Recurrent Fasting Hypoglycemia in a Patient with Insulin-Dependent Diabetes and Monoclonal Gammopathy of Undetermined Significance

Insulin autoimmune syndrome (IAS) and exogenous insulin autoimmune syndrome (EIAS) are characterized by hypoglycemia, hyperinsulinemia and the presence of insulin antibodies (IAs). This case illustrates the diagnostic dilemma that is faced with regard to distinguishing EIAS from IAS in a diabetic patient on insulin with persistent fasting hypoglycemia who interestingly also had monoclonal gammopathy of undetermined significance (MGUS).

Case Description:

We describe an 80-year-old man with coexistent IgG kappa monoclonal gammopathy of undetermined significance (MGUS) and Type 2 Diabetes Mellitus who presented with recurrent episodes of symptomatic fasting hypoglycemia. Elevated plasma insulin (>1000 mcIU/ml), proinsulin (78 pmol/L) and C-peptide (4.5 HI) levels were detected. CT abdomen and endoscopic ultrasound ruled out endogenous insulin over-production from insulinomas. Over several weeks insulin and oral hypoglycemic agents were withdrawn and a low-carbohydrate diet started with frequent small meals and a bedtime snack. Elevated IAs (>625 uU/ml) were detected while he was off insulin for 6 weeks. Anti-IA2, Anti-ZnT8 and Anti GAD-65 were negative. The fasting hypoglycemic episodes resolved eventually when he was off all anti-diabetic medications but post-prandial hyperglycemia persisted for which Linagliptin was added. Bone marrow biopsy ruled out multiple myeloma, therefore the MGUS was not treated.

Discussion:

There are two broad scenarios in which IAs, hypoglycemia and hyperinsulinemia may occur. The first, EIAS, occurs when IAs are produced in response to exogenous insulin administration. The second scenario, IAS, is characterized by IAs without prior exposure to insulin. These two conditions are difficult to definitively distinguish from each other clinically. Whereas EIAS usually resolves with cessation of insulin, IAS may be self-limited or subside after removal of trigger factors, virus or drugs, and rarely requires immunosuppression or plasmapheresis. It is interesting that our patient had MGUS, an association reported previously in IAS. Although he achieved symptomatic relief of hypoglycemia merely with cessation of insulin without treatment of MGUS, the IAs still remained elevated 6 weeks later, and we wondered whether this was due to the underlying monoclonal gammopathy. However, as IAs may persist for up to 2 years after insulin cessation, mere elevation of IAs cannot differentiate between EIAS and IAS related to MGUS. Regardless of this diagnostic dilemma, he had a favorable outcome after cessation of insulin and continued follow up of his MGUS.