Insulin receptor tyrosine kinase activity is abnormal in circulating cells and cultured fibroblasts but normal in transformed lymphocytes from a type A insulin-resistant patient.
The function of the insulin receptor subunits isolated from cells of a patient with the type A syndrome of insulin resistance was examined. Iodine 125-labeled insulin binding, insulin-stimulated phosphorylation of both endogenous and exogenous substrates, and internalization of 125I-insulin were evaluated. 125I-insulin binding to intact peripheral monocytes and erythrocytes, cultured skin fibroblasts, and cultured Epstein-Barr virus-transformed lymphocytes, as well as to partially purified receptor preparations from these cells, was entirely normal. In contrast, the insulin-stimulated receptor autophosphorylation and tyrosine kinase activity of the partially purified monocyte, erythrocyte, and fibroblast receptor preparations were markedly diminished. Solubilized, lectin-purified receptors from virally transformed cultured lymphocytes, however, demonstrated normal insulin-sensitive kinase activity. The patient's peripheral monocytes did not internalize 125I-insulin at 37 degrees C, but her transformed lymphocytes internalized it normally, as assessed by electron microscopic autoradiography. Our findings suggest that the discordance between the functions of the alpha-subunits and beta-subunits of the insulin receptor from monocytes of this insulin-resistant patient (Science 1984;223:932-4) extends to other freshly isolated cell types and persists in her cultured cells. Viral transformation of her cells results directly or indirectly in normal expression of the receptor kinase activity. Whether the defective kinase activity of the insulin receptor and the impaired receptor internalization exhibited by her monocytes ultimately cause the patient's insulin resistance awaits further studies.
Grunberger
G
G
Diabetes Branch, National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Maryland.
Comi
R J
RJ
Carpentier
J L
JL
Podskalny
J M
JM
McElduff
A
A
Taylor
S I
SI
Gorden
P
P
D000328:Adult; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology*; D004705:Endocytosis; D005260:Female; D005347:Fibroblasts / Q000201:enzymology*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D007962:Leukocytes / Q000201:enzymology*; D008213:Lymphocyte Activation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism*
D007328:Insulin; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin