Insulin antagonistic effects of insulin receptor antibodies on plasma membrane (Ca2+ + Mg2+) ATPase activity: a possible etiology of type B insulin resistance.
The regulatory effect of insulin on plasma membrane (Ca2+ + Mg2+)ATPase activity in target tissues for insulin was proposed to be of importance in mediating the hormone's cellular action. Consequently, polyclonal insulin receptor antibodies from patients with type B insulin resistance (B7 and B10) were used as probes to further explore a possible role for this ATPase in insulin action. The antibodies B7 and B10 obtained during the active phase of the disease manifested insulinomimetic actions in rat renal cortical basolateral membranes by displacing [125I]insulin bound to the membranes and stimulating the tyrosine kinase activity of solubilized insulin receptors in a dose-dependent manner. In contrast, these antibodies had insulin antagonistic effects on the membrane (Ca2+ + Mg2+)ATPase activity. While insulin stimulated, both antibodies inhibited the ATPase basal activity in a dose-dependent manner. Furthermore, the stimulatory effect of insulin on the ATPase was completely abolished by the antibodies. Immunoglobulin fractions obtained from patient B10 in the clinically inactive phase of the disease and from pooled normal human sera did not affect basal or insulin-stimulated ATPase activity. The effects of insulin receptor antibodies on basal and insulin-stimulated (Ca2+ + Mg2+)ATPase activities were specific. The receptor antibody did not affect PTH-stimulated (Ca2+ + Mg2+) ATPase activity, nor did it affect other kidney basolateral membrane ATPase basal activities. The data reveal that insulin receptor antibodies have a direct regulatory effect on the plasma membrane (Ca2+ + Mg2+) ATPase. We suggest that the insulin antagonistic effects of the insulin receptor antibodies on the ATPase might explain in part the impaired insulin action in type B insulin resistance.
Nagy
K
K
Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan 48201.
Grunberger
G
G
Levy
J
J
D000818:Animals; D000906:Antibodies / Q000502:physiology*; D001692:Biological Transport; D017301:Ca(2+) Mg(2+)-ATPase / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism*; D002462:Cell Membrane / Q000201:enzymology*; D007074:Immunoglobulin G / Q000502:physiology; D007329:Insulin Antagonists / Q000494:pharmacology*; D007333:Insulin Resistance / Q000502:physiology*; D007672:Kidney Cortex / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D010281:Parathyroid Hormone / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011972:Receptor, Insulin / Q000276:immunology*
D000906:Antibodies; D007074:Immunoglobulin G; D007329:Insulin Antagonists; D010281:Parathyroid Hormone; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin; D017301:Ca(2+) Mg(2+)-ATPase; D000252:Calcium-Transporting ATPases; D002118:Calcium