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Guanine nucleotide binding regulatory proteins in liver from obese humans with and without type II diabetes: evidence for altered "cross-talk" between the insulin receptor and Gi-proteins.
- Source :
-
Journal of cellular biochemistry [J Cell Biochem] 1994 Mar; Vol. 54 (3), pp. 309-19. - Publication Year :
- 1994
-
Abstract
- A novel pathway for physiological "cross-talk" between the insulin receptor and the regulatory Gi-protein has been demonstrated. We tested the hypothesis that a coupling defect between Gi and the insulin receptor is present in the liver of obese patients with and without type II diabetes. Insulin 1 x 10(-9) M (approximately ED50) and 1 x 10(-7) M (Max) inhibited pertussis toxin-catalyzed ADP ribosylation of Gi in human liver plasma membranes from lean and obese nondiabetic patients. However, 1 x 10(-7) M insulin was without effect in membranes from patients with type II diabetes. This coupling defect was not intrinsic to Gi, since Mg2+ and GTP gamma S inhibited pertussis toxin-catalyzed ADP ribosylation in both diabetic and nondiabetic patients. Binding of insulin of the alpha-subunit and activation of the tyrosine kinase intrinsic to the beta-subunit of the insulin receptor are not responsible for the coupling defect. 125I insulin binding is the same in obese patients with or without diabetes. Tyrosine kinase of the insulin receptor is decreased in diabetes. However, a monoclonal antibody to the insulin receptor (MA-20) at equimolar concentrations with insulin equally inhibits pertussis toxin-catalyzed ADP ribosylation of Gi without activating tyrosine kinase or insulin receptor autophosphorylation. Immunodetection of G-proteins suggested that Gi3 alpha was normal in diabetes and Gi1-2 alpha was decreased by 40% in the diabetic group as compared to the obese nondiabetic group but was normal when compared to the lean non diabetic group. We conclude that the novel pathway of insulin signaling involving the regulatory Gi proteins via biochemical mechanisms not directly involving the tyrosine kinase of the insulin receptor is altered in obese type II diabetes and offers a new target for the search of the mechanism(s) of insulin resistance.
- Subjects :
- Adenosine Diphosphate Ribose metabolism
Antibodies, Monoclonal pharmacology
Cholera Toxin pharmacology
Cytosol metabolism
GTP-Binding Proteins deficiency
Guanosine 5'-O-(3-Thiotriphosphate) pharmacology
Humans
Insulin pharmacology
Membrane Proteins metabolism
Pertussis Toxin
Poly(ADP-ribose) Polymerases metabolism
Receptor Protein-Tyrosine Kinases metabolism
Receptor, Insulin immunology
Virulence Factors, Bordetella antagonists & inhibitors
Virulence Factors, Bordetella pharmacology
Diabetes Mellitus physiopathology
Diabetes Mellitus, Type 2 physiopathology
GTP-Binding Proteins physiology
Insulin Resistance
Liver metabolism
Obesity physiopathology
Receptor, Insulin physiology
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 0730-2312
- Volume :
- 54
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Journal of cellular biochemistry
- Publication Type :
- Academic Journal
- Accession number :
- 8200911
- Full Text :
- https://doi.org/10.1002/jcb.240540307