The Relationship Between Circulating Free and Bound Insulin, Insulin Antibodies, Insulin Dosage and Diabetic Control in Insulin Treated Diabetics

Abstract

Free and bound insulin concentrations, blood glucose and anti-insulin antibody binding characteristics have been determined in 100 insulin treated diabetics; median serum free insulin was 11 mU/l when fasting and rose to 30 mU/l after the mid-day meal. Significant correlation between blood glucose and serum free (but not bound) insulin was found. No relationship between insulin antibodies and daily insulin dose or diabetic control were found, nor a relationship between free insulin and antibody characteristics.Diabetics treated with conventional bovine insulin preparations develop anti¬ bodies to the injected insulin (Berson 8c Yalow 1964). Their circulating insulin consists of a mixture of free and antibody-bound insulin, the concentrations of which are affected by the characteristics of their anti-insulin antibodies (Molnar et al. 1972). The influence of these antibodies on daily insulin dosage (Kerp et al. 1968; Hum et al. 1969) and on the quality of diabetic control (Dixon et al. 1975;Andersen 1975) is controversial. The relative bio-availabilities of free and bound insulin is in dispute (Dixon et al. 1975;Lev-Ran 8c Ratt 1973) as is the state of the circulating free insulin (Schlichtkrull et al. 1971).In this paper we report measurements of serum free and bound insulin con¬ centrations and their relationships to insulin antibody binding characteristics and the prevailing blood glucose in one hundred long-term bovine insulin treated diabetics. We also attempt to relate these antibody characteristics to the quality of diabetic control and daily insulin dosage.

Immunological Responses to Exogenous Insulin

“…Although anecdotal information from these case reports suggests that very high levels of IAs can be associated with unusual hypoglycemia syndromes, studies of large populations have failed to establish a relationship between IAs and hypoglycemia event rates (58, 59, 251,259,263,265,296,297). c. Hypoglycemia in IIP patients.…”

“…Although information from case reports suggests that high levels of IAs can be associated with prolonged periods of hypoglycemia, studies of large populations have failed to establish a relationship between IAs and hypoglycemia event rates (58,59,251,259,263,265,296,297). In a pooled analysis of phase 2 and phase 3 trials involving more than 350 patients with type 1 diabetes and more than 400 patients with type 2 diabetes treated with inhaled insulin (Exubera), no relationships between hypoglycemic event rates and IA levels were observed (58).…”

Less nocturnal hypoglycemia and better post-dinner glucose control with bedtime insulin glargine compared with bedtime NPH insulin during insulin combination therapy in type 2 diabetes. HOE 901/3002 Study Group.

“…Whether the lack of a clinical sequela of insulin antibodies was due to the fact that an in vitro assay might not adequately reflect the impact of antibodies on insulin bioavailability in vivo or whether insulin antibodies do not limit insulin action cannot be determined based on the present data. The clinical significance of insulin antibodies thus remains controversial (12). One possibility would be that changes in endogenous insulin secretion might act to buffer insulin antibody-induced changes in insulin bioavailability.…”

Selective IgG Subclass Antibody Response to Insulin in Diabetic Patients Receiving Animal Insulin Replacement Therapy

“…The alterations in the IgG subclass profile indicate that (1) when the insulin dosage is moderate (20-45) IU/day), there is mostly IgGl and IgG2 responses and there occurs a gradual quantitative increase in IgG2 and IgG3 and decrease in IgGl response as the therapy continues and that (2) when the patients's re quirement of insulin is high (90-135 IU/day), there is significant decrease in IgGl and IgG2 with concomi tant increase in IgG3 and IgG4, the later being the highest. Several studies suggested that insulin anti bodies at high titers are to a great extent contributing to insulin resistance [9,17,18], others were not able to prove this correlation [10,11], These studies were based on the detection of total IgG AIA and their as sociation with insulin resistance. Recent studies of IgG subclass pattern in uncategorised insulin immu nised diabetic patients by Koch et [25] suggested an induction of IgG4 after prolonged antigenic stimulations, this cannot explain the increase in IgG4 in our group III patients as we should have expected increased IgG4 levels in group II rather than in group III.…”