Endocrine Abstracts (2019) 65 P243 | DOI: 10.1530/endoabs.65.P243

Mass spectrometric characterisation of circulating proinsulin-derived peptides in insulin autoimmune syndrome

David Church1,2,3, David Halsall1, Fiona Gribble2,3, Frank Reimann2,3, Robert Semple4 & Richard Kay2


1Cambridge University Hospitals, NHS Foundation Trust, Cambridge, UK; 2University of Cambridge Metabolic Research Laboratories, Cambridge, UK; 3National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK; 4Centre for Cardiovascular Science, Edinburgh, UK


Autoimmune immunoglobulins directed against peptide hormones are well-described. These are often clinically benign, but may cause a deleterious effect on the accuracy of clinical immunoassays. A notable exception is Insulin Autoimmune Syndrome (IAS, also known as Hirata disease), where antibody-binding has a direct effect on insulin kinetics resulting in aberrant glucose control. Current methods to diagnose IAS rely on crude immune-subtraction techniques such as polyethylene glycol precipitation, or cumbersome size fractionation of the immunoreactive species. The most widely-accepted model for IAS, based on data from studies of insulin kinetics, is that autoantibodies delay insulin clearance. Both the hyper- and hypoglycaemic phases in IAS are then explained by the sequestration of insulin followed by delayed clearance. With the advent of high resolution accurate-mass mass spectrometers and the application of peptidomic approaches for data analysis, it is now possible to examine the structural nature of the antibody-bound peptides in IAS with far greater selectivity. Data presented show, in addition to large amounts of insulin, the presence of proinsulin and proinsulin-derived peptides, in the plasma of six patients with IAS. A combination of size-exclusion chromatography and LC–MS/MS analysis show that, as well as insulin and intact proinsulin, two ‘des’ forms (des 31-32 and des 31–33 − which are partially cleaved proinsulin molecules, the numbered residues absent due to prohormone convertase/carboxypeptidase action) are present in plasma and may be antibody-bound. C-peptide was not present in the antibody-bound fractions. A likely mechanism for the excess of proinsulin and incompletely processed proinsulin species in IAS is one of sequestration by antibody, which, in effect, enriches these species by delaying their clearance rate. As proinsulin, and both des proinsulin forms, have biological activity, they may contribute to hypoglycaemia in IAS, even though are less potent than the mature insulin species.

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