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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 1 290-294
Copyright © 2006 by The Endocrine Society

Plasma Adiponectin Level Is Associated with Insulin-Stimulated Nonoxidative Glucose Disposal

Hisayo Yokoyama, Masanori Emoto, Katsuhito Mori, Takahiro Araki, Megumi Teramura, Hidenori Koyama, Tetsuo Shoji, Masaaki Inaba and Yoshiki Nishizawa

Department of Metabolism, Endocrinology, and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan

Address all correspondence and requests for reprints to: Hisayo Yokoyama, M.D., Ph.D., Metabolism, Endocrinology, and Molecular Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan. E-mail: yock{at}med.osaka-cu.ac.jp.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Impaired nonoxidative glucose disposal and decrease in mitochondrial glucose oxidation both contribute to insulin resistance in diabetic subjects.

Objective: In the present study, we investigated whether plasma adiponectin is associated with glucose oxidation and nonoxidative glucose disposal in subjects with and without type 2 diabetes.

Design: Euglycemic-hyperinsulinemic clamp was performed in 42 type 2 diabetic (T2DM) and 13 nondiabetic (non-DM) subjects. The whole-body glucose disposal rate (GDR) was evaluated as the mean of the glucose infusion rate during steady state of the clamp. Glucose and fat oxidation rates were assessed by indirect calorimetry, and nonoxidative glucose disposal rate was calculated by subtracting glucose oxidation rate from GDR.

Results: Plasma adiponectin level was significantly lower in T2DM than non-DM (2.87 ± 1.40 vs. 3.96 ± 2.39 µg/ml, P = 0.045). GDR (3.39 ± 1.53 vs. 4.83 ± 1.70 mg/kg·min, P = 0.006) and nonoxidative glucose disposal rate (1.89 ± 1.39 vs. 3.11 ± 1.76 mg/kg·min, P = 0.012) were significantly lower in T2DM, compared with non-DM, although no difference was found in glucose oxidation rate between the two groups. In all subjects, plasma adiponectin level was positively correlated with GDR (r = 0.351, P = 0.009) and nonoxidative glucose disposal rate (r = 0.324, P = 0.016) but not glucose oxidation rate. There was no significant correlation between plasma adiponectin level and fat oxidation, either before or during the clamp.

Conclusions: In conclusion, plasma adiponectin level is associated with nonoxidative glucose disposal, which is reduced in type 2 diabetic subjects. Our results suggest that adiponectin controls insulin sensitivity by modulating the glycogen synthetic process in human skeletal muscle.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
OBESE AND TYPE 2 diabetic subjects are characterized by insulin resistance: decreased glucose use, mainly by skeletal muscle, which leads to poor glycemic control and a high incidence for atherosclerotic diseases. Whole-body glucose use consists of mitochondrial glucose oxidation and nonoxidative glucose disposal (i.e. the glycogen synthesis pathway). Until recently it was thought that impaired nonoxidative glucose disposal rather than a decrease in glucose oxidation principally contributed to insulin resistance in obese and type 2 diabetic subjects (1, 2). In fact, improvement of insulin resistance after weight loss in combination with aerobic exercise is due to an increase in nonoxidative glucose disposal in obesity (3). Recently, however, diminished glucose oxidation has attracted attention because poor mitochondrial function has been demonstrated in type 2 diabetic patients or their offspring (4, 5), and mitochondrial function is now thought to affect whole-body glucose use.

Adiponectin, a recently identified protein specifically secreted by adipose tissue, is an attractive target for therapy and research because of its potential contribution to glucose metabolism. Plasma adiponectin levels are known to be lower in subjects with insulin resistance, such as obesity or type 2 diabetes, and to be closely correlated with an index assessed by the euglycemic-hyperinsulinemic clamp (6), a gold standard method for evaluating insulin resistance. Administration of adiponectin is reported to improve insulin sensitivity in mice fed a high-fat diet (7). To date, several mechanisms have been suggested by which adiponectin improves insulin resistance in skeletal muscle. Fruebis et al. (8) found that adiponectin increased fatty acid oxidation in skeletal muscle, using animal models. Subsequently Yamauchi et al. (9) reported that this increase in fatty acid oxidation and glucose uptake by adiponectin resulted from activation of AMP-activated protein kinase (AMPK) in mice skeletal muscle. These findings suggest that the effect of adiponectin on insulin sensitivity is, at least in part, via modulation of intracellular glucose metabolism due to increasing fatty acid oxidation followed by reduction in cytosolic fatty acid in skeletal muscle cells. However, it remains unclear how adiponectin influences human skeletal muscle to increase insulin sensitivity.

In the present study, we investigated the correlation between plasma adiponectin and fat/glucose oxidation and nonoxidative glucose disposal as assessed by indirect calorimetry during euglycemic-hyperinsulinemic clamp in subjects with and without type 2 diabetes.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Forty-two type 2 diabetic (T2DM) and 13 nondiabetic (non-DM) subjects were selected for the present study from patients attending our diabetes center at Osaka City University Hospital. Non-DM included five subjects with impaired glucose tolerance (IGT). The diagnosis of diabetes was based on a previous history of diabetes or the American Diabetes Association criteria (10). Impaired glucose tolerance was confirmed by a 75-g oral glucose tolerance test. In diabetic subjects, the mean known duration of diabetes was 3.7 ± 4.2 yr. Six diabetic subjects were treated with sulfonylureas and none with insulin. Eight subjects showed microalbuminuria. Patients with macroproteinuria or uremia with serum creatinine levels greater than 134.0 µmol/liter and other active medical diseases were excluded from the study.

Informed consent was obtained from all participants, and the study, including the clamp procedure, was approved by the local ethics committee.

Study design

After admission, all subjects were under medical nutritional therapy (energy 25–30 kcal/kg ideal body weight) and euglycemic-hyperinsulinemic clamp (the clamp study was performed within 1–2 wk of admission, as described below). Oral hypoglycemic agents were taken until the day before the clamp study. Before and during steady hyperinsulinemic state of the clamp study, we assessed substrate oxidation using indirect calorimetry.

Anthropometrical measurements and laboratory analysis, including the measurement of plasma adiponectin levels, were also carried out before the clamp study.

Euglycemic-hyperinsulinemic clamp

Oral hypoglycemic agents were taken until the day before the clamp study. The study was performed according to the method of DeFronzo et al. (11) using an STG 22 artificial pancreas model (Nikkiso Co., Tokyo, Japan). After an overnight fast, venous blood sampling and measurement of blood pressure in the supine position were performed, and the euglycemic-hyperinsulinemic clamp protocol was begun as previously described (12, 13). In brief, short-acting insulin (Novolin R; Novo Nordisk, Bagsværd, Denmark) was infused continuously at a rate of 1.25 mU/kg–1·min–1 after a priming insulin infusion during the first 10 min of the clamp, at the same dosage as reported previously. Blood glucose levels were determined every 5 min during the 120-min clamp study, and euglycemia (90 mg/dl) was maintained by infusion of variable amounts of 10% glucose solution. The mean coefficient of variance of blood glucose in maintaining euglycemia was 1.29% and ranged from 0.4 to 2.9%. The mean plasma insulin level during the steady state was 889.7 ± 260.1 (SD) pmol/liter. The whole-body glucose disposal rate (GDR) was evaluated as the mean of the glucose infusion rate during the last 30 min of the clamp.

Indirect calorimetry

Whole-body indirect calorimetry was performed before and during steady hyperinsulinemic state of the clamp study using an electronic spirometry system integrated with a gas analyzer (AE-300S; Minato Medical Science Co., Osaka, Japan). From respiratory gas exchange and nitrogen excretion in urine collected during the clamp, we calculated fat and glucose oxidation as follows (14):

Fat oxidation (grams per minute) = 1.67 x VO2 – 1.67 x VCO2 – 1.92n.

Glucose oxidation (grams per minute) = 4.55 x VCO2 – 3.21 x VO2 – 2.87n.

VO2: O2 consumption (liters per minute), VCO2: CO2 production (liters per minute);

n: urinary nitrogen excretion (grams per minute).

Nonoxidative glucose disposal was estimated by subtracting the glucose oxidation rate from the whole-body GDR.

Anthropometry

Body mass index (BMI) was calculated as body weight x height–2 and expressed in kilograms per square meter. Percentage of body fat was estimated by bioelectrical impedance analysis using the body composition analyzer (BC-118; Tanita Co., Tokyo, Japan).

Measurements

Laboratory analyses were performed after a 12-h overnight fast. Glycated hemoglobin (HbA1c) was measured by HPLC (normal range 4.0–5.8%) and plasma insulin levels by immunoradiometric assay (Insulin Riabead II kit; Dainabot, Tokyo, Japan). Plasma adiponectin levels were measured by a commercially available ELISA kit (Otsuka Pharmaceuticals Inc., Tokyo, Japan). The inter- and intraassay coefficients of variation were less than 10%. Because circulating levels are in micrograms per milliliter concentrations, samples were diluted 1:5100 in buffer before assay.

Statistical analysis

All values are means ± SD, unless otherwise indicated. Statistical analysis was performed using the StatView 5 system (SAS Institute Inc., Cary, NC) for Windows (Microsoft Inc., Redmond, WA). Comparison of mean values between groups was done by ANOVA. The correlation between plasma adiponectin levels and GDR, fat/glucose oxidation, or nonoxidative GDR was examined by simple linear regression analysis. P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The clinical characteristics of the subjects in both groups are shown in Table 1Go. There were no differences in distribution of gender, age, BMI, percentage of body fat, and waist to hip circumference ratio. Fasting plasma glucose level (147 ± 42 vs. 93 ± 9 mg/dl, P < 0.001) and HbA1c (8.7 ± 2.0 vs. 5.3 ± 0.3%, P < 0.001) were significantly higher in T2DM than non-DM subjects. In T2DM, plasma adiponectin level was significantly lower than in non-DM subjects (2.87 ± 1.40 vs. 3.96 ± 2.39 µg/ml, P = 0.045). Furthermore, when we compared plasma adiponectin level between non-DM and the subgroup consisting of 13 age- and BMI-matched T2DM subjects, the mean plasma adiponectin level remained significantly lower in matched T2DM than non-DM (data not shown).


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  		TABLE 1. Clinical characteristics of the subjects

 
As shown in Fig. 1Go, the whole-body GDR during steady hyperinsulinemic state in the clamp study was significantly lower in T2DM compared with non-DM subjects (3.39 ± 1.53 vs. 4.83 ± 1.70 mg/kg·min, P = 0.006). As a component of the whole-body GDR, nonoxidative glucose disposal rate was significantly reduced in T2DM than non-DM (1.89 ± 1.39 vs. 3.11 ± 1.76 mg/kg·min, P = 0.012), whereas no difference was found in glucose oxidation rate between the two groups (1.54 ± 0.81 vs. 1.71 ± 1.32 mg/kg·min, P = 0.572).



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  		FIG. 1. Oxidative/nonoxidative GDR as components of the whole-body GDR during steady hyperinsulinemic state in the clamp study. The whole-body GDR was significantly lower in T2DM compared with non-DM subjects (3.39 ± 1.53 vs. 4.83 ± 1.70 mg/kg·min, P = 0.006). Nonoxidative GDR was significantly more reduced in T2DM than non-DM (1.89 ± 1.39 vs. 3.11 ± 1.76 mg/kg·min, P = 0.012), whereas no difference was found in glucose oxidation rate between the two groups.

 
In all subjects, plasma adiponectin level was significantly positively correlated with whole-body GDR (r = 0.351, P = 0.009, Fig. 2AGo). Next, we examined the correlation between plasma adiponectin levels and glucose oxidation or nonoxidative glucose disposal during steady hyperinsulinemic state in the clamp study. Plasma adiponectin level was significantly correlated with nonoxidative glucose disposal (r = 0.324, P = 0.016, Fig. 2BGo), but there was no significant correlation between plasma adiponectin level and glucose oxidation (Fig. 2CGo). There was no significant correlation between plasma adiponectin level and fat oxidation, either before or during steady state in the clamp study (Fig. 3Go, A and B).



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  		FIG. 2. Correlation between plasma adiponectin level and whole-body GDR, glucose oxidation, or nonoxidative GDR during steady hyperinsulinemic state in the clamp study. Plasma adiponectin level was significantly positively correlated with whole-body GDR (r = 0.351, P = 0.009) (A). Plasma adiponectin level was also significantly correlated with nonoxidative GDR (r = 0.324, P = 0.016) (B). On the other hand, there was no significant correlation between plasma adiponectin level and glucose oxidation (C).

 


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  		FIG. 3. Correlation between plasma adiponectin level and fat oxidation before or during steady hyperinsulinemic state in the clamp study. There was no significant correlation between plasma adiponectin level and fat oxidation either before or during steady state in the clamp study (A and B, respectively).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The objective of the present study was to investigate the impact of plasma adiponectin levels on fat and glucose oxidation and nonoxidative glucose disposal during euglycemic-hyperinsulinemic clamp in subjects with and without type 2 diabetes. We found that plasma adiponectin level was significantly correlated with nonoxidative glucose disposal during the clamp, although it had no significant correlation with glucose oxidation. We could find no association between plasma adiponectin level and fat oxidation in either the basal or the hyperinsulinemic state in the clamp study. These results suggest that adiponectin is related to insulin-stimulated glucose uptake in human skeletal muscle, mainly due to its relevance to nonoxidative glucose disposal.

Our result showed that reduced nonoxidative glucose disposal mainly contributed to reduced glucose uptake during the clamp in T2DM compared with non-DM subjects and was compatible with previous reports that concluded insulin resistance in T2DM was, for the most part, due to impaired glycogen synthesis pathway (1, 2). On the other hand, no difference was found in glucose oxidation rate between the two groups. Damsbo et al. (2) showed in their report that glucose oxidation was more reduced in obese subjects with and without diabetes than lean controls. Therefore, glucose oxidation may be more strongly affected by adiposity than by the diabetic state itself. In our study, in fact, glucose oxidation rate during clamp study was significantly inversely correlated with BMI, percentage of body fat, or plasma fatty acid level (data not shown). The finding may be explained by the Randle cycle, by which, as is well known, increased fatty acid oxidation causes a commensurate decrease in glucose oxidation in skeletal muscle cell (15). No differences in adiposity and plasma fatty acid level between the two groups may explain why both groups had same means of glucose oxidation rate during clamp in the present study.

To the best of our knowledge, there are few previous reports that have addressed the association between adiponectin and nonoxidative glucose clearance or substrate oxidation in human. Stefan et al. (16) reported in their cross-sectional study with nondiabetic Pima Indians and whites that there was no significant association between plasma adiponectin levels and 24-h respiratory quotient (whole body carbohydrate/lipid oxidation rate) assessed using a respiratory chamber. The lack of correlation between plasma adiponectin level and basal fat oxidation rate before the clamp in our population is consistent with their results. It was recently reported that 2 months of treatment with thiazolidinediones increased insulin-stimulated glucose uptake and glycogen synthesis, with no significant effect on carbohydrate or fat oxidation rate in T2DM (17). In their study, plasma adiponectin levels increased markedly after treatment. Even though they did not report any direct association between changes in plasma adiponectin and changes in glycogen synthesis, the results suggested a possible linkage of adiponectin with nonoxidative glucose disposal.

Plasma adiponectin level tends to fall as more visceral fat accumulates (18). However, adiponectin is reported to have a closer association with insulin sensitivity as assessed by euglycemic-hyperinsulinemic clamp than with adiposity itself (6). Our findings were that plasma adiponectin level showed a positive correlation with GDR, despite the absence of significant correlation with any anthropometrical factors (data not shown), and our findings were consistent with previous reports. Similar to most of the opinions (19), our T2DM patients had lower plasma adiponectin levels than non-DM subjects, although their mean BMI was not significantly different. In addition, fat distribution (sc or visceral-dominant) was not evaluated in the present study. These may explain why our subjects, including both non-DM obese and T2DM subjects, lacked a significant correlation between their body weight and BMI and plasma adiponectin level.

It is known that iv or dietary fat challenge acutely induces lipid accumulation in skeletal muscle cells and reduces insulin-stimulated glucose uptake (20, 21). With acute fat loading, a decrease in carbohydrate oxidation is responsible for reduction in insulin-stimulated glucose uptake as well as a decrease in glycogen synthesis, although to a lesser extent (22). On the other hand, previous investigations with animal models have suggested that adiponectin increases fatty acid oxidation (8) followed by a decrease in fatty acids content and consequent glucose uptake (9) in skeletal muscle. Our results, which showed no significant correlation between adiponectin and fat oxidation, were inconsistent with those with animal models. In addition to the difference in species, our condition with no fat loading during the clamp study might explain the discrepancy.

There are several reasons that adiponectin may correlate with nonoxidative glucose disposal not through significant correlation with fat oxidation. First, adiponectin might directly affect increasing glycogen synthesis. AMPK, a metabolite-sensing enzyme in skeletal muscle, is activated by adiponectin (9) and contains a functional glycogen binding domain (23). Therefore, AMPK could be a link between adiponectin and glycogen synthesis. Second, fat oxidation does not always contribute to a decrease in fatty acid accumulation in skeletal muscle cells. Actually, fat oxidation in the postabsorptive state is accelerated in obesity or diabetes (24). In such subjects with high plasma free fatty acid levels, the flux of fatty acids into skeletal muscle cell is expected to exceed the fat oxidation rate, and increased fat oxidation will not necessarily induce favorable effects on insulin signaling transduction cascade or glucose uptake in skeletal muscle.

In conclusion, we demonstrated in the present study that plasma adiponectin level is associated with whole-body glucose disposal during hyperinsulinemic clamp, mostly due to the correlation with nonoxidative glucose disposal, in subjects with and without type 2 diabetes. In the future, interventional studies, which elucidate the effect of change in plasma adiponectin level on improving in insulin stimulated nonoxidative glucose disposal by insulin sensitizer or exercise, are needed.


   Footnotes
 
The authors have no conflict of interest.

First Published Online October 18, 2005

Abbreviations: AMPK, AMP-activated protein kinase; BMI, body mass index; GDR, glucose disposal rate; HbA1c, glycated hemoglobin; non-DM, nondiabetic; T2DM, type 2 diabetes.

Received December 27, 2004.

Accepted October 7, 2005.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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