Insulin Binding to Antibodies is a Risk Factor for Inexplicable Severe Hypoglycaemia in Children with Type-1 Diabetes Mellitus

Seewi, Ora; Jaeger, C.; Rg, Bretzel; Schönaü, Eckhard

doi:10.1055/s-2007-1004565

Cited by 11 publications

(7 citation statements)

References 32 publications

(55 reference statements)

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“…This young lady with type 1 diabetes initially presented with circulating anti-insulin antibodies. Anti-insulin antibodies to human insulin preparation in diabetic children are not an uncommon phenomena and the presence of these antibodies in the patient's circulation is associated with an increase in the frequency of hypoglycaemia (8) (11). The anti-insulin antibody characteristics are one of the causative factors of hypoglycaemic episodes.…”

Section: Discussionmentioning

confidence: 99%

Analytical and clinical challenges in a patient with concurrent type 1 diabetes, subcutaneous insulin resistance and insulin autoimmune syndrome

Jassam

Amin

Holland

et al. 2014

Endocrinology, Diabetes &Amp; Metabolism Case Reports

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SummaryA lean 15-year-old girl was diagnosed with type 1 diabetes based on symptomatic hyperglycaemia and positive anti-islet cell antibodies. Glycaemia was initially stabilised on twice-daily mixed insulin. After 11 months from the time of diagnosis, she complained of hyperglycaemia and ketosis alternating with hypoglycaemia. This progressively worsened until prolonged hospital admission was required for treatment of refractory hypoglycaemia. A high titre of anti-insulin antibodies was detected associated with a very low recovery of immunoreactive (free) insulin from plasma after precipitation with polyethylene glycol, suggesting the presence of insulin in bound complexes. Insulin autoimmune syndrome was diagnosed and metabolic fluctuations were initially managed supportively. However, due to poor glucose control, immunosuppressive therapy was initiated first with steroids and plasmapheresis and later with anti-CD20 antibody therapy (Rituximab). This treatment was associated with a gradual disappearance of anti-insulin antibodies and her underlying type 1 diabetes has subsequently been successfully managed with an insulin pump.Learning points Anti-insulin antibodies may result in low levels of free insulin.Polyclonal anti-insulin antibodies can interfere with the pharmacological action of administered insulin, resulting in hypoglycaemia and insulin resistance, due to varying affinities and capacities.In this patient, rituximab administration was associated with a gradual disappearance of anti-insulin antibodies.It is hypothesised that this patient had subcutaneous insulin resistance (SIR) caused by insulin capture at the tissue level, either by antibodies or by sequestration.A prolonged tissue resistance protocol may be more appropriate in patients with immune-mediated SIR syndrome.

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Section: Discussionmentioning

confidence: 99%

Analytical and clinical challenges in a patient with concurrent type 1 diabetes, subcutaneous insulin resistance and insulin autoimmune syndrome

Jassam

Amin

Holland

et al. 2014

Endocrinology, Diabetes &Amp; Metabolism Case Reports

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“…Prolonged fasting hypoglycaemia due to IAs was documented in a patient with type 2 diabetes treated with insulin, who had inappropriate plasma freeinsulin levels and extremely high IA levels; in this case report, the authors had the possibility to assess the effect of insulin withdrawal on insulin-antibody binding kinetics [40]. In a recent study, insulin binding to antibodies >15% appeared to be a strong risk factor for inexplicable severe hypoglycaemias in type 1 diabetic children [41]. It must be presumed that antibodies first bind the insulin in circulation and then later dissociate from the insulin, allowing activation of cellular insulin receptors.…”

Section: Prolongation Of Insulin Action and Risk Of Hypoglycaemiamentioning

confidence: 93%

Circulating insulin antibodies: influence of continuous subcutaneous or intraperitoneal insulin infusion, and impact on glucose control

Radermecker

Renard

Scheen

2009

Diabetes Metabolism Res

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The purification of animal insulin preparations and the use of human recombinant insulin have markedly reduced the incidence, but not completely suppressed, the development of anti-insulin antibodies (IAs). Advances in technologies concerning the mode of delivery of insulin, i.e. continuous subcutaneous insulin infusion (CSII), continuous peritoneal insulin infusion (CPII) and more recently inhaled insulin administration, appear to significantly increase circulating levels of immunoglobulin G (IgG) anti-IAs in diabetic patients. However, the increase is usually moderate and mostly transient as compared to previous observations with poorly purified animal insulin preparations. The clinical impact of these circulating anti-IAs remains unclear. Nevertheless, several studies have suggested that antibodies could retard insulin action, leading to a worsening of postprandial hyperglycaemia and/or serve as a carrier, thus leading to unexpected hypoglycaemia. CPII may be associated with more marked and sustained increase in IAs levels, possibly related to the use of an unstable insulin and the formation of immunogenic aggregates of insulin. The possible clinical consequences of these high levels of IAs remain to be evaluated because a low-glucose morning syndrome or severe insulin resistance with ketone bodies production have been reported in some cases. In conclusion, even if CSII and CPII may promote the development of circulating IAs, this increase does not lead to immunological insulin resistance, compared to that previously described with animal non-purified insulin preparations, and seems to have only marginal influence on blood glucose control or complications in most diabetic patients.

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“…Non-neutralizing insulin-binding antibodies induced by exogenous insulin may prolong the half-life of insulin in the circulation, thereby lowering insulin requirement [10, 11]. Insulin binding to antibodies has been considered as a risk factor for inexplicable hypoglycaemia in T1DM children [12]. …”

Section: Discussionmentioning

confidence: 99%

Recurrent hypoglycaemia in type-1 diabetes mellitus may unravel the association with Addison’s disease: a case report

et al. 2014

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BackgroundPrimary adrenocortical insufficiency or Addison’s disease is caused by a progressive destruction of the adrenal cortex, resulting into a reduction of glucocorticoids, mineralocorticoids, and androgens. Autoimmune Addison’s disease is the most common etiological form, accounting for about 80% of all cases.Case presentationWe describe the case of a 16-year-old Caucasian boy affected by type-1 diabetes mellitus and autoimmune thyroiditis, who experienced recurrent hypoglycaemia as presenting symptom of Addison’s disease.ConclusionsHypoglycaemia is not a common presenting feature of Addison’s disease, both in patients with type-1 diabetes mellitus and in non-diabetic patients. However, hypoglycaemia may occur in association with primary and secondary glucocorticoid deficiency as a result of an enhanced insulin sensitivity. Hypoglycaemia is the most common acute complication of insulin therapy in patients with type-1 diabetes mellitus. Addison’s disease has been described in approximately 0.5% of patients with type-1 diabetes mellitus, being more frequent in females and occurring in middle-aged patients. An association among type-1 diabetes mellitus, autoimmune thyroiditis, and Addison’s disease is found in the “Schmidt’s syndrome”, a rare disorder that may occur in the paediatric age. Our case suggests that the presence of Addison’s disease should be taken into consideration in patients with type-1 diabetes mellitus and frequent episodes of hypoglycaemia. We wish to highlight that there are no specific indications to screen for the association between Addison’s disease and type-1 diabetes mellitus, although an early diagnosis of Addison’s disease in diabetic patients would prevent the morbidity and potential mortality of this association.

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Insulin Binding to Antibodies is a Risk Factor for Inexplicable Severe Hypoglycaemia in Children with Type-1 Diabetes Mellitus

Abstract: Insulin binding to antibodies >15% appears to be a strong risk factor for inexplicable severe hypoglycaemias in type-1 diabetic children.

Cited by 11 publications

References 32 publications

Analytical and clinical challenges in a patient with concurrent type 1 diabetes, subcutaneous insulin resistance and insulin autoimmune syndrome

Analytical and clinical challenges in a patient with concurrent type 1 diabetes, subcutaneous insulin resistance and insulin autoimmune syndrome

Circulating insulin antibodies: influence of continuous subcutaneous or intraperitoneal insulin infusion, and impact on glucose control

Recurrent hypoglycaemia in type-1 diabetes mellitus may unravel the association with Addison’s disease: a case report

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