A. Kooistra1,2, A. Muller Kobold3, A.P. van Beek2, H.L. Lutgers2
1 Centre for Rehabilitation, Diabetes rehabilitation, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
2Department of Endocrinology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands
3Department of Laboratory Medicine, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
a.kooistra01@umcg.nl
Background: Anti-insulin antibodies are a recognised cause of dysglycaemia and hypoglycaemia in individuals without prior insulin exposure (Insulin Autoimmune Syndrome; Hirata disease). Clinically significant antibody-mediated insulin binding is considered uncommon in insulin-treated type 1 diabetes in the era of recombinant insulin analogues. High-capacity insulin-binding antibodies may alter insulin pharmacokinetics by reducing immediate insulin bioavailability, delaying clearance, and creating a circulating insulin reservoir with subsequent unpredictable insulin release. We describe a case of prolonged hypoglycaemia during a 4-week inpatient diabetes rehabilitation prompting investigation for clinically relevant anti-insulin antibody binding.
Clinical considerations: An 18-year-old man with anti-GAD-positive type 1 diabetes diagnosed in 2024 who received insulin treatment using a MiniMed™ 780G hybrid closed-loop system, was referred for tertiary diabetes rehabilitation because of suboptimal glycaemic control (HbA1c 76 mmol/mol), impaired exercise capacity, fear of hypoglycaemia and difficulties with self-management. During rehabilitation, recurrent hypoglycaemic episodes lasting >4 hours occurred despite >300 g oral carbohydrate and minimal insulin delivery according to pump downloads. Laboratory evaluation during hypoglycaemia demonstrated plasma glucose 4.8 mmol/L, insulin 2,860 mU/L, C-peptide 41 pmol/L and proinsulin 2.7 pmol/L. Anti-insulin aspart antibodies measured 42.0 U/mL. PEG precipitation demonstrated 58.2% macro-insulin and 41.8% free insulin. LC-MS/MS detected endogenous insulin/Actrapid®(not distinguishable by the analytical platform and insulin aspart (NovoRapid®), the latter was markedly elevated (>20,000 pM).
Clinical course: Recurrent prolonged hypoglycaemia developed after the first rehabilitation week, occurring overnight and following minimal exertion. Differential diagnosis included factitious hypoglycaemia and clinically significant anti-insulin antibody binding. Functional in-vitro studies assessing reversible insulin-antibody binding are ongoing.
Discussion: Antibody-bound insulin exhibits reduced receptor-mediated uptake and delayed hepatic and renal clearance, creating a circulating insulin reservoir capable of delayed insulin release and prolonged hypoglycaemia. This case highlights a potentially underrecognised cause of unexplained dysglycaemia in insulin-treated diabetes and the importance of specialised diagnostic testing.