Autoantibodies to the Insulin Receptor

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We have used an adipocyte-like cell line, the 3T3-L1 fatty fibroblasts, to compare acute and chronic effects of autoantibodies directed against the insulin receptor. Acute exposure of the cells in tissue culture to the antibodies resulted in a blockade of insulin binding and stimulation of 2-deoxyglucose transport and glucose oxidation. Maximal acute effects were reached within 30-120 min. Subsequently, the stimulatory response decayed and, after 6 hr in the continuous presence of the antibodies, basal glucose metabolism-had returned to the level observed with unexposed cells and a state of severe insulin resistance prevailed. In contrast to the decay of bioresponse, no change in insulin binding was detectable over the same time period. The mechanism of desensitization seemed to involve events early after insulin binding to receptor because cells exposed to antibody for prolonged periods of time, although unresponsive to insulin and antireceptor antibodies, responded normally to both spermine and vitamin K5, agents that stimulate glucose metabolism independently of the insulin receptor. These data suggest that prolonged or continuous occupancy of the insulin receptor by a ligand, in this case antireceptor antibodies, does not produce a continuous biological response. Instead, there is desensitization at some early step in the pathway for insulin action. These observations have important implications with respect to the mechanism of insulin action andi to other situations in which there is long-term exposure of cells to antibodies that react with membrane components. Antibodies that bind to the insulin receptor have been found in patients with a rare form of insulin-resistant diabetes termed the "syndrome of insulin resistance and acanthosis nigricans type B" (1). These antibodies, which are polyclonal and mainly of the IgG class, block insulin binding (2,3) and, in the presence of a second antibody, can be used to immunoprecipitate solubilized insulin receptors (4). When tested in short-term in vitro experiments, the antireceptor antibodies also have an insulinlike activity. In adipocytes and skeletal muscle, the antireceptor antibodies have been shown to stimulate 2-deoxyglucose transport, glucose incorporation into lipids and glycogen, and glucose metabolism to CO2 (5, 6). In addition, these antibodies mimic insulin's effect on lipolysis, amino acid transport, and enzymatic activity of glycogen synthase and phosphorylase (7,8). These in vitro findings are in contrast to the chronic in vivo effects of these antibodies to produce severe insulin resistance and hyperglycemia.In the present study, we have investigated the effects of the antibodies on insulin binding and glucose metabolism in more long-term experiments, taking advantage of the recently established adipocyte-like cell line, the 3T3-L1 fatty fibroblasts (9-11). As with adipocytes, the antireceptor antibodies inhibit insulin binding and produce acute insulin-like effects in these cells. This insulin-like action, however, is transient; after 6-4...

Section: Resultssupporting

confidence: 78%

Desensitization of the insulin receptor at an early postreceptor step by prolonged exposure to antireceptor antibody

Karlsson

Obberghen

Grünfeld

et al. 1979

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“…In 1975 we discovered that sera of some patients with insulin-resistant diabetes contain autoantibodies to the insulin receptor (6,7,29) and this has provided new probes for the study of insulin action. These antibodies, which were initially found by their ability to inhibit insulin binding to its receptor (6), also produce insulin-like biological effects when exposed to tissues in vitro (10,11).…”

Section: Resultsmentioning

confidence: 99%

Direct demonstration that receptor crosslinking or aggregation is important in insulin action

Kahn

Baird

Jarrett

et al. 1978

Self Cite

348

124

Exposure of adipocytes to antibodies to the insulin receptor results in a blockade of 125I-labeled insulin binding, stimulation of glucose oxidation, and many more insulin-like effects. Allowing for differences in purity, antireceptor antibody is equipotent with insulin on a molar basis. Both the bivalent F(ab')2 and monovalent Fab' fragments of the antireceptor antibody are fully active in inhibiting 25I-labeled insulin binding. Bivalent F(ab')% also retains its insulin-like effects.

“…Plasmas from these patients specifically inhibit the binding of 125I-insulin to insulin receptors on a wide variety of cell types, but have no effect upon the binding of other hormones to their receptors (1), or on cell viability. The binding of '25I-insulin is unaffected by normal plasma, plasma with antiinsulin antibodies, plasma from patients with autoimmune diseases known to be associated with dntilymphocyte antibodies (3), and antihuman-lymphocyte serum generated in rabbits (J. S. Flier, unpublished observation).…”

mentioning

confidence: 97%

“…The inhibitory activity in the plasma of these patients with insulin resistance is quantitatively recovered in the immunoglobulin fraction, and is precipitated completely with antibodies to human immunoglobulins (3). These inhibitors of insulin binding are almost entirely IgG, and possess about equal amounts of K and X light chain determinants (3).…”

mentioning

confidence: 97%

Direct method for detection and characterization of cell surface receptors for insulin by means of 125I-labeled autoantibodies against the insulin receptor.

Jarrett¹,

Roth²,

Kahn³

et al. 1976