Plasma Insulin-binding Capacity Research Articles

Insulin antibodies before and 1 year after the change-over from U40 to U100 insulin preparations in Belgium.

In 1991, Belgium realized, on a national level, a change-over from U40 to U100 insulin. We took advantage of this evolution to investigate the consequences of changing the concentration of insulin. The patients' weight, daily insulin dosis, insulin binding-capacity of plasma and glycated hemoglobin HbA1c were registered before, and after the change of concentration. Overall, none of these parameters underwent an obvious change, except for the percentage of insulin binding that significantly decreased after the adaptation. Especially in the range of 40% or more insulin binding, the decrease becomes very pronounced. In conclusion, changing the insulin concentration from U40 to U100, did not lead to any harmful clinical consequence. On the contrary, a positive influence of this adaptation, in terms of decreased amount of insulin antibodies was suggested. Probably this decrease is not clinically relevant, since neither the glycated hemoglobin, nor the total daily insulin dose underwent a similar change.

Resistance and allergy to recombinant human insulin

Insulin allergy and antibody-mediated resistance may complicate therapy with animal insulins. We describe a 53-year-old man manifesting both resistance and persistent systemic allergy despite treatment with recombinant human insulin. Insulin resistance and symptoms of allergy appeared in this patient several months after initiating therapy with mixed beef-pork insulin, as is often the case. Symptoms initially improved, but persisted, and then worsened again, despite continuous human insulin therapy. Total insulin-binding capacity by Scatchard analysis, high plasma insulin-binding capacity, and specific anti-insulin antibody levels were consistent with an immunologic form of insulin resistance. Glucocorticoid therapy was required both to reduce allergic findings and to restore glycemic control. Although recently available human insulins may be less immunogenic than animal forms, immune responses to exogenous human insulin still may pose significant clinical problems.

Correlates of insulin antibodies in newly diagnosed children with insulin-dependent diabetes before insulin therapy.

Insulin antibodies, as measured by plasma radiolabeled insulin-binding capacity, were determined in 124 newly diagnosed insulin-dependent diabetic (IDDM) children before and after 1, 3, and 5 days of insulin therapy. Controls were 35 nondiabetic children with plasma insulin binding capacity of 1.0 +/- 0.7%. The patients were divided into three groups according to their plasma insulin-binding capacity. Group 1 (N = 79) had binding within two standard deviations (SD) of the control mean, group 2 (N = 20) had insulin binding 2-6 SD above controls, and group 3 (N = 25) showed insulin-binding capacity of more than 6 SD above the control mean. After exogenous insulin therapy, plasma 125I-insulin-binding capacity dropped significantly in both groups 2 and 3, concurrent with significant increases in plasma insulin levels. The three groups differed from each other in that patients in group 3 were significantly younger than in the other groups and clinically seemed to be more severely dehydrated, as reflected in their higher levels of serum urea nitrogen, plasma glucose, potassium, and elevated pulse rate. The three groups did not differ in respect to sex, HLA-DR antigens, Coxsackie-B antibody titers, islet cell cytoplasmic antibodies, immunoglobulin level, and C-peptide levels. Only two of 446 siblings of IDDM children showed elevated insulin binding, one of whom developed IDDM 6 wk later. The presence of an insulin-binding substance probably representing insulin antibodies in some cases of newly diagnosed IDDM suggests that autoimmunity in this disorder is not limited to the B-cell membrane and cytoplasm and lends further support to the heterogeneity of IDDM.

EFFECT OF INSULIN ANTIBODIES ON FREE AND TOTAL PLASMA-INSULIN

Insulin administration often causes the development of insulin antibodies. Plasma insulin-binding capacity was assessed and free and total plasma insulin were measured in 96 insulin-dependent diabetic patients. Patients with the highest insulin binding capacity not only had the highest total insulin but also had the lowest free insulin. It is concluded that bound insulin is not unavailable to cells, that sufficient dissociation can occur for this insulin source to make a sizeable contribution to insulin delivery to the cell receptors, and that this can happen at a very low free insulin concentration.

ANTI-INSULIN-ANTIBODIES AND LATE DIABETIC COMPLICATIONS

Two hundred and seventy-four insulin-dependent juvenile diabetics were examined. One hundred and sixty-six patients were without late diabetic complications, while 108 patients had one or more complications. At the time of the investigation patients with and without complications were found to have the same insulin requirement. Retrospectively it was observed, that after treatment for 10 years the insulin requirement was significantly higher among patients who had developed complications after treatment for 19 years as compared to patients who after 19 years of treatment had not developed complications. One hundred and eighty-four patients, of which 110 were without and 74 with late diabetic omplications were examined for anti-insulin-antibodies. Patients with complications, especially those with early onset of proliferative retinopathy or nephropathy had a slightly although insignificantly elevated plasma insulin-binding capacity. The frequency of high titres was significantly greater among patients with complications as compared to the frequency in patients without complications. The observations support the assumption, that insulin-anti-insulin-antibody complexes may aggravate the vascular complications.

EFFECT OF "FRACTIONATED" INSULINS ON TOTAL PLASMA INSULIN BINDING CAPACITY AND INSULIN REQUIREMENT IN SEVERE DIABETES

Serial observations of insulin requirement and total plasma insulin binding capacity have been carried out on six severe diabetics whose treatment was changed from standard soluble and isophane (NPH) insulins to "fractionated" preparations (Nordisk Insulin Ltd). No correlation was found between initial insulin dose and binding capacity, but changes in these two functions during the study period were closely correlated, both for the group as a whole and for individual patients in whom falls in insulin dose occurred. It is concluded that highly purified insulins could be valuable in the treatment of insulin-resistant cases, that their use is frequently associated with a gradual reduction in insulin dose, and that estimation of total plasma insulin binding capacity may indicate which patients are most likely to benefit from fractionated insulin. No sudden change in insulin requirement was seen on changing to purified insulin preparations.

THE IMMUNOGENIC PROPERTIES OF HIGHLY PURIFIED INSULIN PREPARATIONS. THE CLINICAL IMPORTANCE OF INSULIN-BINDING ANTIBODIES

Twenty-four diabetic patients were treated with porcine protamine-insulin (NPH-insulin) containing 7-13 mmol proinsulin per mol insulin and 27 diabetic patients were treated with porcine protamine-insuline (HP-insulin) containing 0.36 mmol proinsulin per mol insulin. 75% of the patients treated with NPH-insulin and 15% of the patients treated with HP-insulin formed detectable insulin-binding antibodies. The difference in the antibody titre in the two groups was significant. As a group, patients treated with HP-insulin did not have significant rise in the plasma insulin-binding capacity when compared to pre-treated values. When comparing patients with antibodies and patients without detectable antibodies no difference in the degree of regulation could be demonstrated between the two groups. Young patients with antibodies had a higher insulin requirement per kg per day than patients without detectable antibodies. Among patients in remission those without detectable antibodies had a longer remission period than those with antibodies. Apart from the difference in antibody formation and hence a different distribution in the groups compared, the patients treated with NPH-insulin and HP-insulin did not differ with regard to the degree of regulation, the insulin requirement or the duration of the remission period.

THE PLACENTAL BARRIER TO HUMAN INSULIN-I-125 IN INSULIN DEPENDENT DIABETIC MOTHERS

Although the normal human placenta is impermeable to insulin, the effect of anti-insulin antibodies upon the placental barrier to insulin has not been defined. The placental transfer of human insulin-I125 was examined in normal (n=4) and insulin-dependent diabetic mothers (n=4) by infusing human insulin-I125 at a constant rate for 60-90 min. prior to delivery and measuring immuno-precipitable insulin-I125 radioactivity in the maternal and umbilical venous plasma at delivery. In normal mothers plasma insulin-I125 radioactivity was 683±110 cpm/ml (Mean±SEM) in the maternal vein and 6±2 cpm/ml in the umbilical vein. In three diabetic mothers with high plasma insulin binding capacity (1850-8400 μU/ml) the umbilical venous insulin-I125 was 10±10 cpm/ml when the maternal plasma insulin-I125 was maintained at 1388±356 cpm/ml, even though the antibodies were present in the fetal plasma. In another insulin-dependent diabetic mother with negligible anti-insulin antibodies, no placental transfer of human insulin-I125 was demonstrated. Thus, in both normal and diabetic mothers, placental transfer of human insulin-I125 is negligible and the presence of maternal anti-insulin antibodies does not induce insulin transfer.