High molecular weight multimer form of adiponectin as a useful marker to evaluate insulin resistance and metabolic syndrome in Japanese men

Abstract

Adiponectin is an adipocyte-specific secretory protein that possesses antidiabetic and antiatherosclerotic properties. Recent studies have demonstrated that the high molecular weight (HMW) multimer form is the active form of this protein. In patients with type 2 diabetes mellitus, HMW-total adiponectin ratio was reported to be a more useful marker than total adiponectin in the prediction of insulin resistance and metabolic syndrome. In the present study of healthy Japanese male subjects without any medication, we investigated the hypothesis that measuring only HMW adiponectin may be as effective as HMW-total ratio to predict insulin resistance and/or metabolic syndrome. This was a working community–based cross-sectional study of 637 male subjects aged 30 to 65 years. Total and HMW adiponectin concentrations in serum were measured by enzyme-linked immunosorbent assay using commercially available kits. Serum HMW adiponectin level was inversely correlated with homeostasis model assessment of insulin resistance (HOMA-IR) (r = −0.375, P < .0001) even after adjustment for age and body mass index (r′ = −0.245, P < .0001). When we divided the study subjects into quartile groups with equal numbers of subjects, HOMA-IR in the 4 groups based on serum HMW adiponectin level was significantly different (P < .01). Metabolic syndrome score in the 4 groups based on serum HMW adiponectin level was also significantly different (P < .01). Area under the curve of receiver operator characteristic curves of HMW adiponectin (0.73) to evaluate the presence of insulin resistance (HOMA-IR >2.5) was larger than that of total adiponectin (0.68) or HMW-total ratio (0.70). Area under the curve of receiver operator characteristic curves of HMW adiponectin (0.70) to evaluate the presence of metabolic syndrome (body mass index–based modified criteria) was also larger than that of total adiponectin (0.65), but equal to that of HMW-total ratio (0.70). These results suggest that simply measuring HMW adiponectin may be as effective as HMW-total ratio to evaluate the presence of insulin resistance and metabolic syndrome, at least in nondiabetic subjects who are not receiving any medication.

Introduction

Adiponectin (also named Acrp30[1], AdipoQ[2], GBP28[3], and apM1[4]) is an adipocyte-specific secretory protein that circulates in serum in at least 3 forms: low molecular weight, middle molecular weight, and high molecular weight (HMW) form multimer including 12mer and 18mer [5], [6], [7]. Serum adiponectin level is reported to correlate well with insulin sensitivity and lipid metabolism [8], [9]. There have been many reports that adiponectin is related to metabolic syndrome [10], [11], type 2 diabetes mellitus [12], [13], [14], obesity [15], and arteriosclerosis [16], [17]. Its level is reported to be decreased in patients and animal models of obesity, diabetes, and coronary artery disease (CAD) [15], [18], [19], [20]; and weight reduction increased the adiponectin level in obese patients [19]. Moreover, adiponectin is reported to have protective activities on the vasculature [16], [17], [21], [22], [23].

Recent studies have demonstrated that the HMW multimer form of adiponectin is the active form of this protein [6], [24], [25]. For example, it was reported that the HMW form of adiponectin stimulated the phosphorylation of 5′-adenosine monophosphate–activated protein kinase [6], [24]; the HMW form was the most active form in suppressing hepatic glucose production [6]; and Kobayashi et al [25] reported that only HMW adiponectin selectively suppressed endothelial cell apoptosis, whereas neither the middle nor the low molecular weight form had this effect. It was also reported that the ratio of HMW to total adiponectin, but not the absolute amount (total) of adiponectin, determines insulin sensitivity in humans and rodents [26]. Despite having similar total adiponectin levels to their wild-type littermates, db/db diabetic mice have a much lower percentage of the HMW form in circulation.

Clinical data also confirmed that type 2 diabetes mellitus patients with CAD have a selective reduction in HMW adiponectin [25], [26], [27]. Furthermore, weight reduction [25] preferentially increased the HMW form of adiponectin, but not the other 2 oligomeric complexes. Waki et al [6] revealed that human adiponectin with rare missense mutations (G84R and G90S) did not form HMW multimers. These mutations were associated with insulin resistance and type 2 diabetes mellitus. They concluded that the proportion of each adiponectin oligomeric complex is important for the antidiabetic and antiatherogenic activities of this protein [6].

In patients with type 2 diabetes mellitus receiving medication including thiazolidinediones, HMW-total adiponectin ratio was reported to be more useful than simply measuring serum total adiponectin level. For example, Pajvani et al [26] reported that the HMW-total ratio was significantly more useful to monitor the improvement of insulin sensitivity in response to thiazolidinediones in type 2 diabetes mellitus; Hara et al [11] reported that the HMW-total ratio had better predictive power for the prediction of insulin resistance and metabolic syndrome than plasma total adiponectin level; and Aso et al [27] also reported that the HMW-total ratio was more useful to evaluate CAD in patients with type 2 diabetes mellitus than simply measuring serum total adiponectin. However, no studies have compared the HMW adiponectin level with the HMW-total ratio to predict insulin resistance and/or metabolic syndrome in healthy subjects.

In the present study of healthy Japanese male subjects without any medication, we investigated the hypothesis that measuring HMW adiponectin may be as effective as HMW-total ratio to predict insulin resistance and/or metabolic syndrome.