Resolution of dysglycaemia after treatment of monoclonal gammopathy of endocrine significance

Abstract

In very rare cases of monoclonal gammopathy, insulin-binding paraprotein can cause disabling hypoglycaemia. We report a 67-year-old man re-evaluated for hyperinsulinaemic hypoglycaemia that persisted despite distal pancreatectomy. He had no medical history of diabetes mellitus or autoimmune disease but was being monitored for an IgG kappa monoclonal gammopathy of undetermined significance. On glucose tolerance testing, hyperglycaemia occurred at 60 min (glucose 216 mg/dL) and hypoglycaemia at 300 min (52 mg/dL) concurrent with an apparent plasma insulin concentration of 52 850 pmol/L on immunoassay. Laboratory investigation revealed an IgG2 kappa with very high binding capacity but low affinity (Kd 1.43 × 10-6 mol/L) for insulin. The monoclonal gammopathy was restaged as smouldering myeloma not warranting plasma cell-directed therapy from a haematological standpoint. Plasma exchange reduced paraprotein levels and improved fasting capillary glucose concentrations. Lenalidomide was used to treat disabling hypoglycaemia, successfully depleting paraprotein and leading to resolution of symptoms.

Keywords: MGUS; hyperinsulinaemia; hypoglycaemia; insulin autoantibodies; lenalidomide; myeloma; plasma exchange; smouldering myeloma.

Figure 1.

Capillary zone electrophoresis pre/post light chain capture. Results of capillary zone electrophoresis of serum (A), following addition of anti-kappa (B), and following addition of anti-lambda (C). Results were consistent with a monoclonal band, which was reduced with anti-kappa but not anti-lambda.

Figure 2.

Prolonged oral glucose tolerance test (A). Fasting capillary blood glucose measured pre, and venous blood glucose measured post, 75 g oral glucose load. (Venous sample collected at time 0 was unsuitable for analysis due to haemolysis.) Gel filtration chromatography of plasma post addition of synthetic human insulin (B). Results from presentation, follow-up, pre plasma exchange, and post plasma exchange are shown. Elution volumes of immunoglobulin G (IgG), albumin (Alb), and monomeric insulin (mIns) are shown (molecular weights 150, 66.5, and 5.8 kDa, respectively). High-molecular-weight insulin (HMWIns) is antibody-bound insulin that elutes with immunoglobulin, and the slur between peaks is produced by dissociation of immunocomplexes during filtration. Radioligand binding assay (C). Data were consistent with an antibody of high capacity and low affinity (Kd 1.43 × 10⁻⁶ mol/L) to bind insulin.

Figure 3.

Insulin binding by antibody class (A). Results are expressed as arbitrary units (AU) derived from a logarithmic standard curve. Data demonstrated most insulin binding using protein A Sepharose (GB-PAS) and protein G Sepharose (PGS), consistent with anti-insulin IgG. Insulin binding by IgG subclass (B). Results are expressed as nano unit of insulin bound per millilitre of serum (nU/mL). Data are consistent with anti-insulin IgG2. Insulin recovery following light chain capture (C). Results expressed as percentage recovery of insulin immunoreactivity (%). Depletion of paraprotein with anti-kappa but not anti-lambda was confirmed with capillary zone electrophoresis (Figure 1B and C). InsAb +, positive control; InsAb -, negative control. Patient results are consistent with anti-insulin kappa.