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

Abstract

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.

Insulin hypersensitivity in type 1 diabetes: investigation and treatment with immunodepletion

“…High‐affinity IgG antibodies will cause insulin resistance. With low‐affinity antibodies, insulin may separate from the antibody complex causing troublesome delayed hypoglycaemia . Our patient exhibited the clinical characteristics of the former, predominantly.…”

“…Our patient exhibited the clinical characteristics of the former, predominantly. Polyclonal antibody generation may occur …”

Hyperinsulinemic hypoglycemia associated with insulin antibodies caused by exogenous insulin analog

“…There are some case reports about IAS-like situation induced by exogenous insulin. Reported in 2014, a lean 15-year-old girl was diagnosed with type 1 diabetes based on symptomatic hyperglycemia and positive anti-islet cell antibodies required for treatment of hyperglycemia and ketosis alternating with refractory hypoglycemia after using twice-daily mixed insulin for 11 months (10). A case report of two patients who developed daytime hyperglycemia and early morning hypoglycemia because of insulin antibody (IA) with affinity lower and binding capacity higher than insulin autoantibodies (IAA) in the insulin autoimmune syndrome (IAS) after insulin treatment being changed from human insulin to analog insulin was published in 2009 (3).…”

The insulin autoimmune syndrome (IAS) as a cause of hypoglycaemia: an update on the pathophysiology, biochemical investigations and diagnosis

“…Potential misdiagnosis is therefore likely to occur if these two interdependent entities namely the presence and nature of endogenous antibodies and immunoassays cross-reactivities are not considered and taken into account. Finally, the term IAS must not be confused with the effect of endogenous insulin antibodies in patients with brittle diabetes triggered by exogenous administration of insulin or insulin analogues causing poor glycaemic control and hypoglycaemia by a mechanism similar to IAS [100][101][102][103].…”