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

• Published in: Diabetes (New York, N.Y.) Vol. 56; no. 6; pp. 1712 - 1717
• Main Authors: Semple, Robert K, Halberg, Nils H, Burling, Keith, Soos, Maria A, Schraw, Todd, Luan, Jian'an, Cochran, Elaine K, Dunger, David B, Wareham, Nicholas J, Scherer, Philipp E, Gorden, Phillip, O'Rahilly, Stephen
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01-06-2007
• Subjects: Adipocytes; Adiponectin - blood; Adult; Antibodies; Autoantibodies - blood; Biological and medical sciences; Body fat; Child; Chromatography; Diabetes; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Ethnicity; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fat cells; Female; Glucose; Humans; Hyperinsulinism - blood; Infrared imaging systems; Insulin; Insulin receptors; Insulin resistance; Insulin Resistance - physiology; Leptin - blood; Longitudinal Studies; Medical sciences; Middle Aged; Molecular Weight; Mutation; Physiological aspects; Plasma; Proteins; Receptor, Insulin - immunology; Receptors; Reference Values; Risk factors; United Kingdom; Endocrinopathy; Antibody; Diabetes mellitus; Insulin resistance; Adipokine; Insulin receptor; Molecular mass; Adiponectin
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db06-1665

Paradoxical Elevation of High–Molecular Weight Adiponectin in Acquired Extreme Insulin Resistance Due to Insulin Receptor
Antibodies
Robert K. Semple 1 ,
Nils H. Halberg 2 ,
Keith Burling 1 ,
Maria A. Soos 1 ,
Todd Schraw 2 ,
Jian'an Luan 3 ,
Elaine K. Cochran 4 ,
David B. Dunger 3 ,
Nicholas J. Wareham 5 ,
Philipp E. Scherer 2 ,
Phillip Gorden 4 and
Stephen O'Rahilly 1
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
Abstract
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/m 2 ]), 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.
FPLC, fast-protein liquid chromatography
HMW, high molecular weight
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 26 February 2007. DOI: 10.2337/db06-1665.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted February 17, 2007.
Received November 28, 2006.
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