Paradoxical elevation of high molecular weight adiponectin in acquired extreme insulin resistance due to insulin receptor antibodies Received for publication 28 November 2006 and accepted in revised form 17 February 2007. Running Title: Adiponectin in Type B Insulin Resistance

Objective: Total plasma adiponectin and high molecular weight (HMW) polymeric adiponectin are strongly positively correlated with insulin sensitivity. However we have recently reported paradoxical hyperadiponectinemia in patients with severe insulin resistance due to genetically defective insulin receptors. This implies either that the insulin receptor has a critical physiological role in controlling adiponectin production and/or clearance, or that constitutive insulin receptor dysfunction influences adiponectin levels through developmental effects. The aim of the current study was to distinguish between these possibilities using a human model of reversible antibody-mediated insulin receptor dysfunction, and to refine the previous observations by determining adiponectin complex distribution. Research Design and Methods: Cross-sectional and longitudinal determination of fasting plasma adiponectin and adiponectin complex distribution in patients with extreme insulin resistance due to insulin receptor mutations, anti-insulin receptor antibodies (type B insulin resistance), or of undefined cause. Results: Despite extreme insulin resistance, patients with type B insulin resistance (all female; mean age 42 years (range 12-54)) had dramatically elevated total plasma adiponectin compared to the general population (mean 43.0 mg/l (range 31.3-54.2) vs mean 8.9 mg/l (range 1.5-28.5 for B.M.I.<25 kg/m2)), which was accounted for largely by HMW polymers. Hyperadiponectinaemia resolved in parallel with reduction of insulin receptor antibodies and clinical resolution of insulin resistance. Conclusions: While the well established inverse relationship between plasma insulin and adiponectin levels may, in part, reflect positive effects of adiponectin on insulin sensitivity, these data suggest that the magnitude of the effect of insulin action on adiponectin levels may have been underestimated.