High molecular weight multimer form of adiponectin as a useful marker to evaluate insulin resistance and metabolic syndrome in Japanese men
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.
Section snippets
Subjects
This study included 637 Japanese male teachers and workers at Keio University aged 30 to 65 years who underwent an annual health checkup. Subjects with endocrine disease or significant renal or hepatic disease and those receiving medication for diabetes mellitus, hypertension, or hyperlipidemia were excluded. The present study was conducted according to the principles expressed in the Declaration of Helsinki. Informed consent was obtained from each subject after full explanation of the purpose,
Results
The clinical and laboratory characteristics of 637 healthy male subjects are shown in Table 1. All metabolic parameters listed, excluding age and height, were significantly different between the metabolic syndrome group and the nonmetabolic syndrome group.
Table 2 shows the correlation coefficients of HMW, total, and the ratio of adiponectin with various parameters in 637 healthy male subjects. There were no correlations of age with HMW, total, or the ratio of adiponectin. There were strong
Discussion
There have been many reports that the ratio of HMW to total adiponectin, but not the absolute amount of adiponectin, determines insulin sensitivity in diabetic rodents [5], [26]. Clinical data have also confirmed that patients with type 2 diabetes mellitus and CAD had a selective reduction in HMW adiponectin [25], [26], [27]. Furthermore, weight reduction [25] or treatment of type 2 diabetes mellitus patients with the insulin-sensitizing agent rosiglitazone [26] preferentially increased the HMW
Acknowledgments
The authors thank Fujirebio, Tokyo, Japan, for technical assistance with the ELISA system of HMW adiponectin. This study was supported in part by a grant-in-aid from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (to HH), and by research grants (to HH) from Keio University, Tokyo, Japan.
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