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Paradoxical Elevation of High–Molecular Weight Adiponectin in Acquired Extreme Insulin Resistance Due to Insulin Receptor Antibodies

¹ Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Cambridge, U.K
² Department of Cell Biology, Division of Endocrinology, and Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, New York
³ Department of Paediatrics, University of Cambridge, Addenbrooke's Hospital, Cambridge, U.K
⁴ Clinical Endocrinology Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, Bethesda, Maryland
⁵ MRC Epidemiology Unit, Institute of Public Health, University of Cambridge, Elsie Widdowson Laboratory, Fulbourn Road, Cambridge, U.K

Address correspondence and reprint requests to Dr. Robert K. Semple, Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2QR, U.K. E-mail: rks16{at}cam.ac.uk

Abbreviations: FPLC, fast-protein liquid chromatography; HMW, high molecular weight

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. Cross-sectional and longitudinal determination of fasting plasma adiponectin and adiponectin complex distribution was undertaken in patients with extreme insulin resistance due to insulin receptor mutations, anti-insulin receptor antibodies (type B insulin resistance), or an undefined cause. Despite extreme insulin resistance, patients with type B insulin resistance (all women; mean age 42 years [range 12–54]) had dramatically elevated total plasma adiponectin compared with the general population (mean 43.0 mg/l [range 31.3–54.2] vs. 8.9 mg/l [1.5–28.5 for BMI <25 kg/m²]), which was accounted for largely by HMW polymers. Hyperadiponectinemia resolved in parallel with reduction of insulin receptor antibodies and clinical resolution of insulin resistance. Although 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.

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