A novel approach to a rare case of non-islet cell hypoglycaemia

Summary Insulin autoimmune syndrome (IAS) is a rare cause of non-islet cell hypoglycaemia. Treatment of this condition is complex and typically involves long-term use of glucocorticoids. Immunotherapy may provide an alternative in the management of this autoimmune condition through the suppression of antibodies production by B-lymphocyte depletion. We present a case of a 62-year-old male, with refractory hypoglycaemia initially presenting with hypoglycaemic seizure during an admission for acute psychosis. Biochemical testing revealed hypoglycaemia with an inappropriately elevated insulin and C-peptide level and no evidence of exogenous use of insulin or sulphonylurea. Polyethylene glycol precipitation demonstrated persistently elevated free insulin levels. This was accompanied by markedly elevated anti-insulin antibody (IA) titres. Imaging included CT with contrast, MRI, pancreatic endoscopic ultrasound and Ga 68-DOTATATE position emission tomography (DOTATATE PET) scan did not reveal islet cell aetiology for hyperinsulinaemia. Maintenance of euglycaemia was dependent on oral steroids and dextrose infusion. Complete resolution of hypoglycaemia and dependence on glucose and steroids was only achieved following treatment with plasma exchange and rituximab. Learning points Insulin autoimmune syndrome (IAS) should be considered in patients with recurrent hyperinsulinaemic hypoglycaemia in whom exogenous insulin administration and islet cell pathologies have been excluded. Biochemical techniques play an essential role in establishing high insulin concentration, insulin antibody titres, and eliminating biochemical interference. High insulin antibody concentration can lead to inappropriately elevated serum insulin levels leading to hypoglycaemia. Plasma exchange and B-lymphocyte depletion with rituximab and immunosuppression with high dose glucocorticoids are effective in reducing serum insulin levels and hypoglycaemia in insulin autoimmune syndrome (IAS). Based on our observation, the reduction in serum insulin level may be a better indicator of treatment efficacy compared to anti-insulin antibody (IA) titre as it demonstrated greater correlation to the frequency of hypoglycaemia and to hypoglycaemia resolution.

Immunotherapy-Related Autoimmune Diabetes Mellitus and Exogenous Insulin Antibody Syndrome in a Patient With Metastatic Oral Squamous Cell Carcinoma

Introduction: Exogenous insulin antibody syndrome (EIAS) is a rare condition characterized by wide glycemic excursions and recurrent hypoglycemia in the presence of high insulin antibody titers. It has been described in diabetic patients treated with exogenous insulin. Programmed death ligand 1 (PD-L1) inhibitors are known to cause autoimmune diabetes mellitus, but PD-L1-related EIAS has not yet been reported to our best knowledge. Case Description: A 63 years old Caucasian man with history of recurrent oral squamous cell cancer presented to emergency room with polyuria, polydipsia, nausea, and vomiting 3 months after initiation of immunotherapy (Durvalumab and cetuximab). He had no prior history of diabetes mellitus or hypoglycemia. He was admitted to hospital for management of diabetic ketoacidosis (Anion gap of 24 mEq/L, venous blood glucose of 805 mg/dL, Venous PH of 7.12, large urine ketone, A1C of 8.9%). After a brief hospital stay, the patient was discharged home on insulin glargine and metformin. His immunotherapy was resumed after hospital discharge. When the patient was seen by Endocrinologist in the clinic, metformin was discontinued and prandial insulin lispro was added. This basal-bolus insulin regimen improved his glycemic control initially. However, without significant changes in his lifestyle or medical condition, he developed worsening postprandial hyperglycemia and recurrent fasting hypoglycemia. Up-titration of his mealtime insulin did not lower postprandial hyperglycemia but possibly worsened fasting hypoglycemia. EIAS was suspected after reviewing his continuous glucose monitoring data. Further work up at this point revealed mildly elevated glutamic acid decarboxylase antibodies (5.9 units/mL, normal range 0.5 - 5.0) and markedly elevated insulin antibody level (77.0 µU/mL, normal range <5). His blood C-peptide was undetectable when his venous blood glucose was 252 mg/dl. In addition, his total insulin level (198 uU/mL) was much higher than his free insulin level (38 uU/mL) following an insulin lispro injection. The patient was diagnosed with EIAS. Switching insulin lispro to insulin aspart while he was on a different immunotherapy medication (Pembrolizumab) immediately reduced his average blood glucose and reduced his total daily insulin dosage by more than 50%. This improvement in glycemic control with insulin aspart only lasted for about 1 week. Unfortunately, the patient’s squamous cancer progressed on immunotherapy. He was referred to hospice care and passed away. Conclusion: Evaluation for EIAS would be reasonable in insulin-treated diabetic patients who develop wide glucose excursions and unexplained fasting hypoglycemia while on immunotherapy.

“The Unusual Suspect” - Insulin Autoimmune Syndrome, an Extremely Rare Cause of Hypoglycemia

Background: Insulin autoimmune syndrome (IAS), also called Hirata syndrome, is a rare diagnosis which is characterized by hypoglycemia, normal or elevated fasting insulin level, and elevated anti-insulin antibody titers. Clinical Case: 45-year-old nondiabetic Caucasian female presented to the emergency department (ED) with chief complaint of near-syncope. She reported difficulty concentrating and feeling faint roughly 1 hour after consuming breakfast. Upon ED arrival, fingerstick glucose (FSG) was 47 mg/dL. Her symptoms resolved with ingestion of orange juice and repeat blood glucose (BG) 15 minutes later was 120 mg/dL. She reported similar symptoms in the last 5 years happening “every few months” without a predictable pattern; twice with witnessed loss of consciousness. Workup for syncope in the past included normal neurologic, cardiac, and tilt-table testing. She had no prior low FSG/BG recorded, no personal history of bariatric surgery or family history of diabetes mellitus and no access to antihyperglycemic medications. Past medical history included ulcerative colitis and medications included sulfasalazine and multivitamins. Pertinent review of systems was negative for weight loss, nausea, and diarrhea. Vital signs were within normal limits. Physical exam was unremarkable. Height was 165 cm, weight 67.8 kg and body mass index 24.9 kg/m2. Blood draw after overnight fast revealed BG of 78 mg/dL, C-peptide 0.7 ng/mL (ref range 0.8–3.5), insulin 10 µIU/mL (3–19), proinsulin <1.6 pmol/L (<8.0), insulin-like growth factor-2 (IGF-2) 339 ng/mL (180–580) and insulin antibody level 10.0 U/mL (0.0–0.4). She was managed conservatively with frequent small meals and patient has continued to do well without recurrence of symptoms. Conclusion: IAS is an exceedingly rare disease entity with about 460 cases described in literature, mostly in patients of Asian descent. Workup for hypoglycemia in non-diabetic patients should include insulin antibody titers to rule out IAS. There appears to be a genetic predisposition to developing IAS in patients with major histocompatibility complex (MHC) genes HLA-DQA1, HLA-DQB1 and HLA-DRB1. It is now being more frequently described in patients of non-Asian descent, particularly those with other autoimmune or plasma cell dyscrasias. It is also associated with drugs containing sulfhydryl groups and viral infections. Treatment should be tailored to severity of disease. Most drug induced IAS resolves after cessation of culprit drug. Conservative management is usually the first step with frequent, low carbohydrate meals with diazoxide or octreotide as adjunctive options. Immunosuppression (high-dose prednisolone or rituximab) and plasma exchanged are reserved severe or refractory cases.

Associations of insulin-induced lipodystrophy in children, adolescents, and young adults with type 1 diabetes mellitus using recombinant human insulin: a cross-sectional study

Objective Insulin-induced lipodystrophy is of two types, lipohypertrophy and lipoatrophy. Lipodystrophy often leads to worsening of glycemic control in type 1 diabetes mellitus. Our objective was to identify the clinical, immunological, and other factor(s) associated with the development of lipodystrophy. Methods In this observational cross-sectional hospital-based study, 95 children, adolescents, and young adults with type 1 diabetes mellitus were observed for the development of lipodystrophy. Injection technique, insulin dose, and glycemic parameters were noted. Serum TNF-α, IL-1β, and anti-insulin antibody levels were measured. Histopathological examination of the lipodystrophic area was done in a small number of people. Results Among the participants, 45.2% of participants had lipohypertrophy and 4.2% had lipoatrophy exclusively; 3.1% of participants had coexisting lipohypertrophy and lipoatrophy. Improper injection site rotation technique was more common in participants with lipohypertrophy in comparison to those without lipodystrophy. The age of onset of diabetes, duration of insulin use, and the number of times of needle reuse were not significantly different between the lipohypertrophy and nonlipodystrophy groups. Serum TNF-α, IL-1β, and anti-insulin antibody levels; HbA1c; rate of hypoglycemia; and body weight-adjusted dose requirement were higher among the participants with lipohypertrophy. On histopathology, scant, or no inflammatory infiltrate was found in lipoatrophic and lipohypertrophic areas, respectively. Conclusion Improper insulin injection technique and higher levels of proinflammatory cytokines and anti-insulin antibody are associated with lipodystrophy in type 1 diabetes mellitus. HbA1c and rate of hypoglycemia are higher in people with lipodystrophy.