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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.