Hyperglycemia, Hypoglycemic Attacks, and Production of Anti-Insulin Antibodies Without Previous Known Immunization: Immunological and Functional Studies in a Patient

Abstract

A forty-two-year-old man with hyperglycemia and pronounced reactive hypoglycemia after meals and oral glucose is reported. He produced anti-insulin antibodies without previous known immunization.Labeled insulin, when mixed with the patient's serum, passed with the serum proteins on gel filtration, and was found among the 7S globulins on preparative ultracentrifugation, in the anodic y-region on agar electrophoresis, and among the anodic yG-globulins on immunoelectrophoresis. The clearance of labeled insulin in vivo was very slow, and the glucose response to intravenous insulin was absent. The free binding capacity in serum was several thousand MU./ ml. Acid splitting of the insulin-anti-insulin complexes revealed 7,000 /tU./ml. or more of endogenous insulin, and antibodies which bound human and pig insulin better than bovine insulin. After oral glucose the patient's serum insulin increased by 2,300 jtU./ml. Some new principles are introduced in the quantitative studies on serum insulin and antibodies. Theoretical restrictions on these and other quantitations are discussed.The hyperglycemia may be explained by the antibodies binding secreted insulin, and the hypoglycemia by an insulin overshoot from maximally stimulated /3-cells when saturation of the binding capacity was approached. Carbohydrate restriction prevented the hypoglycemic attacks. The cause of the antibody production and the properties of the antibodies are discussed. DIABETES 21:814-26, July, 1972.

Insulin antibodies prevent insulin-receptor interactions

“…In diabetic patients insulin antibodies are induced only after exogenous insulin injections [26] although occasional patients have insulin antibodies, without having had previous insulin injections [27,28]. The present data indicate that insulin antibodies may theoretically contribute to the insulin resistance shown by some patients thus confirming previous hypotheses [15,16].…”

Characterization of circulating insulin and proinsulin-binding antibodies in autoimmune hypoglycemia.

“…Seven other patients with similar clinical and laboratory features have been described (4)(5)(6)(7)(8)(9). In all of these cases, the more conventionally recognized causes of hypoglycemia were excluded, and a differential diagnosis between factitious and autoimmune hypoglycemia remained.…”

“…However, the absence in her serum of C-segment-directed proinsulin antibodies, which might have arisen in response to the small amounts of proinsulin present in commercial insulin preparations, renders this possibility less likely (vide infra). Previous studies (4,5,7,8) have attempted to solve the diagnostic dilemma of factitious vs. an autoimmune basis for the development of insulin antibodies by performing competition studies in which radiolabeled porcine and bovine insulin were displaced from specific antibody sites by unlabeled porcine, bovine, and(or) human insulin. The displacement curves obtained with antibodies from these hypoglycemic patients have been interpreted as indicating a higher affinity for human insulin.…”

“…More recently, a number of patients with spontaneous hypoglycemia in association with insulin antibodies have been reported (4)(5)(6)(7)(8)(9). An autoimmune origin has been proposed for these antibodies in view of the absence of a history of previous insulin administration (4)(5)(6)(7)(8)(9) and the finding of a higher affinity for human insulin (4,5) in some, but not all of the reported cases (7). The association of spontaneous hypoglycemia with apparent insulin autoantibodies in Graves' disease has also been described (8).…”

Der Analysen-Leerwert beim Radioimmunoassay: Einflüsse auf die unspezifische Antigen-Bindung und ihr Effekt auf die Richtigkeit der Ergebnisse bei der Insulin-Bestimmung

“…In zunehmendem Maße mitgeteilte Befunde, die ein von Erfahrung und Norm abweichendes Verhalten bei radioimmunologischen Tests beschreiben (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20), zeigen, daß den Test beeinflussende Faktoren existieren, von denen sich einige mit einer ungewöhnlichen Verhaltensweise der unspezifischen Bindungen erklären lassen (9,(12)(13)(14)(15)(16)(17)(18)(19)(20) …”