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DOI: 10.1530/EJE-07-0043
European Journal of Endocrinology, Vol 157, Issue 2, 167-174
Copyright © 2007 by European Society of Endocrinology
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CLINICAL STUDY

The increase in abdominal subcutaneous fat depot is an independent factor to determine the glycemic control after rosiglitazone treatment

Soo-Kyung Kim1,2, Kyu-Yeon Hur3, Hae-Jin Kim4, Wan-Sub Shim3, Chul-Woo Ahn2,3, Seok-Won Park1, Yong-Wook Cho1, Sung-Kil Lim2,3, Hyun-Chul Lee2,3 and Bong-Soo Cha2,3

1 Department of Internal Medicine, College of Medicine, Pochon CHA University, Sungnam, South Korea, 463–712, 2 Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea, 120–749, 3 Department of Internal Medicine, Yonsei University College of Medicine, 134 Shinchon-Dong, Seodaemoon-Ku, PO Box 120-749, Seoul, South Korea, and 4 Department of Internal Medicine, Ajou University School of Medicine, Suwon, South Korea, 443–721

(Correspondence should be addressed to B S Cha; Email: bscha{at}yumc.yonsei.ac.kr)


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Conclusions
 References
 
Objective: The goal was to investigate the interrelationships between the hypoglycemic effects of rosiglitazone and the changes in the regional adiposity of type 2 diabetic patients.

Design and methods: We added rosiglitazone (4 mg/day) to 173 diabetic patients (111 males and 62 females) already taking a stable dose of conventional antidiabetic medications except for thiazolidinediones. The abdominal fat distribution was assessed by ultrasonography at baseline and 12 weeks later. Using ultrasonographic images, the s.c. and visceral fat thickness (SFT and VFT respectively) were measured.

Results: Rosiglitazone treatment for 3 months improved the glycemic control. However, the response to rosiglitazone was no more than 36.4%; the deterioration of the glycemic control was found in 16.8% of subjects. In addition, rosiglitazone treatment significantly increased the body fat mass, especially the s.c. fat. However that did not alter the visceral fat content. The percentage changes in fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c) concentrations after treatment were inversely correlated with the increase in SFT (r=–0.327 and –0.353, P<0.001 respectively) and/or body weight (r=–0.316 and –0.327, P<0.001 respectively). Multiple regression analysis revealed that the improvement in the FPG after rosiglitazone treatment was correlated with the baseline FPG (P<0.001) and the change in the SFT (P=0.019), and the reduction in the HbA1c was related with the baseline FPG (P=0.003) and HbA1c (P<0.001) and the changes in the SFT (P=0.010) or VFT (P=0.013).

Conclusions: The increase in the s.c. fat depot after rosiglitazone treatment may be an independent factor that determines the hypoglycemic efficacy.


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Conclusions
 References
 
Insulin resistance and impaired insulin secretion are the major characteristic features of type 2 diabetes (1). In addition, insulin resistance and/or hyperinsulinemia are closely associated with other disease states, including hypertension, polycystic ovary syndrome, atherosclerosis, and coronary artery disease (2, 3). Therefore, reducing the insulin resistance might have wide applicability as a therapeutic approach for treating or preventing type 2 diabetes and/or various other related metabolic disorders. Thiazolidinediones (TZDs) have been developed to alleviate the peripheral insulin resistance (4, 5), and presents a new line of therapy for treating type 2 diabetes as insulin sensitizers.

TZDs activate the nuclear peroxisome proliferator-activated receptor (PPAR)-{gamma}, which is a receptor subfamily that regulates the genes controlling glucose homeostasis and lipid metabolism (4, 6). PPAR-{gamma} is expressed predominantly in adipose tissue and the activation of PPAR-{gamma} promotes the expression of the lipogenic genes, which results in adipocyte growth and differentiation (7). Therefore, these PPAR-{gamma} agonists are adipogenic, and chronic treatment with PPAR-{gamma} agonist could induce weight gain. However, the effects of PPAR-{gamma} agonists on the adipocytes may be variable according to the distribution site. TZDs are found to promote the differentiation of the preadipocytes to adipocytes in the s.c. fat tissue, but this action is not observed in the visceral fat tissue despite similar expression of PPAR-{gamma} (8). Okuno et al. (9) reported that the size of the adipocytes, which form adipose tissue, became smaller in obese Zucker rats treated with troglitazone, and that the number of small adipocytes increased by 400%, while the number of insulin-resistant large adipocytes decreased by 50%. These findings suggest that PPAR-{gamma} ligand-induced remodeling of the adipose tissue may be one of the mechanisms by which TZDs improve insulin resistance and hyperglycemia despite the weight gain commonly observed in humans (10–13). However, no previous studies have demonstrated a definite interrelationship between the hypoglycemic effect of TZDs and a change in the body fat distribution.

In the present study, we investigated the relationship between the hypoglycemic effects of rosiglitazone and the alteration in body fat distribution in type 2 diabetic patients. This study particularly focused on whether the change in the s.c. fat mass measured by ultrasonography (US) correlates with the improvement in glucose homeostasis.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Conclusions
 References
 
Subjects

One hundred and seventy-three patients with type 2 diabetes mellitus (111 men and 62 women; mean age, 53.5±9.3 years) were recruited from our outpatient clinics. The mean body mass index (BMI) and mean duration of diabetes were 24.8±3.0 kg/m2 and 5.7± 5.2 years respectively. All patients had showed stable fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c), and were taking a stable dose of sulfonylurea, metformin, and/or insulin for at least 6 months prior to study. If patients had been previously receiving antihypertensive or hypolipidemic agents, only those without any changes in dose for at least 6 months before the study were enrolled. Thereafter, there were no changes in any medications during the period of the rosiglitazone treatment. The exclusion criteria were as follows: a history of treatment with TZDs, antiobesity drugs, or corticosteroids, a weight change of more than 1 kg during the last 6 months, symptomatic heart failure, renal or hepatic dysfunction, a history of diabetic ketoacidosis, and women with a childbearing potential. The Ethics Committee of Yonsei University College of Medicine approved the study, and informed consent was obtained from each subject before participation.

Study design

All subjects had previously received dietary supervision. At the beginning of the study, the patients were instructed to maintain the same level of energy intake and physical activity as before throughout this study. The eligible patients were started on rosiglitazone treatment (4 mg/day) for 12 weeks.

Before and after rosiglitazone treatment, all of the participants underwent a standard examination, which included: the fasting and postprandial-2 h glucose, HbA1c, C-peptide, insulin, total cholesterol, HDL-cholesterol, triglyceride, aspartate aminotransferase (AST)/alanine aminotransferase (ALT), high-sensitivity C-reactive protein (hsCRP), insulin, and adiponectin concentrations; measurements of blood pressure, height, weight, waist, and hip circumference by the same investigator. As an indicator for insulin resistance, we used a homeostasis model assessment for insulin resistance (HOMA-IR). The total body and abdominal fat distributions were measured using the bioelectrical impedance analyzer and US respectively.

Body fat distribution

The body composition was measured using the bioelectrical impedance analysis method. The resistance and reactance measurements were made using a four-terminal bioimpedance analyzer (InBody 3.0, Biospace, Seoul, Korea) using the procedures and anatomical sites described by Lukaski et al. (14).

The US was performed using an SA 9900 (Medison, Seoul, Korea), as described by Suzuki et al. (15) and Armellini et al. (16). Transverse scanning was performed to measure the s.c. fat thickness (SFT) using a 7.5 MHz probe and visceral fat thickness (VFT) using a 3.5 MHz probe, 1 cm above the umbilicus. The SFT was defined as the thickness between the skin-fat interface and the linea alba, and the VFT was defined as the distance between the anterior wall of the aorta and the internal face of the recto-abdominal muscle perpendicular to the aorta. These indices were measured directly from the frozen images using an electronic caliper. The intraobservational reproducibility of the ultrasonographic estimations was 1.2–1.9% and 2.1–2.5% for the VFT and the SFT respectively. The reproducibility between the two operators was 1.5–2.5% and 2.8–3.5% for the VFT and the SFT respectively.

Definition of response

The responses to the rosiglitazone treatment were defined as follows according to the percentage decrease in FPG and in HbA1c: the best response fulfilled both >20% decrease in the FPG and >15% decrease in HbA1c after 12 weeks of rosiglitazone treatment when compared with the baseline value; a good response fulfilled either >20% decrease in FPG or >15% decrease in HbA1c when compared with the baseline value; an adverse response fulfilled both >10% increase in FPG and >8% increase in HbA1c when compared with baseline; and no response was defined as not satisfactory by every other criterion. In addition, responders were defined as groups showing the best or good responses, and nonresponders were defined as groups showing no response or an adverse response.

Analytical methods

The glucose concentrations were measured using the glucose oxidase method on a Hitachi 747 autoanalyzer (Hitachi). HbA1c was measured by an ion-exchange HPLC (Variant II; Bio-Rad). The plasma insulin and C-peptide concentrations were measured by RIA using the double-antibody method with a commercially available RIA kit (Linco Research Inc., St Charles, MO, USA). The plasma cholesterol and triglyceride concentrations were measured using a direct enzymatic method (Hitachi 747), and triglyceride levels were measured by an enzymatic colorimetric method (Hitachi 747). Serum ALT and AST activities were measured by kinetic photometric methods using a Hitachi 747 analyzer. The adiponectin concentrations were quantified using a RIA kit (Linco Research Inc.). The hsCRP concentrations were measured using nephelometer analyzer (Dade Behring Diagnostics, Marburg, Germany).

Statistical analysis

All of the data are expressed as means±S.D. Statistical analyses were performed using the SPSS 11.0 software package (SPSS Inc., Chicago, IL, USA). The values before and after treatment were compared using a paired t-test. The intergroup comparisons were performed using a one-way ANOVA followed by a Scheffe’s post hoc test. The Pearson correlation coefficient was used to estimate the linear relationship between the continuous variables. Multiple linear regression analysis was used to assess the multiple correlations between the percentage decrease in FPG or HbA1c and the baseline variables or their changes. The percentage decrease in FPG or HbA1c was the dependent variable, and the baseline FPG or HbA1c and anthropometric indices (baseline and their changes) were the independent variables. Data with a P value <0.05 were considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Conclusions
 References
 
Changes in clinical and laboratory indices after rosiglitazone treatment

Table 1Go shows the baseline clinical and anthropometric data of all participants. One hundred and seventy-three patients (111 males and 62 females) completed the 12-week study.


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  		Table 1 Clinical and anthropometric indices before and after the 12 week rosiglitazone treatment.
 
Rosiglitazone treatment significantly decreased the FPG, postprandial-2 h glucose, and HbA1c concentrations. The fasting concentrations of total and HDL-cholesterol increased after rosiglitazone treatment. Although not significantly, the triglyceride concentration slightly increased. The concentrations of hsCRP, fasting insulin, and C-peptide, and the value of HOMA-IR, fell significantly after the treatment. The increase in adiponectin concentration after rosiglitazone treatment was close to twofold (Table 1Go).

Whilst the glycemic control and insulin resistance improved as the result of rosiglitazone treatment, the body weight, BMI, waist circumference, waist-to-hip ratio, and fat mass were significantly increased. No change in the lean body mass was observed during the treatment. An assessment of the abdominal fat distribution using US demonstrated that the rosiglitazone treatment resulted in a significant increase in the SFT and a decrease in the VFT:SFT ratio. However, the VFT between before and after treatment was similar (Table 1Go).

Comparisons of the clinical and biochemical characteristics before and after treatment, according to the response to rosiglitazone

Table 2Go shows the baseline characteristics of the patients according to their responses to the rosiglitazone treatment. Variables such as age, sex, duration of diabetes, treatment modalities, lipid profiles, and the concentrations of fasting serum insulin and adiponectin were not significantly different among all the groups. However, the groups with the better response had higher baseline FPG and HbA1c concentrations (P for trend <0.001 respectively) and were more obese (BMI, P for trend=0.025). Also, the HOMA-IR, fat mass, and VFT tended to increase in the better responders, although not significantly.


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  		Table 2 Baseline characteristics according to the hypoglycemic response to rosiglitazone.
 
Groups with the best or good response showed a larger increase in the body weight and SFT after the rosiglitazone treatment when compared with the groups with an adverse or no response (Table 3Go). However, there were no differences in the changes of insulin, C-peptide, and adiponectin concentrations, VFT, and VFT:SFT ratio among the groups.


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  		Table 3 Changes in the laboratory and anthropometric indices after the rosiglitazone treatment according to the response.
 
Relationships of the changes in glucose and lipid concentrations with the change in body fat distribution after rosiglitazone treatment

The increase in the SFT or body weight correlated with the improvement in the FPG and HbA1c concentrations after the rosiglitazone treatment (Fig. 1Go). However, no significant correlation was observed between the percentage change in the FPG or HbA1c and the change in the VFT and hsCRP or adiponectin concentrations.


Figure 1
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  		Figure 1 The linear correlation between the changes in the fasting plasma glucose or HbA1c and the changes in the subcutaneous fat thickness (SFT) and weight.

 
On the contrary, the increase in VFT was related with the increase in the total cholesterol and triglyceride concentrations (r=0.240, P=0.003 and r=0.337, P<0.001 respectively), and the decrease in the HDL-cholesterol concentration (r=–0.222, P=0.006). Additionally, the positive change of HOMA-IR was correlated with the increase in the VFT (r=0.286, P=0.008).

Factors affecting the response to rosiglitazone

Using the changes in the FPG or HbA1c concentrations as the dependent variable in multiple regression analysis, the percentage decrease in the FPG concentration after treatment was correlated with the baseline FPG concentration and the increase in the SFT. In addition, the baseline FPG or HbA1c concentrations and the changes in the SFT or VFT were significantly related to the percentage decrease in the HbA1c concentration (Table 4Go). However, the baseline body weight, BMI, fat mass, and their changes did not contribute independently to the improvements in the FPG or HbA1c concentrations.


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  		Table 4 Multiple regression analysis of the clinical and anthropometric indices with the rosiglitazone response.
 

   Conclusions
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Conclusions
References
 
The present study demonstrates that rosiglitazone treatment for 3 months significantly reduced the FPG and HbA1c concentrations, despite considerably increasing s.c. fat mass and body weight. Furthermore, the improvement in glycemic control after treatment with PPAR-{gamma} agonist closely correlated with the increase in s.c. fat mass and weight gain. Namely, the more the body weight or SFT was increased, the better the hypoglycemic effect of rosiglitazone treatment. Additionally, multiple regression analyses showed that the increases in s.c. fat mass as well as the reduction in visceral fat mass after rosiglitazone treatment were independent factors that might determine the hypoglycemic effect of rosiglitazone.

Unlike the previous results (11, 17), this study found no significant reduction in the visceral fat mass. This finding can be partially explained by the fact that treatment with sulfonylureas might increase the visceral fat mass (18). In the present study, the combination treatments of sulfonylurea (n=31) or sulfonylurea/metformin (n=48) resulted in an increase in VFT (1.79±3.70 or 0.68±4.08 mm respectively) after 3 months, while the combination treatment with only metformin (n=77) reduced the VFT (–0.93± 4.02 mm, P for trend =0.068). However, there were no differences in baseline SFT and VFT among treatment modalities (data not shown). Therefore, it is possible that the decrease in visceral fat mass caused by rosiglitazone was offset by the increase in visceral fat content caused by the combination therapy with sulfonylurea.

The predominant accumulation of fat in the visceral cavity plays a decisive role in the development of insulin resistance, and eventually metabolic syndrome and/or cardiovascular disease (19). Therefore, reducing the visceral fat content may be very important for improving the insulin resistance and reducing the cardiovascular risks. However, the reduction in visceral adiposity may not be the only determinant of rosiglitazone efficacy. Virtanen et al. (20) have demonstrated that metformin treatment has no effect on the whole-body insulin sensitivity despite the significant reduction in visceral fat content. Considering these findings, the more important determinant for the hypoglycemic efficacy of rosiglitazone may be the increase in s.c. fat content, rather than the reduction in visceral fat content.

Although the increase in the VFT by rosiglitazone treatment was not significant, it was positively correlated with the increase in the total cholesterol and triglyceride concentrations, and inversely with the increase with HDL-cholesterol. Additionally, the change in HOMA-IR was positively correlated with the increase in the VFT. This finding suggests that the improvement in dyslipidemia or insulin resistance may be partly related to the reduction in the visceral fat mass rather than to the increase in s.c. fat mass, in contrast to hypoglycemic effect.

Adipocytokines, such as adiponectin and leptin, have been suggested to be associated with general adiposity and insulin resistance (21). Many studies have shown that adipocytokines increase or decrease after weight loss or treatment of TZDs (22, 23). While leptin has shown conflicting results concerning the changes in its concentration after TZDs treatment (24, 25), adiponectin constantly increases after TZDs. Circulating adiponectin concentrations are lower in obese individuals (26) and patients with coronary artery disease (27) or type 2 diabetes (26), and many animal studies have illustrated the possibility of using adiponectin to improve insulin resistance or to prevent its complications (28). Because the PPAR-{gamma} agonist markedly increases the plasma adiponectin concentration in type 2 diabetic subjects (29), it is anticipated that some beneficial effects of rosiglitazone may result partly from the increase in the adiponectin concentration after treatment. Contrary to this expectation, we could not observe any correlation between the change in adiponectin concentration and either the improvement in FPG, HbA1c, lipid profile, or insulin resistance, even if the plasma adiponectin concentration was increased nearly twofold after the rosiglitazone treatment. However, a matter of interest was the correlation between the increase in adiponectin concentration and the increase in the SFT (r=0.233, P=0.020). This finding suggests that the increase in the adiponectin concentration after treatment with PPAR-{gamma} agonist may have resulted from increasing the s.c. fat deposit or increasing the insulin-sensitive small adipocytes. Further prospective investigation would be needed to identify whether a significant increase in the adiponectin concentration by the PPAR-{gamma} agonist may contribute to the antihyperglycemic and antiatherogenic benefits in the type 2 diabetic patients.

In this study, it was interesting that responders, defined as groups showing the best or good responses, were no more than 36.4%. This proportion was lower than that in previous studies (30, 31). And the glycemic control in 16.8% of subjects was not improved, but rather aggravated. Therefore, TZDs might be effective only in the specific population group. However, TZDs have reported having antiinflammatory or antiatherogenic effects in addition to hypoglycemic effect (30, 32). Presumably, the adequate indication for using TZDs must be presented though well-controlled studies.

This study performed US to assess the body fat distribution. Although CT or MRI at the abdominal level is recognized as the standard method (33), US also is a reliable and convenient way of quantifying the amount of visceral fat (34). In our previous data (35), the parameters used in this study, SFT and VFT, correlated well with s.c. and visceral fat area as measured by CT (r=0.806 and 0.799, P<0.001 respectively).

In this study, the treatment period was somewhat brief at only 3 months. Although the hypoglycemic effects of TZDs reach a maximum by 24 weeks, this study showed the significant improvement of glycemic control and change of body fat distribution in diabetic patients having quite fair HbA1c concentrations, despite a short term of rosiglitazone treatment. However, it remains unclear whether the effects on the changes in fat distribution would continue during chronic rosiglitazone treatment. In addition, the criteria for defining a response in this study were somewhat arbitrary. The definitions reported in previous studies (30, 31) may be inadequate to assess the full effect of TZDs, because only one of FPG or HbA1c concentrations could be improved in some patients. Therefore, this study defined the response for efficacy of rosiglitazone using both FPG and HbA1c criteria. Finally, this study was a prospective observation study in diabetic patients who were already treated with various antidiabetic, antihypertensive, or hypolipidemic medication. Although patients had been taking stable doses for at least 6 months and were instructed to maintain the same level of energy intake and physical activity, these medications and the differences in lifestyle were capable of affecting the lipid profile, insulin sensitivity, and body fat distribution. Therefore, long-term placebo-controlled study may be needed to assess the definite relationship between the effect of TZDs and the change in body fat distribution.

In conclusion, this study presented that rosiglitazone improves the glycemic control and insulin resistance, and increases the body fat mass, especially in s.c. fat mass, although not in all subjects. This increase in s.c. fat depot may be the independent factor that determined the hypoglycemic efficacy of rosiglitazone. In contrast, the reduction in the visceral fat amount may be the prime determinant to improve dyslipidemia.


   Acknowledgements
 
This work was supported in part by the Basic Research Program of the Korea Science & Engineering Foundation (R13-2002-054-01001-0 (2002)).


   References
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 Abstract
 Introduction
 Patients and methods
 Results
 Conclusions
 References
 

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Received 22 January 2007
Accepted 7 May 2007





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