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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 G i ‐proteins
Author(s) -
Caro José F.,
Raju Madhu S.,
Caro Maricelina,
Lynch Christopher J.,
Poulos John,
Exton John H.,
Thakkar Jay K.
Publication year - 1994
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.240540307
Subject(s) - insulin receptor , medicine , endocrinology , insulin , autophosphorylation , irs2 , pertussis toxin , tyrosine kinase , insulin receptor substrate , diabetes mellitus , g protein , biology , receptor , chemistry , insulin resistance , biochemistry , protein kinase a , kinase
A novel pathway for physiological “cross‐talk” between the insulin receptor and the regulatory G i ‐protein has been demonstrated. We tested the hypothesis that a coupling defect between G i and the insulin receptor is present in the liver of obese patients with and without type li diabetes. Insulin 1 × 10 −9 M (∼ ED 50 ) and 1 × 10 −7 M (Max) inhibited pertussis toxin‐catalyzed ADP ribosylation of G i in human liver plasma membranes from lean and obese nondiabetic patients. However, 1 × 10 −7 M insulin was without effect in membranes from patients with type II diabetes. This coupling defect was not intrinsic to G i , since Mg 2+ and GTPγS inhibited pertussis toxin‐catalyzed ADP ribosylation in both diabetic and nondiabetic patients. Binding of insulin of the α‐subunit and activation of the tyrosine kinase intrinsic to the β‐subunit of the insulin receptor are not responsible for the coupling defect. 125 I 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 G i without activating tyrosine kinase or insulin receptor autophosphorylation. Immunodetection of G‐proteins suggested that G i3α was normal in diabetes and G i1‐2α 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 G i 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.