Characterisation of adiponectin multimers and the IGF axis in humans with a heterozygote mutation in the tyrosine kinase domain of the insulin receptor gene

Objective: Low levels of adiponectin, IGF-binding protein (IGFBP)-1, and IGFBP-2, 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 characterize the multimeric distribution of adiponectin and the IGF-axis in humans with a heterozygous INSR mutation (Arg1174Gln).Methods: Blood samples obtained in six Arg1174Gln-carriers and 10 lean, healthy controls before and after an euglycemic-hyperinsulinemic clamp were examined for plasma adiponectin multimers, leptin, total IGF-I, IGF-II, free IGF-I, IGFBP-1 and IGFBP-2.Results: Despite 10-fold elevated fasting insulin and marked insulin resistance in Arg1174Gln-carriers, the levels of total adiponectin, leptin, IGFBP-1 and IGFBP-2 were similar to those observed in controls, while total IGF-I, IGF-II and free IGF-I levels were increased. The relative fraction of high-molecular weight (HMW)-adiponectin was increased, whereas both the absolute concentration and fraction of low-molecular weight (LMW)-adiponectin were reduced in Arg1174Gln-carriers. Interestingly, exogenous insulin failed to suppress total adiponectin in Arg1174Gln-carriers, but reduced IGFBP-1 and increased IGFBP-2 as in controls.Conclusion: The normal levels of adiponectin, IGFBP-1 and IGFBP-2 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 IGF-I and IGF-II and a potentially improved distribution of adiponectin multimers these changes may contribute to rescue insulin action in insulin receptor deficient individuals.