Insulin antibodies prevent insulin-receptor interactions

Pirro, R. De; Fusco, Angelo; Spallone, Liliana; Magnatta, R; Lauro, Renato

doi:10.1007/bf00421857

Cited by 13 publications

(5 citation statements)

References 26 publications

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“…The relationship between the two variables is of the same order as the reduction seen on initial transfer to purified insulins. Studies in vitro have demonstrated the ability of insulin antibody to block insulin: insulin receptor interaction [18]. The results of the present study are compatible with this idea.…”

Section: Discussionsupporting

confidence: 89%

The effect of insulin antibodies on insulin dose and diabetic control

1982

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Summary.In a single blind randomised cross-over study, 40 patients were changed from ordinary bovine to highly purified porcine insulins for a period of 6 months. Half were later rechallenged with bovine insulin. Sequential determinations of IgG insulin binding capacity for bovine insulin were correlated with insulin dose and diabetic control. After changing to highly purified insulins the following correlations were observed between percentage change in insulin dose and change in insulin binding capacity: at 2 months r = 0.35 (p < 0.05), at 4 months r = 0.38 (p < 0.02) and at 6 months r = 0.37 (p < 0.02). When the patients who showed substantial changes in HbA~ were removed from the analysis, the remaining 29 demonstrated a clearer relationship between these two variables (r = 0.56,p < 0.01). Removal of patients with a low initial insulin binding capacity left 18 patients with stable diabetes, and changes in insulin binding capacity and insulin dose showed an even closer correlation for this group (r = 0.77, p < 0.001). A similar degree of positive correlation was observed after rechallenge with bovine insulin. We conclude that the level of circulating insulin antibody affects the dose of insulin required to maintain stable diabetic control.Key words: Insulin, insulin antibody, diabetic control.Most patients treated with ordinary bovine insulins develop circulating insulin antibodies [1]. Higt/ly purified porcine insulins are much less immunogenic and patients changing to these insulins often experience a reduction in insulin requirement [2,3], a fall in circulating insulin binding capacity [4] and an increase in circulating levels of free insulin [5]. Although antibody mediated insulin resistance is unusual [6], injection site lipoatrophy is a common complication of the use of ordinary bovine insulins [7]. Other possible effects of insulin antibodies are less clear. Andersen [8] showed that the presence of antibodies was associated with a reduction in the honeymoon period independent of the level of diabetic control and the hypothesis that insulin antibody might 'buffer' the effect of circulating insulin [9] has not been substantiated. We report a study of the relationship between changes in insulin antibody, insulin dose and diabetic control in established diabetics changing from ordinary bovine soluble and isophane to highly purified porcine equivalents and the effects of rechallenge with the original insulins. Patients and MethodsThe practice of one hospital diabetologist was surveyed to identify all the patients aged between 16 and 65 years who had had diabetes for at least 3 years and had been treated regularly with ordinary bovine soluble and isophane insulins for at least that time. Those who were blind or pregnant or who had other serious medical or psychological illness were excluded. Fifty-nine of the 71 eligible patients consented to be studied and 40 completed the 18 month protocol. These 14 women and 26 men were aged between 16 and 64 years (mean 40 years). The age at diagnosis ranged from 2 to 5...

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Section: Discussionsupporting

confidence: 89%

The effect of insulin antibodies on insulin dose and diabetic control

1982

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“…As already reported, AIA do influence metabolic control [31][32][33][34][35] particularly postprandial blood glucose. Some authors [9] found no direct correlation between the AIA levels and glycaemic control, nor did we.…”

Section: Discussionsupporting

confidence: 65%

Immunogenicity of intraperitoneal insulin infusion using programmable implantable devices

et al. 1995

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SummaryIntraperitoneal insulin infusion using implantable devices in insulin-dependent diabetic (IDDM) patients is promising since it improves diabetic control and decreases frequency of hypoglycaemia. However, preliminary data show a striking increase in plasma levels of anti-insulin antibodies with this therapy. In order to more precisely evaluate the immunogenicity and its consequences, anti-insulin antibody levels in 62 IDDM patients were assessed every 3 months during a 2-year period following pump implantation. At the same time, diabetes control was evaluated with HbA~c , mean blood glucose levels, standard deviation of the daily blood glucose levels and the frequency of low blood glucose (< 3.58 mmol/1). Factors involved in antibody formation such as age, gender, HLA typing, and complement C4 alleles were also studied. After implantation, anti-insulin antibody levels increased significantly from 3.14 % (range 0-26 %) to 8.34 % (0-49 %) after 1 year and remained elevated. Patients were divided into two groups: responders able to show at least one antiinsulin antibody titre higher than 15 % and non-responders whose titres were always lower than 6 %. None of the factors studied was shown to statistically influence the anti-insulin antibody titres. Non-respouders had significantly better metabolic results than the responders. Severe hypoglycaemic episodes decreased dramatically in both groups. Insulin requirements were comparable at time 0 and decreased initially in both groups. They remained low for the non-responders but returned to pre-implantation values for responders. Intraperitoneal insulin infusion led to a high immunogenetic response towards insulin in about half of the patients, leading to only moderately deleterious effects on metabolic control. Further studies are necessary to document other consequences (such as the role of circulating immune complexes). [Diabetologia (1995) que mainly due to the improvement in quality of life. The first results of efficacy studies are encouraging [3] since they demonstrate a drastic reduction in the incidence of severe hypoglycaemic episodes when compared to subcutaneous insulin administration [2,4]. However, preliminary data from our group and from others have shown a striking increase in anti-insulin antibody levels (AIA) in plasma during longterm i.p. insulin infusion using implanted devices [5][6][7][8][9]. The aim of this study was to evaluate more precisely the immunogenicity of this new method of treatment, to define the different factors involved and to assess the eventual clinical and metabolic consequences of this immune reaction.

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“…In conclusion, contradictory results of different authors (Shechter et al, 1979 a;De Pirro et al, 1980) with respect to the influence of insulin antibodies on receptor binding may possibly be due to the different size of insulin-antibody complexes formed with different antibodies. Our results support the hypothesis that receptor aggregation via insulin crosslinking is involved in the mechanism of the expression of insulin bioactivity (Jeffrey, 1982).…”

Section: Discussionmentioning

confidence: 82%

Effect of Antibody-Mediated Crosslinking of Insulin on Its Bioactivity and Receptor Binding^*

Keilacker¹,

Knospe²,

Ziegler³

et al. 2009

Exp Clin Endocrinol Diabetes

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Precipitating anti-insulin antibodies or anti-insulin IgG/anti-IgG complexes bind insulin in a highly aggregated form and thus should preferably be capable of inducing receptor aggregation, which has recently been suggested to be a precondition for insulin bioactivity. We, therefore, studied the influence of antibody-mediated crosslinking of insulin on the glucose conversion into CO2 in rat fat cells and glycogen synthesis in rat liver cells. As far as possible receptor-bound insulin was measured in parallel. Insulin bound to antibodies with low insulin precipitating capacity had no or little bioactivity and receptor reactivity on fat cells. The bioactivity, however, could be restored in part by addition of a second antibody. On liver cells, second antibody-mediated crosslinking of insulin-antibody complexes resulted in an enhancement of receptor reactivity, and insulin bioactivity of such crosslinked immune complexes was demonstrable. An insulin-precipitating antiserum was shown to form insulin-antibody complexes with significant bioactivity in fat cells which correlated with their receptor binding. In each case antibodies had no or little effect in the absence of insulin. Our data suggest that insulin neutralization by antibodies can be compensated by crosslinking the insulin-antibody complexes or by formation of big complexes precipitating by themselves. This is probably due to the induction of receptor aggregation.

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Insulin antibodies prevent insulin-receptor interactions

Cited by 13 publications

References 26 publications

The effect of insulin antibodies on insulin dose and diabetic control

The effect of insulin antibodies on insulin dose and diabetic control

Immunogenicity of intraperitoneal insulin infusion using programmable implantable devices

Effect of Antibody-Mediated Crosslinking of Insulin on Its Bioactivity and Receptor Binding^*

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Insulin antibodies prevent insulin-receptor interactions

Cited by 13 publications

References 26 publications

The effect of insulin antibodies on insulin dose and diabetic control

The effect of insulin antibodies on insulin dose and diabetic control

Immunogenicity of intraperitoneal insulin infusion using programmable implantable devices

Effect of Antibody-Mediated Crosslinking of Insulin on Its Bioactivity and Receptor Binding*

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Effect of Antibody-Mediated Crosslinking of Insulin on Its Bioactivity and Receptor Binding^*