]triphosphate (GTP[S]) inhibited insulin-stimulated phosphorylation of the beta-subunit, histone Hf2b and poly(GluNa4,Tyr1) by 22%, 65% and 65% respectively. Phosphorylation of calmodulin by the insulin receptor kinase was also inhibited by 1 mM-GTP[S] both in the absence (by 88%) and in the presence (by 81%) of insulin. In the absence of insulin, 1 mM-GTP had the same effect on calmodulin phosphorylation as 1 mM-GTP[S]. However, when insulin was present, GTP was less effective than GTP[S] (41% versus 81% inhibition). Concentrations of GTP[S] greater than 250 microM are necessary to inhibit phosphorylation. Although these concentrations are relatively high, the effect of GTP[S] is not due to competition with [32P]ATP for the insulin receptor kinase since (1) other nucleotide triphosphates did not inhibit phosphorylation as much as did GTP[S] (or GTP) and (2) the Vmax of the ATP-dependent kinase reaction was decreased in the presence of GTP[S]. GTP[S] (1 mM) also inhibited insulin binding to isolated receptors and plasma membranes, by 80% and 50% respectively. Finally, an antibody raised to a peptide sequence common to the alpha-subunits of G-proteins Gs, Gi, Go and transducin detected G-proteins in plasma membranes but failed to detect them in the insulin receptor preparation. These results indicate that GTP inhibits insulin receptor function, but does so through a mechanism that does not require a conventional GTP-binding protein.

scholarly journals ATP-dependent Desensitization of Insulin Binding and Tyrosine Kinase Activity of the Insulin Receptor Kinase

1998 ◽  
Vol 273 (34) ◽  
pp. 22007-22013 ◽  
Author(s):  
Jean-Olivier Contreres ◽  
Robert Faure ◽  
Gerardo Baquiran ◽  
John J. Bergeron ◽  
Barry I. Posner
Keyword(s):  
Tyrosine Kinase ◽  
Insulin Receptor ◽  
Kinase Activity ◽  
Insulin Binding ◽  
Receptor Kinase ◽  
Tyrosine Kinase Activity ◽  
Insulin Receptor Kinase

scholarly journals Lipid-induced insulin resistance in cultured hepatoma cells is associated with a decreased insulin receptor tyrosine kinase activity.

1991 ◽  
Vol 2 (1) ◽  
pp. 65-72 ◽  
Author(s):  
P Hubert ◽  
C Bruneau-Wack ◽  
G Cremel ◽  
Y Le Marchand-Brustel ◽  
C Staedel
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Kinase Activity ◽  
Insulin Binding ◽  
Hepatoma Cells ◽  
Receptor Kinase ◽  
Insulin Receptor Tyrosine Kinase ◽  
Normal Medium ◽  
Insulin Receptor Kinase ◽  
Insulin Receptor Kinase Activity

We have shown previously that experimental modifications of the cellular lipid composition of an insulin-sensitive rat hepatoma cell line (Zajdela Hepatoma Culture, ZHC) affect both binding and biological actions of insulin. Discrepancies between insulin binding and actions implied a postbinding defect, responsible for the observed insulin resistance in lipid-treated cells. To elucidate the mechanism for this defect, we have studied insulin binding and insulin receptor kinase activity in partially purified receptor preparations from ZHC cells grown either in normal medium or in medium supplemented with linoleic acid or 25-hydroxycholesterol. Insulin binding to the lectin-purified insulin receptor showed only a small alteration in receptor affinity for the preparations from lipid-treated cells. Insulin-stimulated autophosphorylation of the beta-subunit of the insulin receptor, as well as insulin-induced phosphorylation of the artificial substrate poly(Glu,Tyr)4:1, was significantly decreased in the preparations from lipid-modified cells. Although differences in basal levels were observed, the magnitude of the insulin-stimulated kinase activity was significantly decreased in receptor preparations from lipid-treated cells. These findings indicate that experimental modification of the lipids of cultured hepatoma cells can produce in insulin receptor kinase activity changes that are proportional to the reduced insulin action observed in these cells.

Insulin resistance in uremia: insulin receptor kinase activity in liver and muscle from chronic uremic rats

1988 ◽  
Vol 254 (4) ◽  
pp. E394-E401 ◽  
Author(s):  
F. Cecchin ◽  
O. Ittoop ◽  
M. K. Sinha ◽  
J. F. Caro
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Receptor ◽  
Kinase Activity ◽  
Insulin Binding ◽  
Beta Subunit ◽  
Receptor Kinase ◽  
Ad Libitum ◽  
Insulin Receptor Kinase ◽  
Insulin Receptor Kinase Activity

We have studied the structure and function of the partially purified insulin receptors from liver and skeletal muscle in a rat model of severe chronic uremia. 125I-insulin binding was higher in the liver from uremic rats when compared with ad libitum- and pair-fed controls. Furthermore, the ability of insulin to stimulate the autophosphorylation of the beta-subunit and insulin receptor kinase activity using Glu80, Tyr20 as exogenous phosphoacceptor was increased in the liver of the uremic animals. The structural characteristic of the receptors, as determined by electrophoretic mobilities of affinity labeled alpha-subunit and the phosphorylated beta-subunit, were normal in uremia. 125I-insulin binding and insulin receptor kinase activity were similar in the skeletal muscle from uremic and pair- and ad libitum-fed animals. Thus our data are supportive of the hypothesis that in liver and muscle of chronic uremic rats, insulin resistance is due to a defect(s) distal to the insulin receptor kinase.

scholarly journals Insulin activation of insulin receptor kinase in erythrocytes is not altered in non-insulin-dependent diabetes and not influenced by hyperglycemia

2000 ◽  
Vol 166 (2) ◽  
pp. 275-281 ◽  
Author(s):  
HH Klein ◽  
R Muller ◽  
M Drenckhan ◽  
M Schutt ◽  
B Batge ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Insulin Receptors ◽  
Insulin Binding ◽  
Diabetic Control ◽  
Insulin Dependent Diabetes ◽  
Receptor Kinase ◽  
Kinase Activation ◽  
Insulin Dependent ◽  
Insulin Receptor Kinase

Recent studies suggest that high glucose concentrations impair insulin receptor phosphorylation and kinase activation in certain cell models. To examine whether such an effect of glucose can also be demonstrated in vivo, insulin receptor kinase activation was studied in erythrocytes from 11 patients with non-insulin-dependent diabetes (NIDDM), before and after reduction of hyperglycemia (from 14.6+/-1.6 to 6.6+/-0.5 mmol/l fasting plasma glucose within 8.6+/-0.6 days). For the measurement of receptor kinase activation, cells were incubated with insulin (0-400 nmol/l), solubilized and insulin receptors immobilized to microwells coated with anti-insulin receptor antibody. Kinase activity towards insulin receptor substrate-1 and insulin binding were then measured in these wells. Kinase activities (expressed as amol phosphate transferred per min and per fmol insulin binding activity) were similar before (2.4+/-0.4 and 32.2+/-2.0 amol/min per fmol with 0 and 400 nmol/l insulin, respectively) and after improvement of metabolic control (2.4+/-0.5 and 32.0+/-2.3 amol/min per fmol with 0 and 400 nmol/l insulin, respectively). Moreover, activities were also similar in 22 hyperglycemic patients with NIDDM (2.1+/-0.3 and 35.1+/-1.4 amol/min per fmol with 0 and 400 nmol/l insulin, respectively) compared with those in 21 non-diabetic control individuals (2.1+/-0.3 and 34.2+/-1.2 amol/min per fmol with 0 and 400 nmol/l insulin, respectively). We conclude that insulin activation of erythrocyte insulin receptor kinase is not impaired in NIDDM and is not influenced by hyperglycemia.

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