title: Characterisation of adiponectin multimers and the IGF axis in humans with a heterozygote mutation in the tyrosine kinase domain of the insulin receptor gene.
abstract: OBJECTIVE
  Low levels of adiponectin, IGF-binding protein 1 (IGFBP1) and IGFBP2 and high levels of leptin correlate with several indices of insulin resistance and risk of type 2 diabetes. However, in insulin receptoropathies, plasma adiponectin is paradoxically increased despite severe insulin resistance, whereas the IGF axis is sparsely described. Here, we aimed to characterise the multimeric distribution of adiponectin and the IGF axis in humans with a heterozygous INSR mutation (Arg1174Gln).
  
  
  METHODS
  Blood samples obtained from six Arg1174Gln carriers and ten lean, healthy controls before and after a euglycaemic-hyperinsulinaemic clamp were examined for plasma adiponectin multimers, leptin, total IGF1, IGF2, free IGF1, IGFBP1 and IGFBP2.
  
  
  RESULTS
  Despite tenfold elevated fasting insulin and marked insulin resistance in Arg1174Gln carriers, the levels of total adiponectin, leptin, IGFBP1 and IGFBP2 were similar to those observed in controls, while total IGF1, IGF2 and free IGF1 levels were increased. The relative fraction of high-molecular weight adiponectin was increased, whereas both the absolute concentration and the fraction of low-molecular weight adiponectin were decreased in Arg1174Gln carriers. Interestingly, exogenous insulin failed to suppress total adiponectin in Arg1174Gln carriers, but reduced IGFBP1 and increased IGFBP2 as in controls.
  
  
  CONCLUSIONS
  The normal levels of adiponectin, IGFBP1 and IGFBP2 in the face of highly elevated insulin levels suggest an impaired ability of insulin to suppress markers of common insulin resistance in carriers of a dominant-negative INSR mutation. However, together with the adaptive increases in IGF1 and IGF2 and a potentially improved distribution of adiponectin multimers, these changes may contribute to rescue insulin action in insulin receptor-deficient individuals.
authors.affiliation: Department of Endocrinology, Diabetes Research Centre, Odense University Hospital, Kløvervænget 6, DK-5000 Odense C, Denmark. k.hojlund@dadlnet.dk
authors.forename: Kurt
authors.initials: K
authors.lastname: Højlund
authors.forename: Henning
authors.initials: H
authors.lastname: Beck-Nielsen
authors.forename: Allan
authors.initials: A
authors.lastname: Flyvbjerg
authors.forename: Jan
authors.initials: J
authors.lastname: Frystyk
mesh_terms: D052242:Adiponectin / Q000097:blood / Q000235:genetics*; D000328:Adult; D015415:Biomarkers / Q000097:blood; D005260:Female; D006580:Genetic Carrier Screening; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000097:blood / Q000235:genetics*; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D055503:Protein Multimerization / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D011972:Receptor, Insulin / Q000235:genetics*
chemical_list: D052242:Adiponectin; D015415:Biomarkers; C032231:IGFBP1 protein, human; D018970:Insulin-Like Growth Factor Binding Protein 1; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin