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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-1073
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 12 6523-6528
Copyright © 2005 by The Endocrine Society

Rosiglitazone Treatment Increases Subcutaneous Adipose Tissue Glucose Uptake in Parallel with Perfusion in Patients with Type 2 Diabetes: A Double-Blind, Randomized Study with Metformin

Antti P. M. Viljanen, Kirsi A. Virtanen, Mikko J. Järvisalo, Kirsti Hällsten, Riitta Parkkola, Tapani Rönnemaa, Fredrik Lönnqvist, Patricia Iozzo, Ele Ferrannini and Pirjo Nuutila

Positron Emission Tomography Centre (A.P.M.V., K.A.V., M.J.J., K.H., P.N.), Departments of Radiology (R.P.) and Medicine (T.R.), Turku University Central Hospital, FIN-20520 Turku, Finland; Karolinska Institutet (F.L.), Stockholm, SE-17177 Sweden; and Department of Internal Medicine and Consiglio Nazionale delle Ricerche Institute of Clinical Physiology (P.I., E.F.), 56126 Pisa, Italy

Address all correspondence and requests for reprints to: Pirjo Nuutila, M.D., Ph.D., Turku PET Centre, Kiinamyllynkatu 4-8, FIN-20520, Turku, Finland. E-mail: pirjo.nuutila{at}utu.fi.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: We have shown that rosiglitazone increases whole-body and adipose tissue insulin sensitivity in humans.

Objective: The aim of this study was to further examine whether possible changes in adipose perfusion could explain increased adipose tissue glucose uptake (GU).

Patients: Thirty-seven patients with newly diagnosed type 2 diabetes were included.

Intervention: Patients were randomized into treatment with rosiglitazone, metformin, or placebo for 26 wk in a double-blinded trial.

Design: Femoral adipose flow and GU were measured with [15O]H2O, [18F]fluorodeoxyglucose and positron emission tomography during euglycemic hyperinsulinemia. Adipose masses were measured using magnetic resonance imaging.

Results: Metformin and rosiglitazone treatment improved glycemic control, but only rosiglitazone increased whole-body insulin sensitivity. Rosiglitazone treatment increased flow by 72% (P < 0.01) and GU by 23% (P < 0.05) and thereby decreased adipose tissue glucose extraction by 18% (P < 0.05); no changes were observed in the metformin or placebo-treated groups. When the adipose masses were taken into account, rosiglitazone treatment increased flow by 73% (P < 0.01) and GU by 24% (P < 0.05). During hyperinsulinemia, flow correlated with GU (r = 0.63; P < 0.01).

Conclusions: In conclusion, sc GU is associated with flow in patients with type 2 diabetes. Rosiglitazone treatment enhances GU and flow but decreases glucose extraction, suggesting that perfusion may contribute to adipose tissue insulin sensitization by rosiglitazone.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
ROSIGLITAZONE MALEATE, a member of the thiazolidinedione class of antidiabetic agents, counteracts insulin resistance by binding to the transcription factor peroxisome proliferator-activated receptor-{gamma} (PPAR-{gamma}), promoting synthesis of glucose transporters, and activating adipocyte differentiation (1, 2). In contrast, metformin lowers plasma glucose mostly by reducing hepatic glucose production and gluconeogenesis (3, 4). Because the PPAR-{gamma} receptors are predominantly expressed in adipose tissue, it has been proposed that adipose tissue is the primary target for thiazolidinedione action (5).

Along with skeletal muscle, adipose tissue is an important site of peripheral insulin resistance in type 2 diabetes (6). Insulin-stimulated sc adipose tissue glucose uptake has been shown to be decreased already in young nondiabetic obese subjects compared with lean ones (7). Mechanisms implicated in adipocyte insulin resistance include reduced glucose transporter protein 4 recruitment (8), decreased insulin receptor tyrosine kinase activity (9), decreased expression and insulin-stimulated phosphorylation of insulin receptor substrate 1, and impaired phosphatidylinositol 3-kinase activity and phosphorylation of serine kinase Akt (10).

We have recently demonstrated with the use of positron emission tomography (PET) with [18F]fluorodeoxyglucose ([18F]FDG) that chronic treatment of patients with type 2 diabetes with rosiglitazone, but not metformin, increases femoral sc adipose glucose uptake simultaneously with an improvement in skeletal muscle insulin sensitivity (11). Although the majority of whole-body insulin-stimulated glucose uptake occurs in skeletal muscle, the impact of adipose tissue on whole-body glucose disposal is significant. Reports about adipose tissue perfusion and metabolism are few mainly because of methodological difficulties. Defects in insulin stimulation of skeletal muscle blood flow have been suggested to contribute to insulin resistance (12, 13), although this hypothesis has also been challenged in the literature (14). However, the regulation of blood flow differs between skeletal muscle and fat, in which perfusion is mostly promoted by exercise (15) and meal ingestion (16), respectively, consistent with the different roles of the two organs in energy consumption and storage. PET with [15O]H2O has been evaluated for direct measurements of adipose perfusion (17). We have previously reported a positive correlation between adipose tissue perfusion and glucose uptake in obese and nonobese healthy subjects (7). Subcutaneous adipose perfusion has not been studied in patients with type 2 diabetes, and no information is available on the effects of rosiglitazone on adipose tissue perfusion. In the present study, we examined whether treatment with either rosiglitazone or metformin increases adipose tissue blood flow and whether changes in flow explain the drug-induced increment in regional glucose uptake.


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

A total of 45 patients with type 2 diabetes, as defined by the World Health Organization criteria (18), and without diabetic complications were assigned to the initial intervention protocol, which primarily aimed at measuring changes in skeletal muscle insulin sensitivity and perfusion (15). Changes in visceral and sc adipose tissue masses and glucose uptake have also been reported previously (11). The present study reports on those 37 subjects in whom data on both blood flow and glucose uptake in the femoral region were available. The subjects were recruited by advertisement and among clients of the occupational health service in Turku, Finland. Patients were excluded if they had a fasting plasma glucose value less than 6.1 mmol/liter or more than 11.0 mmol/liter after the run-in period. Furthermore, patients with cardiovascular disease, blood pressure greater than 160/100 mm Hg, previous or present abnormal hepatic or renal function, antidiabetic medication, anemia, or oral corticosteroid treatment were excluded. Written informed consent was obtained after explaining the purpose and potential risks of the study to the subjects. The study protocol was approved by the local ethical committee and conducted according to the principles of the declaration of Helsinki.

Study design

The first part of the study consisted of a 4-wk run-in period with written diet instructions. In the second part, patients were randomized into treatment with rosiglitazone [2 mg twice daily (bid) for 2 wk; thereafter, 4 mg bid], metformin (500 mg bid for 2 wk; thereafter, 1 g bid), or placebo for a 26-wk double-blind trial. PET studies were performed before the intervention and at wk 26, using an identical protocol. The rates of whole-body and femoral sc adipose tissue glucose uptake and blood flow were determined by combining the euglycemic hyperinsulinemic clamp technique with [18F]FDG, [15O]H2O, and PET (15).

PET study protocol

The PET study was performed after an overnight fast. Alcohol was prohibited for 48 h before the study, and the subjects were instructed to avoid strenuous physical activity for 24 h before the study. Two catheters were inserted, one in an antecubital vein for infusion of glucose and insulin and for injection of [15O]H2O and [18F]FDG and one in the opposite radial artery for blood sampling. During the study, subjects were lying in a supine position. At 0 min, an iv infusion of insulin (1 mU/kg·min) was started. The study of femoral fat glucose uptake and blood flow consisted of a 140-min normoglycemic-hyperinsulinemic period. During hyperinsulinemia, normoglycemia was maintained by infusing 20% glucose at a variable rate. Blood flow was measured at 60 min, in the femoral regions using [15O]H2O infusion. Thereafter, a bolus of [18F]FDG was injected for quantification of tissue glucose uptake. In addition, the effect of exercise on glucose uptake was quantified with one-legged exercise using 10% of maximal force (15), but only data on the resting leg were included in the analyses.

Production of PET tracers

[15O]H2O was produced in a water module using a diffusion membrane technique (19). [18F]FDG (t1/2 = 109 min) was synthesized with a computer-controlled apparatus according to a modified method of Hamacher et al. (20).

Image acquisition and processing

An eight-ring ECAT 931/08-tomograph was used for image acquisition (Siemens/CTI, Knoxville, TN). A 5-min transmission scan was performed with a removable ring source containing 68Ge before the emission scan to correct for the tissue attenuation of {gamma}-photons. For image processing, we used a Bayesian iterative reconstruction algorithm, using median root prior with iterations and applying a Bayesian coefficient of 0.3 (21).

Measurement of adipose tissue blood flow

The sc adipose tissue blood flow was measured as previously described (17). [15O]H2O was injected iv, and a dynamic scan was performed for 6 min, using 6 x 5-, 6 x 15-, and 8 x 30-sec frames. The autoradiographic method and a 250-sec integration time were applied to calculate blood flow pixel by pixel.

Measurement of adipose tissue glucose uptake

[18F]FDG was injected iv, and a 20-min dynamic scan was performed, using 2 x 30-, 4 x 60-, and 3 x 300-sec frames. An arterial blood sample was drawn once during each time frame for measurement of plasma radioactivity. Plasma radioactivity was measured with an automatic {gamma}-counter (Wizard 1480 3; Wallac, Turku, Finland). The three-compartment model of [18F]FDG kinetics was used. Plasma and tissue time-activity curves were analyzed graphically (22) to quantitate the fractional rate of tracer uptake (Ki) (17). The rate of glucose uptake is obtained by multiplying Ki by the plasma glucose concentration divided by a tissue-specific lumped constant. The lumped constant accounts for differences in the transport and phosphorylation of [18F]FDG and glucose. A previously validated lumped constant value of 1.14 for adipose tissue was used for [18F]FDG (17).

Regions of interest

The femoral adipose tissue area was measured in the mid-thigh from an area 10 cm in length from magnetic resonance imaging (MRI) images acquired using a 0.23-T Outlook GP (Marconi Medical Systems, Vantaa, Finland) magnetic resonance imager. Transverse T1-weighted field echo images with time repetition of 170 msec were obtained with the same pixel size (256 x 256) as the PET images. Femoral adipose masses were measured plane by plane from MRI images. Blood flow and metabolism were measured by drawing regions of interest (ROI) on MRI images and located in femoral adipose tissue. ROI were carefully placed in the adipose tissue avoiding outer borders of skin and muscle. The ROI were copied into the [18F]FDG and [15O]H2O images to cross-sectional slices from identical planes. All images were matched in pixel size and scale.

Measurement of whole-body glucose uptake

For determination of the rate of whole-body glucose uptake (M-value), the euglycemic insulin clamp technique was used (23). Serum insulin was increased for 120 min using a primed-continuous (1 mU/kg·min) infusion of insulin (Actrapid; Novo Nordisk A/S, Bagsvaerd, Denmark). Normoglycemia was based on plasma glucose measurements performed every 5 min from arterial blood, and whole-body glucose uptake was calculated from the glucose infusion rate during the period of PET scanning and expressed per kilogram of body weight (µmol/min·kg body weight).

Biochemical analyses

Arterial plasma glucose was determined in duplicate by the glucose oxidase method (Analox GM9 Analyzer; Analox Instruments, London, UK). Glycosylated hemoglobin (HbA1c) was measured by fast protein liquid chromatography (MonoS; Pharmacia, Uppsala, Sweden). Serum C-peptide concentrations were measured at baseline and serum free insulin at baseline and at 60-min intervals during insulin infusion using a double-antibody fluoroimmunoassay (Autodelfia; Wallac). Serum free fatty acids (FFA) were determined by an enzymatic method (ACS-ACOD Method; Wako Chemicals, Neuss, Germany). Body fat content was estimated with the impedance method (body impedance analyzer; Akern, RJL Systems, Florence, Italy).

Statistical analysis

Results are given as mean ± SD unless stated otherwise. Serum triglyceride concentrations had a skewed distribution and were therefore log-transformed for statistical analysis. The comparison between the three groups was done using ANOVA with the post hoc Bonferroni procedure to allow for multiple pairwise comparisons. Effects of treatment were examined by comparing pre/posttreatment values using groupwise paired t tests. Univariate associations between the study variables were analyzed by calculating the Pearson’s correlation coefficients. All statistical analyses were performed using statistical analysis system, SAS, version 8.2.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
At baseline, age, gender, body weight, and percent body fat were similar between patients randomized to placebo (n = 11), metformin (n = 12), or rosiglitazone (n = 14). Metformin decreased fasting plasma glucose, HbA1c, and body weight. Rosiglitazone tended to decrease fasting plasma glucose and HbA1c but had no effect on body weight. Placebo had no effect on glucose control or body weight. Fasting serum insulin and FFA levels did not change significantly in any group, whereas serum C-peptide levels decreased in all. Rosiglitazone treatment was associated with a significant increase in M-value (averaging +43%) and a significantly greater suppression of circulating FFA, whereas no changes were observed in the metformin or placebo groups (Table 1Go).


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  		TABLE 1. Clinical characteristics and metabolic data at baseline and after treatment

 
Femoral adipose blood flow was similar between the three groups at baseline. Flow increased by 72% (from 11.3 ± 4.9 to 17.9 ± 6.8 ml/min·kg; P = 0.002) in the rosiglitazone group but remained unchanged in the metformin [from 9.1 ± 2.9 to 9.5 ± 3.0 ml/min·kg; not significant (NS)] and placebo (from 15.0 ± 4.4 to 14.6 ± 6.9 ml/min·kg; NS) groups (Fig. 1Go). Effect of rosiglitazone on blood flow was superior compared with placebo (P = 0.02) and metformin (P < 0.05). Metformin decreased sc adipose masses by 13% (P < 0.05), and no changes were found in placebo or rosiglitazone groups. When the adipose mass was taken into account, rosiglitazone treatment increased the total adipose tissue blood flow by 73% (from 9.1 ± 4.0 to 14.7 ± 6.7 ml/min in 10 cm of thigh fat; P = 0.002) but remained unchanged in the metformin (from 9.1 ± 6.0 to 9.0 ± 6.0 ml/min; NS) and placebo groups (from 13.1 ± 4.8 to 13.4 ± 8.0 ml/min; NS).



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  		FIG. 1. Femoral sc adipose tissue flow (A), glucose uptake (B), and extraction rate (C). *, P < 0.05 vs. baseline; {dagger}, P < 0.05 between groups.

 
The femoral insulin-stimulated glucose uptake increased by 23% in the rosiglitazone group (from 11.8 ± 4.7 to 14.5 ± 7.2 µmol/min·kg; P < 0.05) but remained unchanged in the metformin (from 11.2 ± 4.3 to 12.7 ± 4.1 µmol/min·kg; NS) and placebo (from 12.1 ± 3.6 to 11.2 ± 3.7 µmol/min·kg; NS) groups. When femoral adipose mass was taken into account, rosiglitazone treatment increased the total uptake by 24% (from 9.2 ± 2.9 to 11.0 ± 3.5 µmol/min in 10 cm of thigh fat; P < 0.05) (Fig. 1Go), whereas metformin (from 9.3 ± 3.1 to 10.7 ± 4.6 µmol/min; NS) or placebo treatment (from 11.5 ± 3.8 to 10.5 ± 7.1 µmol/min; NS) had no significant effect.

Fractional adipose glucose extraction calculated by dividing glucose uptake with blood flow decreased with rosiglitazone by 19% (from 1.3 to 1.0 mmol/liter; P < 0.05). This effect was not observed with metformin (from 1.7 to 1.7 mmol/liter; NS) or placebo (from 1.0 to 1.0 mmol/liter; NS) (Fig. 1Go). Insulin-stimulated glucose uptake correlated with blood flow at baseline (r = 0.63; P < 0.0001) and after treatment (r = 0.57; P = 0.0003) (Fig. 2Go). The increase in insulin-stimulated adipose glucose uptake bore a direct relation to the increase in adipose blood flow (r = 0.34; P < 0.05).



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  		FIG. 2. Correlation between glucose uptake and blood flow at baseline (A) and after treatment (B).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The main finding of the present study is that chronic treatment with rosiglitazone, but not metformin or placebo, was associated with a marked increase in femoral sc adipose tissue perfusion in parallel with an improvement in insulin-stimulated glucose uptake in the same region. This result held true whether considering blood flow and glucose uptake per unit fat mass (i.e. in each kilogram of fat tissue) or in a prespecified sc area (10 cm at the mid-thigh). When adipose tissue mass was taken into account, adipose blood flow was closely associated with glucose uptake in all treatment groups. This association was observed both at baseline and after treatment, and moreover the increase in adipose glucose uptake during the trial was associated with the increase in perfusion. These results suggest that adipose tissue perfusion is an important determinant of glucose uptake in the femoral region and that the improvement in glucose uptake with rosiglitazone is to a significant proportion mediated by a coincident increase in tissue perfusion.

Adipose tissue blood flow and glucose uptake can be measured directly and independently from each other with PET, allowing evaluation of the changes in glucose extraction. Adipose tissue blood flow was measured using freely diffusible 15O-labeled water by means of the autoradiographic method previously evaluated for low perfusion levels (24). The ROI placing is guided by the coregistration with MRI images to minimize the interference. Drawing of the ROI is described in detail in the article by Virtanen et al. (7). When placing the ROI, magnetic resonance images are used as anatomic references. ROI are carefully placed in adipose tissue, avoiding outer borders of skin and muscle. ROI are then copied to PET images that are matches in pixel size. Adipose perfusion PET studies have been conducted previously in lean (17, 25) and obese nondiabetic and diabetic subjects (11, 17) in our laboratory. Although drawing of sc ROI in lean subjects requires attention in avoiding underlying muscle, it can be done more easily in obese subjects with excess of adipose tissue as in the present study. The level of adipose tissue blood flow measured with autoradiograph method and PET is similar compared with the recent results of Tan and coworkers (26) (adipose flow, 17 ml/min·kg), where the [133Xe]xenon washout method was used for the abdominal region with patients with type 2 diabetes. Adipose tissue blood flow values are lower with type 2 diabetic patients compared with obese (adipose flow, 26 ml/min·kg) and furthermore even lower compared with nonobese (adipose flow, 48 ml/min·kg) subjects (7), indicating possible continuity in decreased adipose tissue blood flow when developing type 2 diabetes.

Rosiglitazone treatment has been shown to improve muscle blood flow in some studies (27, 28). In contrast, we found only a tendency of increase in muscle flow during insulin stimulation after 24 wk of rosiglitazone treatment (15), although insulin-stimulated glucose uptake was increased by 38% and extraction by 56%. Simultaneously, adipose tissue glucose uptake was increased by 23% and extraction decreased by 19%. Thus, chronic treatment with rosiglitazone decreased glucose extraction rate on femoral adipose tissue despite a simultaneous increase in glucose uptake, underlining the potential importance of perfusion on adipose tissue metabolism.

In this placebo-controlled study, the type 2 diabetic patients were either newly diagnosed or diet treated. Rosiglitazone enhanced whole-body insulin sensitivity as shown before (15, 29, 30, 31) but did not improve glycemic control or lower plasma glucose levels to a significant degree. Both improved and unchanged glycemic control have been reported earlier (29, 32, 33). Metformin improved significantly glycemic control and lowered plasma glucose levels but had no effect on whole-body insulin sensitivity (15). The improvement of glycemic control during metformin therapy is mostly mediated via suppression of hepatic glucose production (3, 34). The lack of the effect on metformin to increase whole-body insulin sensitivity in this trial is in agreement with earlier trials in which well controlled diabetic patients were included (35). Metformin decreased body weight and body mass index as previously reported (3, 36).

PPAR-{gamma} is expressed in white adipose tissue and was originally described to be an important mediator for gene expression, regulating insulin responsiveness and adipocyte differentiation (37, 38). Thereafter, PPAR-{gamma} expression has been shown in several cell types in addition to adipose tissue, including endothelial cells (39), aortic smooth muscle cells (40), and thrombocytes (41), indicating various possible sites of effect for the PPAR-{gamma} agonist rosiglitazone in vasculature. Recent studies have shown that rosiglitazone increases endothelial production and release of the potent vasodilator nitric oxide (NO) in human peripheral skin arteries (42) and improves NO-mediated and smooth muscle-dependent vasodilatation in conduit arteries (43). Rosiglitazone might therefore increase sc adipose tissue perfusion by inducing endothelial nitric oxide production in peripheral arteries or via a direct vasorelaxation effect on the arterial smooth muscle.

In the current study, rosiglitazone treatment increased adipose tissue glucose uptake, which is in line with recent in vitro findings in 3T3-L1 adipocytes (44, 45). It has previously been shown that thiazolidinediones increase glucose transport activity (46). The novel finding of a convincing positive association between perfusion and glucose uptake in femoral adipose tissue is interesting, although the cellular mechanisms cannot be deduced in light of our current results. The proportional increase in adipose perfusion with rosiglitazone was markedly higher than the corresponding increase in adipose glucose uptake. This allows us to speculate that rosiglitazone primarily increases adipose tissue perfusion, and the increase in metabolism is a secondary reflection of the ameliorated tissue perfusion. Alternatively, substrate-driven changes in adipose tissue flow have been reported (16), and adipose flow has been shown to increase in the postprandial period, suggesting the need to deliver substrate to adipose tissue for storage (16). Therefore, more targeted studies will be needed to clarify this interplay. When nondiabetic obese and nonobese patients were studied in our laboratory, a significant correlation was found between visceral and abdominal sc adipose tissue blood flow and glucose uptake (7). Perfusion of adipose tissue deposits was decreased more markedly in these pathological conditions and may contribute to the pathogenesis of adipose tissue insulin resistance.

In summary, femoral adipose tissue glucose uptake is associated with blood flow in patients with type 2 diabetes. Rosiglitazone treatment enhances femoral adipose insulin sensitivity and perfusion in parallel, whereas extraction decreased. These results suggest that perfusion could play a role for peripheral sc adipose tissue metabolism and insulin action. Moreover, enhanced adipose tissue perfusion may explain the increase in adipose tissue insulin sensitivity induced by rosiglitazone.


   Footnotes
 
First Published Online September 27, 2005

Abbreviations: bid, Twice daily; FDG, fluorodeoxyglucose; FFA, free fatty acids; HbA1c, glycosylated hemoglobin; MRI, magnetic resonance imaging; NS, not significant; PET, positron emission tomography; PPAR-{gamma}, peroxisome proliferator-activated receptor-{gamma}; ROI, regions of interest.

Received May 13, 2005.

Accepted September 15, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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