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
Jf. Caro et al., 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, Journal of cellular biochemistry, 54(3), 1994, pp. 309-319
A novel pathway for physiological ''cross-talk'' between the insulin r
eceptor and the regulatory C-i-protein has been demonstrated. We teste
d the hypothesis that a coupling defect between G(i) and the insulin r
eceptor is present in the liver of obese patients with and without typ
e II diabetes. Insulin 1 x 10(-9) M (similar to ED(50)) and 1 x 10(-7)
M (Max) inhibited pertussis toxin-catalyzed ADP ribosylation of G(i)
in human liver plasma membranes from lean and obese nondiabetic patien
ts. However, 1 x 10(-7) M insulin was without effect in membranes from
patients with type II diabetes. This coupling defect was not intrinsi
c to G(i), since Mg2+ and GTP gamma S inhibited pertussis toxin-cataly
zed ADP ribosylation in both diabetic and nondiabetic patients. Bindin
g of insulin of the alpha-subunit and activation of the tyrosine kinas
e intrinsic to the beta-subunit of the insulin receptor are not respon
sible for the coupling defect. (125)l insulin binding is the same in o
bese 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) wi
thout activating tyrosine kinase or insulin receptor autophosphorylati
on. Immunodetection of G-proteins suggested that G(i3 alpha) was norma
l in diabetes and G(i1-2 alpha) was decreased by 40% in the diabetic g
roup as compared to the obese nondiabetic group but was normal when co
mpared to the lean non diabetic group. We conclude that the novel path
way of insulin signaling involving the regulatory C-i proteins via bio
chemical 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. (C)
1994 Wiley-Liss, Inc.