A PDF file should load here. If you do not see its contents
the file may be temporarily unavailable at the journal website
or you do not have a PDF plug-in installed and enabled in your browser.
Alternatively, you can download the file locally and open with any standalone PDF reader:
https://diabetes.diabetesjournals.org/content/56/6/1712.full.pdf
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)