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

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.

Figure 1

Longitudinal course of patient 1 during spontaneous resolution of type B insulin resistance. A) total plasma adiponectin B) adiponectin complex distribution determined before and after resolution of insulin resistance.

Figure 2

A) Adiponectin complex distribution from patients with severe insulin resistance and controls. CONTROL = healthy volunteers (3 female (mean age 35 years, mean BMI 20 kg/m², mean fasting blood glucose 91 mg/dl, mean fasting insulin 40.3 pmol/l, mean total adiponectin 7.8 mg/l); 3 male (mean age 35 years, mean BMI 22.7 kg/m², mean fasting blood glucose 90 mg/dl, mean fasting insulin 40.3 pmol/l, mean total adiponectin 5.0 mg/l); INSR = patients with loss-of-function insulin receptor mutations; Type B = patients with type B insulin resistance; SIR = patients with severe insulin resistance of undefined genetic aetiology. Error bars represent standard deviations. B)-F) Representative FPLC elution profiles with Western blots for each patient group studied.

Figure 2

A) Adiponectin complex distribution from patients with severe insulin resistance and controls. CONTROL = healthy volunteers (3 female (mean age 35 years, mean BMI 20 kg/m², mean fasting blood glucose 91 mg/dl, mean fasting insulin 40.3 pmol/l, mean total adiponectin 7.8 mg/l); 3 male (mean age 35 years, mean BMI 22.7 kg/m², mean fasting blood glucose 90 mg/dl, mean fasting insulin 40.3 pmol/l, mean total adiponectin 5.0 mg/l); INSR = patients with loss-of-function insulin receptor mutations; Type B = patients with type B insulin resistance; SIR = patients with severe insulin resistance of undefined genetic aetiology. Error bars represent standard deviations. B)-F) Representative FPLC elution profiles with Western blots for each patient group studied.