High-molecular-weight adiponectin is a predictor of progression to metabolic syndrome: a population-based 6-year follow-up study 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 low- nor the middle-molecular-weight form had this effect.
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].
Several reports have shown that HMW adiponectin is more useful than total adiponectin. Especially 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 HMW-total adiponectin 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 adiponectin ratio had better predictive power for the prediction of insulin resistance and metabolic syndrome than plasma total adiponectin level; and Aso et al [27] reported that HMW-total adiponectin ratio was more useful to evaluate CAD in type 2 diabetes mellitus patients than simply measuring serum total adiponectin. We have reported a cross-sectional study in healthy Japanese male subjects without any medication that showed that measuring HMW adiponectin was as effective as HMW-total adiponectin ratio to predict insulin resistance and/or metabolic syndrome [28].
Recently, longitudinal data concerning HMW adiponectin have been reported. For example, decreased HMW adiponectin was an independent risk factor for the progression to type 2 diabetes mellitus in Japanese Americans during a 5.4-year follow-up study [29]; and Inoue et al [30] reported that serum HMW adiponectin level was a predictor of future cardiovascular events in patients with CAD during 7 years of follow-up.
The aim of this study was to investigate longitudinally whether measuring serum HMW adiponectin might be useful to predict the progression to metabolic syndrome compared with total adiponectin or HMW-total ratio in nondiabetic Japanese subjects.
Section snippets
Subjects
This study included 416 Japanese male teachers and workers at Keio University, aged 30 to 59 years at baseline, who underwent annual health checkups in both 2000 and 2006. Subjects with metabolic syndrome, endocrine disease, or significant renal or hepatic disease, and those receiving medication for diabetes mellitus at baseline were excluded. Twenty-six subjects were receiving hydroxymethylglutaryl–coenzyme A inhibitor, but none was receiving niacin in this study. The present study was
Results
Of 416 men, 27 developed metabolic syndrome during the follow-up period of 6 years. Baseline characteristics of subjects who did and did not develop metabolic syndrome are shown in Table 1. At baseline, HMW adiponectin concentration was significantly lower in subjects who developed metabolic syndrome than in those who did not (P = .0143).
Baseline characteristics of subjects with HMW adiponectin concentration less than or equal to 2.65 μg/mL and those with HMW adiponectin concentration greater
Discussion
Recently, longitudinal studies showing the clinical usefulness of HMW adiponectin level in circulation have been reported: for example, it was reported that decreased HMW adiponectin was an independent risk factor for the progression to type 2 diabetes mellitus in Japanese Americans during a 5.4-year follow-up study [29]. Inoue et al [30] also reported that serum HMW adiponectin level may serve as a predictor of future cardiovascular events in patients with CAD.
The present longitudinal study
Acknowledgment
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.
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Disclosure statement: Fujirebio, Tokyo, Japan (formerly Chugai Diagnostic Science, Tokyo), and Dr Hirose have a partial patent concerning HMW adiponectin measurement.