After secretion from the pancreatic β cells, insulin exerts its pleiotropic effects by binding to its widely expressed cell surface receptor and triggering a cascade of intracellular signalling events, suppressing hepatic glucose production and inducing glucose uptake into fat and muscle among many other effects. Insulin is also cleared rapidly from the circulation, with a half-life of around 5 min, a process which is partly mediated by insulin receptor binding. This rapid clearance is critical to normal glucose homeostasis. Autoantibodies may perturb the highly dynamic glucose-insulin negative feedback loop in two major ways, both of which may lead to severe hypoglycaemia and/or hyperglycaemia. First, antibodies against the insulin receptor often have the ability to activate the receptor inappropriately irrespective of circulating insulin levels. This may produce severe hypoglycaemia, although the chronic presence of these antibodies more commonly desensitizes the receptors, producing severe type B insulin resistance. Second, high affinity, high capacity antibodies against insulin itself may perturb insulin kinetics sufficiently to produce severe hypoglycaemia associated with the presence of macroinsulin complexes. Either pathological anti insulin receptor or pathological anti-insulin antibodies may arise either spontaneously or in the context of pre-existing diabetes, which may complicate interpretation of diagnostic tests. Rapid diagnosis is important, and in some cases may lead to use of potent multimodal immunosuppression to correct the severe metabolic disorder. How to select appropriate patients for antibody testing, and how best to utilise laboratory investigation to generate clinically meaningful results will be discussed.
Declaration of funding
This work was supported. Details are included below. Dr Semple is supported by a Fellowship from the Wellcome Trust (098498/Z/12/Z).