title: IGF-I treatment of insulin resistance.
abstract: Severe insulin resistance resulting from known or putative genetic defects affecting the insulin receptor or post-insulin receptor signalling represents a clinical spectrum ranging from Donohue's and Rabson-Mendenhall syndrome, where the genetic defect is identified, through to the milder phenotype of type A insulin resistance, where a genetic defect can only be detected in around 10% of cases. Paradoxically, subjects with these conditions may present with hypoglycaemia due to mismatch of post-prandial glucose excursion and compensatory hyperinsulinaemia. Ultimately, treatment with insulin and insulin sensitisers will be unsuccessful and subjects may succumb to diabetes or its complications. Recombinant human IGF-I alone or combined with its binding protein (IGFBP-3) provides an alternative therapy as IGF-I receptor shares structural and functional homology with the insulin receptor and recombinant human insulin-like growth factor I (rhIGF-I) therapy could improve glucose disposal by signalling through the IGF-I receptor, whilst reducing the adverse effects of high insulin concentrations. There are also data which indicate that IGF-I signalling through the IGF-I receptor on the pancreatic beta-cell may be important in maintaining insulin secretion. Pilot studies confirmed that rhIGF-I could reduce glucose and insulin levels in subjects with type A insulin resistance and those with Rabson-Mendenhall syndrome with sustained beneficial effects on HbA1c. Continued study has confirmed efficacy of rhIGF-I when combined with IGFBP-3 in the treatment of Donohue's and type A insulin resistance subjects. Observations that IGF-I treatment can improve C-peptide levels in these subjects may indicate that it might be more valuable as a first line intervention to preserve beta-cell function, rather than its current use as a medication of last resort in subjects where all other therapies have failed.
authors.affiliation: University of Cambridge, Department of Paediatrics, Box 116, Addenbrookes Hospital, Hills Road, Cambridge, CB2 2QQ, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: McDonald
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Williams
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Regan
authors.forename: Robert K
authors.initials: RK
authors.lastname: Semple
authors.forename: David B
authors.initials: DB
authors.lastname: Dunger
mesh_terms: D004359:Drug Therapy, Combination; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000627:therapeutic use; D007334:Insulin-Like Growth Factor I / Q000627:therapeutic use*; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000627:therapeutic use; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000235:genetics