Complex Distribution, Not Absolute Amount of Adiponectin, Correlates with Thiazolidinedione-mediated Improvement in Insulin Sensitivity

Abstract

Adiponectin is an adipocyte-specific secretory protein that circulates in serum as a hexamer of relatively low molecular weight (LMW) and a larger multimeric structure of high molecular weight (HMW). Serum levels of the protein correlate with systemic insulin sensitivity. The full-length protein affects hepatic gluconeogenesis through improved insulin sensitivity, and a proteolytic fragment of adiponectin stimulates ␤ oxidation in muscle. Here, we show that the ratio, and not the absolute amounts, between these two oligomeric forms (HMW to LMW) is critical in determining insulin sensitivity. We define a new index, S A , that can be calculated as the ratio of HMW/(HMW ؉ LMW). db/db mice, despite similar total adiponectin levels, display decreased S A values compared with wild type littermates, as do type II diabetic patients compared with insulin-sensitive individuals. Furthermore, S A improves with peroxisome proliferator-activated receptor-␥ agonist treatment (thiazolidinedione; TZD) in mice and humans. We demonstrate that changes in S A in a number of type 2 diabetic cohorts serve as a quantitative indicator of improvements in insulin sensitivity obtained during TZD treatment, whereas changes in total serum adiponectin levels do not correlate well at the individual level. Acute alterations in S A (⌬S A ) are strongly correlated with improvements in hepatic insulin sensitivity and are less relevant as an indicator of improved muscle insulin sensitivity in response to TZD treatment, further underscoring the conclusions from previous clamp studies that suggested that the liver is the primary site of action for the full-length protein. These observations suggest that the HMW adiponectin complex is the active form of this protein, which we directly demonstrate in vivo by its ability to depress serum glucose levels in a dose-dependent manner.

Improved insulin sensitivity and adipose tissue dysregulation after short-term treatment with pioglitazone in non-diabetic, insulin-resistant subjects

“…We also found HMW adiponectin to be increased, but no correlation was seen with the improvement in whole-body insulin sensitivity measured as glucose disposal rate. Since the liver seems to be the primary site of action for HMW adiponectin, this finding was not unexpected and is in agreement with the recent study [11].…”

“…This is accompanied by improvements in different metabolic variables in obese and diabetic, but not in lean insulin-sensitive subjects [40]. This discrepancy has been recently elucidated by the finding that it is not the absolute amount, but rather the distribution of low-and highmolecular weight adiponectin that is important for improved insulin sensitivity in the liver [11]. We also found HMW adiponectin to be increased, but no correlation was seen with the improvement in whole-body insulin sensitivity measured as glucose disposal rate.…”

“…One such molecule of great current interest is adiponectin, which is only secreted by the adipose cells [8][9][10]. Thiazolidinediones not only increase the concentration of total circulating adiponectin but also alter the relative abundance of the different molecular weight complexes [11].…”

Adiponectin: a relevant player in PPARγ-agonist-mediated improvements in hepatic insulin sensitivity?

“…db/db mice and lean heterozygote littermates have comparable levels of total adiponectin despite a marked difference in insulin sensitivity. 47 However, analysis of the relative distribution of the adiponectin complexes in these mice indicates a marked reduction in the percentage of the HMW form of the protein in db/db mice compared to lean db/ þ animals. 47 The same study also demonstrates that human insulin-resistant subjects have a significantly decreased HMW/total adiponectin ratio compared to lean controls, even when adjusted to the same total adiponectin levels.…”

Negative association between plasma levels of adiponectin and polychlorinated biphenyl 153 in obese women under non-energy-restrictive regime

“…9 From three distinct multimeric complexes identified in human plasma, high (HMW), medium (MMW) and low (LMW) molecular weight, only the HMW adiponectin plasma levels are positively associated with insulin sensitivity. 10 To verify a hypothesis that PCB 153 may modify secretory functions of adipose tissue in obese women, plasma levels of PCB 153, adiponectin and other inflammatory markers were measured in a small cohort of obese patients before and after a weight-reducing regimen, which was based on a low-calorie-diet intervention. Lean patients were used as controls.…”