Role of human skeletal muscle insulin receptor kinase in the in vivo insulin resistance of noninsulin-dependent diabetes mellitus and obesity

1994 ◽  
Vol 78 (2) ◽  
pp. 471-477 ◽  
Author(s):  
J. J. Nolan
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Receptor ◽  
Human Skeletal Muscle ◽  
Dependent Diabetes Mellitus ◽  
Receptor Kinase ◽  
Insulin Receptor Kinase

Delayed onset of insulin activation of the insulin receptor kinase in vivo in human skeletal muscle

Diabetes ◽  
1994 ◽  
Vol 43 (1) ◽  
pp. 118-126 ◽  
Author(s):  
G. R. Freidenberg ◽  
S. Suter ◽  
R. R. Henry ◽  
J. Nolan ◽  
D. Reichart ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Receptor ◽  
Human Skeletal Muscle ◽  
Receptor Kinase ◽  
Delayed Onset ◽  
Insulin Receptor Kinase

Delayed Onset of Insulin Activation of the Insulin Receptor Kinase In Vivo in Human Skeletal Muscle

Diabetes ◽  
1994 ◽  
Vol 43 (1) ◽  
pp. 118-126 ◽  
Author(s):  
G. R. Freidenberg ◽  
S. Suter ◽  
R. R. Henry ◽  
J. Nolan ◽  
D. Reichart ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Receptor ◽  
Human Skeletal Muscle ◽  
Receptor Kinase ◽  
Delayed Onset ◽  
Insulin Receptor Kinase

scholarly journals Elevated protein tyrosine phosphatase activity and increased membrane viscosity are associated with impaired activation of the insulin receptor kinase in old rats

1994 ◽  
Vol 298 (2) ◽  
pp. 443-450 ◽  
Author(s):  
O Nadiv ◽  
M Shinitzky ◽  
H Manu ◽  
D Hecht ◽  
C T Roberts ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Receptor Kinase ◽  
Membrane Viscosity ◽  
Liver Membranes ◽  
Old Rats ◽  
Insulin Receptor Kinase

Insulin resistance is very common in the elderly, and may be associated with glucose intolerance or frank diabetes. In previous studies we demonstrated that insulin resistance in old Wistar rats is associated with decreased autophosphorylation and activation of the hepatic insulin receptor kinase (IRK) in vivo. We now show that this defect can be reproduced in vitro, where the extent of insulin-induced activation of IRK in liver membranes of old rats was decreased by approximately 50% compared with young controls. The defect could be largely abolished after solubilization of the membranes with Triton X-100. We also show that: (a) the viscosity of membranes from the old rats was significantly (P < 0.001, n = 4) higher (by 15%) compared with young controls; (b) incubation of plasma membranes from old animals with lecithin liposomes, which lowered their cholesterol levels, partially abolished the defect in IRK activation; and (c) Triton extracts of liver membranes prepared from old rats did not interfere with the activation of IRK derived from young controls. Additionally, non-membrane components did contribute to the development of this defect. We observed a significant (approximately 30%) (P < 0.001, n = 18) elevation of cytosolic protein tyrosine phosphatase (PTP) activity directed against the beta subunit of the insulin receptor in livers of old rats. No such elevation of PTP activity could be demonstrated with synthetic substrates. Our findings are consistent with a model in which increased membrane viscosity as well as enhancement of a cytosolic PTP activity both markedly inhibit the activation in vivo of the hepatic IRK in old animals.

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.

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