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

Diabetes, Jun 2007

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

Robert K. Semple Nils H. Halberg Keith Burling Maria A. Soos Todd Schraw Jian'an Luan Elaine K. Cochran David B. Dunger Nicholas J. Wareham Philipp E. Scherer Phillip Gorden Stephen O'Rahilly 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. Crosssectional 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. Diabetes 56:1712-1717, 2007 - Tmolecules with endocrine actions of relevance he ability of white adipose tissue to elaborate to fuel metabolism is well established (1). Most abundant of these adipose tissue derived factors is adiponectin, a multimeric protein with homology to complement factor 1q (1). Adiponectin has excited considerable interest as a marker of insulin resistance because of the strong correlation between its plasma levels and insulin sensitivity (1) and because low plasma adiponectin is predictive of future type 2 diabetes (2). Furthermore, based on the elevation of adiponectin seen upon treatment with thiazolidinediones (3), the insulin-sensitizing effect of either infusion or transgenic overexpression of adiponectin in insulin-resistant rodents (4 6), and the significant association between genetic variants in the adiponectin gene and type 2 diabetes risk in human populations (1), it has been suggested that defects in adiponectin production and/or action may be an etiological factor in a significant proportion of human insulin resistance. Correcting suppressed adiponectin in insulin resistance has thus become an attractive therapeutic strategy. However, we have recently reported paradoxical hyperadiponectinemia in patients with insulin receptor lossof-function mutations and have suggested that this arises either from abnormal adipose tissue development or from loss of insulin action in mature adipose tissue (7). In this study, we sought to discriminate between these possibilities by studying a group of patients with acquired loss of insulin receptor function and extreme insulin resistance due to insulin receptor blocking antibodies (type B insulin resistance). The proportion of adiponectin accounted for by high molecular weight (HMW) adiponectin multimers or the absolute concentration of HMW multimers correlates better with insulin sensitivity in normal and type 2 diabetic populations than total plasma adiponectin (1), and human mutations in the adiponectin gene that are associated with type 2 diabetes produce mutant species that show impaired multimerization (8). This led us also to refine the previous findings by determining adiponectin complex distribution in patients with either congenital or acquired insulin receptor dysfunction or idiopathic severe insulin resistance. Peruvian African American African American African American African American Indian African American MCTD, mixed connective tissue disease; SLE, systemic lupus erythematosis. RESEARCH DESIGN AND METHODS Subjects with severe insulin resistance were recruited with informed consent in line with procedures approved either by the local research ethics committee in Cambridge, U.K., or by the institutional review board of the National Institute of Diabetes, Digestive, and Kidney Diseases, Bethesda, Maryland. Type B insulin resistance was diagnosed on the basis of clinical and biochemical evidence of severe hyperins (...truncated)


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Robert K. Semple, Nils H. Halberg, Keith Burling, Maria A. Soos, Todd Schraw, Jian'an Luan, Elaine K. Cochran, David B. Dunger, Nicholas J. Wareham, Philipp E. Scherer, Phillip Gorden, Stephen O'Rahilly. Paradoxical Elevation of High–Molecular Weight Adiponectin in Acquired Extreme Insulin Resistance Due to Insulin Receptor Antibodies, Diabetes, 2007, pp. 1712-1717, 56/6, DOI: 10.2337/db06-1665