The bioavailability of circulating antibody-bound insulin following insulin withdrawal in Type I (insulin-dependent) diabetes

Abstract

Summary. Insulin withdrawal studies were performed in 12Type1 (insulin-dependent) C-peptide negative diabetic patients with low to moderate insulin antibody levels, to assess the biological availability of antibody-bound insulin and its clinical significance. There was a highly significant correlation between the extent to which the free insulin concentration was maintained during the period of insulin withdrawal and both the level of insulin-binding by serum and the total insulin concentration at the start of the study. During insulin withdrawal, the patients who best maintained their circulating free insulin levels showed the smallest increases in blood glucose and 3-hydroxybutyrate concentrations. We conclude that antibody-bound insulin is available for physiological action, and that in those individuals with moderate antibody concentrations it is capable, in the fasting state, of maintaining free insulin levels. In these circumstances insulin antibodies are behaving as simple carrier proteins.Key words: Type 1 diabetes, insulin, insulin antibody, pharmacokinetics.Most clinical studies concerning insulin antibodies have been directed towards the deleterious effects, such as insulin resistance, which are associated with very high antibody levels [1]. Little is known about the effect of the more modest levels of antibodies that exist in most Type 1 (insulin-dependent) diabetic patients. In these patients, it is evident from measurement of antibody-bound insulin that substantial quantities of insulin may be present in the plasma and it has been suggested that this source of insulin could act as a buffer to fluctuations in insulin levels [2].A correlation between the level of insulin binding by serum and diabetic control as judged by the haemoglobin A1 percentage has been demonstrated in C-peptide negative patients on a once-daily insulin regimen [3], but this association was not observed when the patients were changed to a twice-daily insulin regimen. The problem of whether antibody-bound insulin is available for biological action, and the extent to which it might be clinically useful, is of particular interest because over recent years there has been a reduction in both the prevalence of insulin antibodies and the insulin-binding levels found in those who do form antibodies. This is a consequence of the increased purity of insulin preparations and the increase in the use of porcine insulin. To assess the availability of insulin from the antibodybound pool, we performed studies on Type 1 diabetic patients who had low to moderate serum insulin binding and no residual C-peptide secretion. After careful depletion of subcutaneous insulin, subjects were stabilised on intravenous insulin which was then discontinued. The only source of free insulin would then be from the pool of insulin bound to antibody. The concentrations of free and total insulin in serum and of glucose and 3-hydroxybutyrate in blood were measured to assess the bioavailability of this source of insulin. Subjects and Methods SubjectsThe twelve Type 1...

Disappearance rate of insulin antibodies after discontinuing insulin treatment in 42 Type 2 (non-insulin-dependent) diabetic patients

“…Some authors have suggested that circulating insulin antibodies in low-to-moderate amounts may be beneficial, rather than harmful, at least for some types of insulin treatment strategies [3,5,16]. In this context, it is of note that persistence of insulin antibodies after discontinuation of insulin therapy did not appear to prevent the achievement of satisfactory control in the patients of this study.…”

“…Vaughan et al [3] have shown that in non-insulin-resistant diabetic patients, the insulin-binding capacity of serum (in general 10 U/l) is compatible with the maintenance of free insulin in the physiological range (5-80 mU/1). If insulin clearance occurs entirely via free insulin, antibodies in such titres will act as a simple binding protein without influencing insulin requirements in the long run [7].…”

“…In addition to their wellrecognized adverse effects, the presence of insulin antibodies has often been considered to have some beneficial effects, at least under certain circumstances [2,3]. Regardless of the clinical significance of circulating insulin antibodies, assessment of their kinetics is of considerable interest [1,[4][5][6][7][8].…”

The Effect of Insulin Antibodies on the Metabolic Action of Inhaled and Subcutaneous Insulin

“…Thus, to measure low-affinity IABs, test serum was incubated with 10 Ϫ8 mol/l insulin. The 10 Ϫ8 -mol/l concentration (1,508 U insulin/ml) was selected since it is within the range of total (bound and free) insulin concentrations observed in patients with high levels of IABs (29,30). This assay measures binding capacities of both low-and high-affinity IABs.…”

Insulin antibody determination: Theoretical and practical considerations

“…The production of insulin antibody is not only of academic interest for it does have a role in insulin allergy, injection site lipoatrophy [17] and some types of insulin resistance as well as having more subtle effects on the dose requirement, and on the pharmacokinetics of injected insulin [18][19][20][21]. Insulin-antibody complexes may have a deleterious effect in patients with vascular disease but there are insufficient data to be sure.…”