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.

Impaired insulin action but normal insulin receptor activity in diabetic rat liver: effect of vanadate

1990 ◽  
Vol 258 (3) ◽  
pp. E459-E467 ◽  
Author(s):  
O. Blondel ◽  
J. Simon ◽  
B. Chevalier ◽  
B. Portha
Keyword(s):  
Insulin Receptor ◽  
Insulin Action ◽  
Diabetic Rats ◽  
Receptor Kinase ◽  
Peripheral Tissues ◽  
Impaired Insulin ◽  
Insulin Dependent ◽  
Insulin Receptor Kinase ◽  
Impaired Insulin Action

In vivo insulin resistance is a characteristic of the liver and peripheral tissues in 10-wk-old female rats with non-insulin-dependent diabetes induced by streptozotocin given on day 5 after birth. Oral administration of vanadate (0.2 mg/ml) for 20 days in the diabetic rats lowered their plasma glucose levels to normal values without affecting their basal plasma insulin levels. In the basal state as well as after submaximal or maximal hyperinsulinemia (euglycemic clamp studies), peripheral glucose utilization and hepatic glucose production in vivo were normalized in the diabetic rats after the vanadate treatment. In wheat germ agglutinin purified receptors, 125I-labeled porcine insulin binding, basal and insulin-stimulated insulin receptor kinase activities for both the autophosphorylation of the beta-subunit and the phosphorylation of the artificial substrate poly (Glu-Tyr) 4:1, were found identical in diabetic and control rats, treated or not with vanadate. Liver phosphoenolpyruvate carboxykinase activity was significantly enhanced in untreated diabetic rats (P less than 0.01) as compared with control rats and returned to normal values after the 20-day vanadate treatment. Thus, in that model of non-insulin-dependent diabetes, 1) oral vanadate exerts a corrective insulin-like effect on impaired insulin action both at the level of liver and peripheral tissues, 2) impaired insulin action with no alteration of the insulin receptor tyrosine kinase is observed in the liver of untreated rats, and 3) corrective effect of vanadate on liver glucose metabolism is probably distal to the insulin receptor 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.

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.

Increased in-vivo insulin sensitivity but normal liver insulin receptor kinase activity in dwarf chickens

1990 ◽  
Vol 126 (1) ◽  
pp. 67-74 ◽  
Author(s):  
I. Guéritault ◽  
J. Simon ◽  
B. Chevalier ◽  
M. Derouet ◽  
M. Tixier-Boichard ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Tyrosine Kinase ◽  
Insulin Receptor ◽  
Kinase Activity ◽  
Insulin Receptors ◽  
Oral Glucose ◽  
Receptor Kinase ◽  
Tyrosine Kinase Activity ◽  
Insulin Receptor Kinase

ABSTRACT The effects of the recessive and sex-linked dw gene on insulin sensitivity and liver insulin receptors were compared in normal (Dw-dw) and dwarf (dw-dw) brother or half-brother chickens. At 3·5 weeks of age, following an overnight fast, exogenous insulin (0–6·9 nmol/kg body weight) was slightly but significantly more hypoglycaemic in dwarf chickens. At 4 weeks of age, following an oral glucose load (2 g/kg), glucose tolerance was the same in both genotypes, whereas plasma insulin levels were greatly decreased in dwarf chickens. At 5 weeks of age, plasma concentrations of glucose and insulin were the same in both genotypes in the fasting state and decreased in the fed state in dwarf chickens. In liver membranes prepared from fasted chickens, insulin binding was increased in dwarf chickens, while the affinity of insulin receptors and the insulin-degrading activity of the membranes were the same in both genotypes. Following solubilization with Triton X-100, liver receptors were successively purified on lentil then wheat germ lectins. Autophosphorylation of the β-subunit did not differ between either the genotype or the nutritional (fed or fasted) state. In the basal state (in the absence of insulin) the tyrosine kinase activity of the receptor towards artificial substrate poly(Glu,Tyr)4:1 was significantly decreased in dwarf chickens by fasting. However, the change in tyrosine kinase activity of the receptor in response to insulin was similar, irrespective of the genotype and the nutritional state. Therefore, the slight increase in insulin sensitivity observed in vivo in dwarf chickens is accounted for, at least partly, by a slight increase in liver insulin receptor number, but not by a change in the kinase activity of liver insulin receptors. In addition, post-insulin receptor kinase events and/or GH-dependent counter-regulatory mechanisms may superimpose and increase the insulin sensitivity of dwarf chickens. Journal of Endocrinology (1990) 126, 67–74

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.

Effects of hypercortisolemia and diabetes on skeletal muscle insulin receptor function in vitro and in vivo

1989 ◽  
Vol 256 (1) ◽  
pp. E39-E48 ◽  
Author(s):  
N. E. Block ◽  
M. G. Buse
Keyword(s):  
Insulin Receptor ◽  
Receptor Tyrosine Kinase ◽  
Insulin Binding ◽  
Insulin Administration ◽  
Receptor Kinase ◽  
Insulin Receptor Tyrosine Kinase ◽  
Kinase Activation ◽  
Intravenous Insulin

Activation of skeletal muscle insulin receptor tyrosine kinase in vitro and in vivo was studied in two rat models of insulin resistance: insulinopenic diabetes and hypercortisolemia. In control rats, intravenous insulin administration resulted in dose-dependent in vivo activation of the muscle insulin receptor kinase towards histone H2b. Half-maximal and maximal activation were observed 5 min after injecting 0.1 and 0.5 U insulin/100 g, respectively. Diabetes (7 days) induced with streptozotocin did not affect insulin binding affinity of solubilized muscle receptors but depressed receptor kinase activation in vivo by 52 or 40% after intravenous insulin administration (0.1 or 2 U/100 g, respectively). Cortisone treatment (5 days) resulting in weight loss, hyperglycemia, and hyperinsulinemia did not affect the number, insulin binding affinity, or kinase activity of solubilized receptors activated with insulin in vitro or in vivo. It is concluded that impaired insulin receptor tyrosine kinase activation was demonstrated in vivo in rats with insulinopenic diabetes and that glucocorticoid-induced insulin resistance probably reflects postreceptor defect(s) in muscle.

scholarly journals Internalization and Activation of the Rat Liver Insulin Receptor Kinase in vivo

1989 ◽  
Vol 264 (22) ◽  
pp. 12931-12940 ◽  
Author(s):  
M N Khan ◽  
G Baquiran ◽  
C Brule ◽  
J Burgess ◽  
B Foster ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Rat Liver ◽  
Receptor Kinase ◽  
Insulin Receptor Kinase

Erythrocyte Insulin Binding in Insulin-Dependent Diabetes Mellitus: Lack of Relationship to Duration and Control of Diabetes in Children and Adolescents

PEDIATRICS ◽  
1980 ◽  
Vol 66 (3) ◽  
pp. 385-390
Author(s):  
Michael S. Kappy ◽  
Leslie P. Plotnick ◽  
Joann C. Findlay ◽  
Richard D. Kayne
Keyword(s):  
Diabetes Mellitus ◽  
Children And Adolescents ◽  
Insulin Dependent Diabetes Mellitus ◽  
Insulin Binding ◽  
Diabetic Control ◽  
Insulin Dependent Diabetes ◽  
Liver Fat ◽  
Dependent Diabetes Mellitus ◽  
Control Of Diabetes ◽  
Insulin Dependent

Insulin binding was measured in the erythrocytes (RBCs) of four children and 12 adolescents with insulin-dependent diabetes mellitus in the basal (fasting, nonketotic) state. Children and adolescents with insulin-dependent diabetes mellitus showed normal binding of insulin to their RBCs when expressed as the total insulin bound over the physiologic range of insulin concentrations. The insulin receptor concentration and receptor binding affinity for insulin were also normal. These parameters of insulin binding were not correlated with either the duration of diabetes or the degree of diabetic control in the patients. Since insulin binding by erythrocytes has been shown to reflect binding by traditional target tissues (liver, fat), the data suggest that alterations in binding of insulin to cells in children and adolescents with insulin-dependent diabetes mellitus probably play little, if any, role in the response of these patients to exogenous insulin or in the control of their glucose metabolism in the basal state.

Sign in / Sign up

Export Citation Format

Share Document