Clinical and biochemical aspects of the insulin autoimmune syndrome (IAIS)

Abstract

A 44-year old patient presented with recurrent hypoglycemic attacks after ingestion of carbohydrates. High insulin levels in the range of 350 microU/ml (normal range less than 20 microU/ml) were detected which rose to peak levels of 2,460 microU/ml (normal range less than 300 microU/ml) after oral glucose. The apparently high insulin concentrations were caused by insulin autoantibodies interfering in the radioimmunoassay (RIA) system (and thus with correct insulin quantitation). 125I-insulin added to the patient's serum was not bound to dextran-coated charcoal but was precipitated with antihuman IgG serum. The antibodies bound human, porcine, and bovine insulin with similar affinity. Following Sephadex G-50 gel filtration, the patient's insulin eluted after the void volume. Free insulin was extracted from serum using Sep-Pak C 18 cartridges and characterized by high pressure liquid chromatography (HPLC); it eluted similarly to synthetic human insulin. Quantitation of free insulin during a hypoglycemic attack (3.5 h after oral glucose, with a blood sugar of 20 mg/dl) showed an increased insulin level of 50 microU/ml. Insulin receptor concentration on erythrocytes was near the lower normal limit. We believe that the insulin antibodies present in this patient's serum (who supposedly never received insulin) led to the formation of a large circulating insulin pool, binding the insulin released after glucose stimulation, and causing hypoglycemias by delayed postprandial liberation of bound insulin.

Clonally restricted insulin autoantibodies in a cohort of 2200 healthy blood donors

“…It is interesting to note that in two patients suffering from a non-drug related autoimmune hypoglycaemic syndrome [33,34], very high plasma concentrations of insulin autoantibodies qualitatively similar to those found in blood donors were identified. In both instances, the anti-insulin IgG were of low affinity and structurally homogeneous (73 K in one case and 71 K in the other one).…”

Hypoglycaemia due to interaction of glimepiride with isoniazid in a patient with type 2 diabetes mellitus

“…However, we were not able to perform in our hospital more sensitive diagnostic tests owing to their invasiveness. IAS, which has been described in very rare cases after isoniazid treatment,3 12 is excluded in our patient because of high C peptide levels. Indeed, patients with IAS usually exhibit very high insulin levels (sometimes >1.000 μU/ml) because of the high capacity of insulin-binding autoantibodies 3 12.…”

“…IAS, which has been described in very rare cases after isoniazid treatment,3 12 is excluded in our patient because of high C peptide levels. Indeed, patients with IAS usually exhibit very high insulin levels (sometimes >1.000 μU/ml) because of the high capacity of insulin-binding autoantibodies 3 12. This contrasts with normal C peptide levels, suggesting the absence of genuine endogenous excess insulin secretion 3 12.…”

Imaging of the Buffering Effect of Insulin Antibodies in the Autoimmune Hypoglycemic Syndrome1

“…The half-life of injected insulin in these patients is also significantly prolonged (19), and the release of insulin from the circulating autoantibody pool is expected to be a function of the laws of the equilibrium of mass action and not in response to changes in blood glucose levels, therefore resulting in hypoglycemia. Patients consistently have late hypoglycemia after carbohydrate ingestion or exogenous insulin administration (14,20), but not after prolonged fasting (11). Although the hypothesis is attractive, it has not been tested using insulin biodistribution studies in vivo.…”

“…According to this mechanism, the availability of the secreted hormone to receptors in the liver and peripheral tissues would be decreased due to insulin binding to circulating antibodies. This could account for the lack of prompt hypoglycemic response after acute stimulation of insulin secretion or exogenous insulin administration (19) and for the impaired glucose tolerance or overt diabetes reported in some of these patients (11,14,20). The half-life of injected insulin in these patients is also significantly prolonged (19), and the release of insulin from the circulating autoantibody pool is expected to be a function of the laws of the equilibrium of mass action and not in response to changes in blood glucose levels, therefore resulting in hypoglycemia.…”