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Elevated Plasma Adiponectin in Humans with Genetically Defective Insulin Receptors

Departments of Clinical Biochemistry (R.K.S., M.A.S., J.C.W., S.O.) and Medicine (C.S.M., M.G., V.K.K.C.), University of Cambridge, Addenbrooke’s Hospital, Cambridge CB2 2QQ, United Kingdom; Clinical Endocrinology Branch (E.K.C., P.G.), National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892; and Medical Research Council Epidemiology Unit (J.L., N.J.W.), Institute of Public Health, University of Cambridge, Elsie Widdowson Laboratory, Cambridge CB1 9NL, United Kingdom

Address all correspondence and requests for reprints to: Dr. R. Semple, Department of Clinical Biochemistry, University of Cambridge, Addenbrooke’s Hospital, Cambridge CB2 2QR, United Kingdom. E-mail: rks16{at}cam.ac.uk.

Context: Adiponectin has been suggested to play a role in the etiopathogenesis of at least some forms of insulin resistance, in part based on a strong correlation between plasma levels of adiponectin and measures of insulin sensitivity.

Objective: The objective of the study was to establish whether this relationship is maintained at extreme levels of insulin resistance.

Design/Setting: This was a cross-sectional study in a university teaching hospital of subjects recruited from the United Kingdom and the United States.

Participants: Participants included 75 subjects with a range of syndromes of severe insulin resistance and 872 nondiabetic controls.

Outcome Measures: Fasting plasma insulin, adiponectin, and leptin were measured.

Results: Unexpectedly, subjects with mutations in the insulin receptor, despite having the most severe degree of insulin resistance, had elevated plasma adiponectin [median 24.4 mg/liter; range 6.6–36.6 (normal adult range for body mass index 20 kg/m² = 3–19 mg/liter)], whereas all other subjects had low adiponectin levels (median 2.0 mg/liter; range 0.12–11.2). Plasma leptin in all but one subject with an insulin receptoropathy was low or undetectable [median 0.5 ng/ml; range 0–16: normal adult range for body mass index of < 25 kg/m² = 2.4–24.4 (female) and 0.4–8.3 ng/ml (male)].

Conclusions: We conclude that the relationship between plasma adiponectin and insulin sensitivity is complex and dependent on the precise etiology of defective insulin action and that the combination of high plasma adiponectin with low leptin may have clinical utility in patients with severe insulin resistance as a marker of the presence of a genetic defect in the insulin receptor.

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