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Paradoxical elevation of high molecular weight adiponectin in acquired extreme insulin resistance due to insulin receptor antibodies

¹Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2QQ, United Kingdom
²Department of Cell Biology, Division of Endocrinology, and Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA
³Clinical Endocrinology Branch, National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Maryland 20892
⁴Department of Paediatrics, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2QQ, United Kingdom
⁵MRC Epidemiology Unit, Institute of Public Health, University of Cambridge, Elsie Widdowson Laboratory, Fulbourn Road, CB1 9NL, Cambridge, United Kingdom

Correspondence: rks16{at}cam.ac.uk

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.

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