Antibodies to Covalent Aggregates of Insulin in Blood of Insulin-Using Diabetic Patients

Abstract

A covalent aggregate twice the size of insulin accounts for approximately 28% of total circulating insulin immunoreactivity in type I diabetic patients. These aggregates are probably covalent dimers of insulin and should contain unique epitopes distinct from the parent molecule. Therapeutic insulin contains a similar material and is the source of the circulating aggregate. Anti-aggregate antibodies were detected by binding-inhibition techniques in 9 of 29 long-term diabetic patients. These antibodies were directed against structures distinct from those of the parent molecule insulin monomer. All antibody-positive patients were men whose blood also contained antibodies to insulin monomer. We conclude that the blood of approximately 30% of insulin-using diabetic patients contains antibodies directed against epitopes unique to the insulin aggregates. Because insulin monomer and aggregates probably share a common primary amino acid sequence, the anti-aggregate antibodies are probably directed against conformational determinants. Further work is needed to determine whether such aggregates promote or accentuate the development of anti-insulin antibodies in certain genetically predisposed individuals.

Immunogenicity of intraperitoneal insulin infusion using programmable implantable devices

“…We found no data in the literature concerning the eventual immunogenicity of the high molecular weight component found by analysing the residual insulin by size exclusion chromatography [29]. Insulin aggregates have been shown to induce specific antibodies [30] and may be involved in the immune reaction observed.…”

Structural Characterization and Immunogenicity in Wild-Type and Immune Tolerant Mice of Degraded Recombinant Human Interferon Alpha2b

“…Aggregates in therapeutic protein formulations are known to be important factors in inducing an antibody response (4)(5)(6)(7)(8). The immunological mechanism of this antibody induction is not completely understood.…”

“…This may occur in patients who are treated with products which are homologues of human proteins. The exact mechanisms by which therapeutic proteins break tolerance is unknown, although impurities and aggregates are known to be important factors (2)(3)(4)(5)(6)(7)(8). Impurities may act as danger signals initiating a response to self-antigens and aggregates may present the self-antigens in a repetitive array form, which is supposed to activate B-cells without T-cell help (9)(10)(11).…”

Immediate-Type Human Insulin Allergy Successfully Treated by Continuous Subcutaneous Insulin Infusion.

“…Cutaneous insulin allergy remains a clinical problem despite the use of highly purified human insulin. It is likely that insulin aggregates (e.g., covalent dimers) contribute to the insulin antibody formation (2,3). Continuous subcutaneous insulin infusion (CSII) therapy has been well accepted by insulin-dependent diabetes mellitus (IDDM) patients and can result in improvement of metabolic control (4), and delay or prevent diabetic complication (5).…”