The insulin autoimmune syndrome (IAS) as a cause of hypoglycaemia: an update on the pathophysiology, biochemical investigations and diagnosis

Abstract

Abstract:Insulin autoimmune syndrome (IAS) is considered to be very rare in Caucasians. Understanding its pathophysiology is paramount in (a) appreciating its potential impact on analyses of pancreatic hormones and (b) explaining its highly variable clinical manifestations in non-diabetic, non-acutely ill patients with indeterminate hypoglycaemia. The underlying aetiology of IAS is the presence of variable affinity/avidity endogenous insulin antibodies in significant amounts. The two types of insulin antibodies namely antibodies which bind insulin and/ or proinsulin(s) and receptor antibodies (insulin mimetic) will be discussed. Their biochemical and immunological roles in causing hypoglycaemia will be highlighted. Clinical manifestations of IAS can vary from mild and transient to spontaneous, severe and protracted hypoglycaemia necessitating in extreme cases plasmapheresis for glycaemic control. Antibodies of IAS can interfere in pancreatic immunoassay tests causing erroneous and potentially misleading results. Thorough testing for endogenous insulin antibodies must be considered in the investigations of non-diabetic, non-acutely ill patients with indeterminate and/or unexplained hypoglycaemia.Keywords: endogenous insulin antibodies; Hirata's disease, insulin autoimmune hypoglycaemia; hypoglycaemia in non-diabetic; insulin autoimmune syndrome (IAS); interference in immunoassays of insulin, proinsulin and C-peptide; wrong immunoassay results .

Glucose Changes in a Patient With Insulin Autoimmune Syndrome Demonstrated by Continuous Glucose Monitoring

“…Later, in the late postprandial state, insulin is released from the insulin-antibody complexes, and the freed insulin may reach inappropriately high levels to cause hypoglycemia. If the patient's auto-antibodies have a high insulin-binding capacity that enables slow, continuous release of freed insulin from the insulin-antibody complexes, then hypoglycemia is apt to occur in the fasting state as well (9,10). Our patient was diagnosed with IAS on the basis of his extremely high level of insulin during hypoglycemia and the presence of anti-insulin auto-antibodies despite absence of exposure to exogenous insulin.…”

“…To diagnose the underlying cause of endogenous insulin-induced hypoglycemia, the timing of hypoglycemia may offer some clues. Patients with insulinoma typically have fasting hypoglycemia (8), and by contrast, most patients with IAS have hypoglycemia in the late postprandial state (4 to 6 hours after eating) (9,10). Unlike insulinoma, auto-antibodies against endogenous insulin play a major role in glucose dysregulation in IAS (10).…”

Insulin Autoimmune Syndrome in a 25-Year-Old, Previously Healthy Kuwaiti Man

“…Furthermore, the C-peptide level was within the reference range, indicating a similar nonextended half-life with possible insulin to C-peptide ratio >1, but the insulin level could not be measured beyond 301 uIU/mL. Also, high serum insulin levels can be accompanied by low proinsulin and C-peptide levels, misleading the diagnosis as injectable insulin administration [3]. Our patient denied using exogenous insulin while proinsulin was below the reference range and the C-peptide level was normal.…”

“…e condition is known as Hirata's disease (HD), a er Yukimasa Hirata, the author who first described the syndrome in 1970 [2]. It is now recognized as the third most common cause of hypoglycaemia in Asian patients [3] following insulinoma and nonpancreatic neoplasia as the first and second most common aetiologies, respectively [3]. e syndrome affects both sexes equally [4] and is more frequent in patients over 40 years of age.…”

“…A few case reports of IAS associated with the use of alpha lipoic acid (ALA) were also reported [10,11]. Also, insulin autoantibodies may be triggered by exposure to viruses like mumps, rubella, Coxsackie B in uenza, hepatitis C, chickenpox, and measles by acting as super-antigens or they may manifest spontaneously [3].…”