Original Article
Korean Diabetes J 2010;34:191-199
Effects of Rosiglitazone on Inflammation in Otsuka Long-Evans Tokushima Fatty RatsJin Woo Lee1, Il Seong Nam-Goong1, Jae Geun Kim2, Chang Ho Yun3, Se Jin Kim1, Jung Il Choi2, Young IL Kim1, Eun Sook Kim11Department of Internal Medicine, Ulsan University Hospital, Ulsan University Col age of Medicine, 2Biomedical Research Center, Ulsan University Hospital, 3Department of Biological Sciences, University of Ulsan, Ulsan, Korea Background: Inflammation plays a role in the response to metabolic stress in type 2 diabetes. However, the effects of rosiglita-
zone on inflammation of skeletal muscle have not been ful y examined in type 2 diabetes. Methods: We investigated the effects of the insulin-sensitizing anti-diabetic agent, rosiglitazone, on the progression of skeletal
muscle inflammation in Otsuka Long-Evans Tokushima Fatty (OLETF) type 2 diabetic rats. We examined the expression of se- rologic markers (serum glucose, insulin and free fatty acid) and inflammatory cytokines (tumor-necrosis factor-α, interleukin [IL]-1β and IL-6) in OLETF rats from early to advanced diabetic stage (from 28 to 40 weeks of age). Results: Serum glucose and insulin concentrations were significantly decreased in rosiglitazone-treated OLETF rats compared
to untreated OLETF rats. Rosiglitazone treatment significantly decreased the concentrations of serum inflammatory cytokines from 28 to 40 weeks of age. The mRNA expression of various cytokines in skeletal muscle was reduced in rosiglitazone-treated OLETF rats compared with untreated OLETF rats. Furthermore, rosiglitazone treatment resulted in the downregulation of ERK1/2 phosphorylation and NF-κB expression in the skeletal muscle of OLETF rats. Conclusion: These results suggest that rosiglitazone may improve insulin sensitivity with its anti-inflammatory effects on skele-
Keywords: Diabetes mellitus, type 2; Inflammation; Muscle, skeletal; Rats, inbred OLETF; Rosiglitazone
Some studies have reported that TNF-α is positively associ-ated with insulin resistance, which is accompanied by diabetes Activation of inflammation by metabolic stress in diabetes is and obesity [5,6]. In some studies that investigated the relation-associated with insulin deficiency caused by destruction of pan- ship between insulin resistance and TNF-α, increases in TNF-α creatic beta cel s and insulin resistance in adipose tissue and liv- were found in the skeletal muscle of patients who had a high er [1,2]. Adipocytes, which secrete several adipokines (leptin, re- insulin resistance [7]. In addition, TNF-α inhibits activation sistin, tumor-necrosis factor [TNF]-α, interleukin [IL]-6, and of the insulin receptor tyrosine kinase by blocking insulin re-PAI-1), induce insulin resistance and inflammation throughout ceptor substrate (IRS) phosphorylation and Akt substrate 160 the entire body through a decrease in adiponectin [3]. The se- phosphorylation, which are important proteins in the insulin cretion of cytokines caused by the activation of NF-κB also in- signaling pathway in skeletal muscle [8-10]. Based on these re- duces insulin resistance in fatty liver [4].
sults, it seems that an increase in TNF-α is not just a byprod- This is an Open Access article distributed under the terms of the Creative Commons At- tribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) Department of Internal Medicine, Ulsan University Hospital, Ulsan University which permits unrestricted non-commercial use, distribution, and reproduction in any Col age of Medicine, 290-3 Junha-dong, Dong-gu, Ulsan 682-714, Korea medium, provided the original work is properly cited.
Received: Nov. 3, 2009; Accepted: Mar. 30, 2010 Copyright 2010 Korean Diabetes Association uct of inflammation, but may directly influence inflammation the 28th and 40th weeks, LETO rats (n = 6) were fed normally, of skeletal muscle.
and OLETF rats were divided into a non-treated group (n = 8) Thiazolidinedione (TZD) is an insulin sensitizer that func- and a rosiglitazone-treated (GlaxoSmithKline Pharmaceuti- tions not only to enhance the effect of insulin by controlling cals, Philadelphia, PA, USA) group (3 mg/kg body weight, n = gene transcription through binding with nuclear receptor per- 8) (Fig. 1). At the 40th week, weight and urine glucose levels oxisome proliferator activated receptor (PPAR)-γ, but also to were measured, and the rats were sacrificed to collect gastroc-inhibit inflammation of adipose tissue, immunologic cel s and nemius muscle samples. blood vessels through several inflammatory pathways (STAT, The body weights of the animals were measured every 4 AP-1 and NF-κB pathway) [11-13].
days at 4 o’clock in the afternoon between the 8th and 40th In this study, we investigated the role of skeletal muscle in- flammation in the pathogenesis of insulin resistance in type 2
diabetes in the Otsuka Long Evans Tokushima Fatty (OLETF) Serologic tests
rat, a well-known type 2 diabetes animal model. OLETF rats At the 28th and 40th weeks, fasting blood was extracted from
progress to hyperglycemia in postnatal week 18 and fibrosis of the hearts of OLETF and LETO rats. Plasma was separated from
pancreatic beta cel s in postnatal week 40 [14]. We also inves-
whole blood and refrigerated at -70°C. Serum glucose level was tigated whether the anti-inflammatory effect of rosiglitazone, measured by glucose oxidase reaction method using an enzyme which has been shown in adipose tissue and inflammatory cel s, reagent (Asan Pharmaceutical Co., Seoul, Korea). The concen-is also present in skeletal muscle.
tration of insulin was measured by enzyme-linked immuno-sorbent assay (ELISA) kit (Shibayagi Co., Ishihara, Japan). The concentration of free fatty acids was measured by the kinetic alkaline picrate method using an enzyme reaction kit (Asan Laboratory animals
Pharmaceutical Co.). Homeostasis model assessment (HOMA)- Five-week-old OLETF rats (n = 21) and Long-Evans Tokushi- insulin resistance (IR) and HOMA-β (HOMA beta cell func- ma Otsuka (LETO) rats (n = 11) were obtained from the Ot- tion) were estimated using the following formula: [Fasting in- suka Pharmaceutical Co. Ltd. (Tokushima, Japan). Each rat was sulin (μIU/mL) × fasting plasma glucose (mmol/L)]/22.5;
housed in a separate cage and was fed animal feed. The cages HOMA-β = 20°C fasting insulin (μU/mL)/fasting glucose (mg/
were maintained at a constant temperature of 22 ± 2°C and the dL) – 63 [15].
light-dark cycle was adjusted automatical y every 12 hours. To
extract tissues before the experiment, 5 rats from the OLETF Measurement of inflammatory cytokines
group and 5 rats from the LETO group were sacrificed. Between At the 28th and 40th weeks, the concentrations of TNF-α, IL-
Fig. 1. Experimental schedule in Otsuka Long-Evans Tokushima Fatty (OLETF) and Long-Evans Tokushima Otsuka (LETO)
Anti-inflammation of rosiglitazone in OLETF rats 1β and IL-6 were measured from the sampled blood plasma brane was blocked with 10% skim milk at room temperature using an ELISA kit (eBioscience, San Diego, CA, USA).
for 1 hour, and then the membrane was reacted for 2 hours at room temperature with a dilution of monoclonal antibody for Expression of inflammatory cytokine genes
β-actin, ERK1/2 MAPK or NF-κB (Cell Signaling Technology; To extract gastrocnemius muscle samples, the rats were sacri- #9101, #3036); antibodies were diluted with Tris-buffered sa- ficed by intraperitioneal injection of 2.5% tribromoethanol at line containing 0.05% tween (TBS-T). The membrane was then the 28th and 40th weeks. The extracted gastrocnemius sam- washed three times with TBS-T. Then the membrane was re- ples were immediately frozen with liquid nitrogen and ground acted with HRP-conjugated anti-rabbit IgG secondary antibody
with a homogenizer. Total RNA was separated from the ground at room temperature for an hour, and bands were visualized
tissues using TRIzol reagent. The cDNA was synthesized using with an enhanced chemiluminescence kit and X-ray film (Am-
oligo-(dT) primer and AccuScriptTM high fidelity 1ST strand ersham Pharmacia Biotech, San Francisco, CA, USA).
cDNA synthesis kit (Stratagene) at 65°C for 5 minutes, at 42°C
for 1 hour and at 70°C for 15 minutes. For the PCR reaction, Statistical analysis
10 × PCR buffer (10 mM Tris-HCl, pH 8.3, 50 mM KCl, 0.1% All results are shown as the mean and standard deviation based
Triton X-100), 250 μM dNTP mix, 1 U Taq polymerase (Taka-
on three experiments. Statistical analysis of the difference be- ra) and a specific primer for each cytokine were mixed with 1 tween groups was analyzed by one-way ANOVA (GraphPad
μg cDNA. The reaction was incubated at 94°C for 30 seconds Prism program; GraphPad Software Inc., San Diego, CA, USA)
for denaturation, at 57-62°C for 30 seconds for annealing, and and Student t-test. A P value less than 0.05 was considered sta-
at 72°C for 30 seconds for extension. This cycle was repeated tistical y significant.
25-35 times. ACTIN was used for the comparison with PCR
reaction. The primer sequences for the PCR reaction are shown RESULTS
Actin; Forward, 5’-TCA TGA AGT GTG ACG TTG ACA Changes in body weight
TCC GT-3’; Reverse, 5’-CCT AGA AGC ATT TGC GGT GCA The weights of the OLETF and LETO rats were measured ev-
CGA TG -3’, TNF- α ; Forward, 5’-AAA GCA TGA TCC GAG ery 4 weeks between the 18th and 40th week. The weights of
both OLETF and LETO rats decreased with time until the 36th 3’, IL-6: Forward, 5’-CCG GAG AGG AGA CTT CAC AG-3’; week. An insignificant decrease in weight in normal y fed OLETF Reverse, 5’-AGA ATT GCC ATT GCA CAA C-3’, IL-1β; For- rats was observed at the 40th week. The increase in the weight ward, 5’-CAT CTT TGA AGA AGA GCC CG-3’; Reverse, 5’- of the OLETF rats was greater than that of the LETO rats, re- gardless of rosiglitazone administration. At the 36th week, the average weight of the LETO rats was 534.9 ± 7.7 g, while that Inflammatory signal molecules
of rosiglitazone-treated OLETF rats was 733.9 ± 18.6 g, and Ground gastrocnemius muscle liquid, which was extracted that of untreated OLETF rats was 681.1 ± 18.0 g. At the 40th from the 28th and 40th week, was washed twice with HBSS week, the average weight of the LETO rats was 558.3 ± 8.7 g, buffer, and then lysed on ice with RIPA buffer (50 mM HEP- while that of untreated OLETF rats was 655.7 ± 48.9 g and that ES, pH 7.4, 150 mM NaCl, 1% deoxycholate, 1 mM EDTA, 1 of the rosiglitazone-treated OLETF rats increased up to 757.8 mM PMSF, 1 μg/mL aprotinin). To observe NF-κB expression, ± 19.0 g (Fig. 2). The weight gain of the rosiglitazone-treated the nucleus was extracted using NE-PER nuclear and cytoplas- OLETF rats was greater than that of the untreated OLETF rats mic extraction reagent (Pierce, Rockford, IL, USA). The protein at the 32nd week. However, the difference was not statistical y
was measured by the Bradford method. The same quantity (20 significant until the 40th week.
μg) of protein was mixed with 2X sample buffer (100 mM Tris-
HCl, pH 6.8, 200 mM dithithreitol, 4% SDS, 0.2% bromophenol Changes in serologic markers
blue, 20% glycerol). Then, the mixture was separated with 10% To investigate the chemical changes related to the administra-
SDS-PAGE. After electrophoresis, the protein was transferred tion of rosiglitazone, blood was obtained from both OLETF
to nitrocel ulose membrane at 4°C, 30 V for 16 hours. The mem-
and LETO rats at the 28th and 40th week. Concentrations of Fig. 2. Changes of body weight in Long-Evans Tokushima
Otsuka (LETO) and Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Body weights were measured at 28, 32, 36, and 40 weeks, and changes are represented as the average weights on indicated days. Values are presented as mean ± standard deviation. ROSI, rosiglitazone. aP < 0.001 as compared to free fatty acid (FFA), insulin and glucose were measured from the plasma (Fig. 3). At the 28th week, the fasting glucose con- centrations of the LETO and OLETF rats were 167.9 ± 40.1 mg/dL and 229.8 ± 44.2 mg/dL, respectively. The glucose level was higher in the OLETF rats than in the LETO rats. At the 40th week, the glucose level of the LETO rats was 164.5 ± 26.8 mg/dL, while that of the rosiglitazone-treated OLETF rats was 224.1 ± 42.5 mg/dL, and that of the untreated OLETF rats was 276.7 ± 44.4 mg/dL. The glucose level of the rosiglitazone- treated OLETF rats decreased significantly compared with that At the 28th week, the insulin concentrations of the LETO rats and OLETF rats were 0.94 ± 0.1 ng/mL and 2.66 ± 0.4 ng/ mL, respectively. The insulin concentration of the OLETF rats increased more than that of the LETO rats (P < 0.05). At the 40th week, the insulin concentration of the LETO rats was 1.89 ± 1.6 ng/mL, that of the rosiglitazone-treated OLETF rats was 2.01 ± 1.4 ng/mL and that of the untreated OLETF rats was 1.89
± 1.6 ng/mL. The insulin concentration decreased significantly Fig. 3. Changes in concentration of serological markers in
Long-Evans Tokushima Otsuka (LETO) and Otsuka Long- in the rosiglitazone-treated group (P < 0.05, Fig. 3).
Evans Tokushima Fatty (OLETF) rats. Glucose, insulin and There were no statistical y significant changes in HOMA-β free fatty acid in sera of LETO or OLETF rats were measured and HOMA-IR among the LETO rats, rosiglitazone-treated by colorimetric and enzymatic assay at 28 and 40 weeks. Val- and untreated OLETF rats (data not shown). The mean values ues were represented as mean ± standard deviation. FFA, free of HOMA-IR among the LETO rats, rosiglitazone-treated and fatty acid. aP < 0.05 and bP < 0.01 as compared to each group. untreated OLETF rats were 0.8 ± 0.35, 2.4 ± 1.05 and 1.83 ± ROSI is an abbreviation for rosiglitazone. Anti-inflammation of rosiglitazone in OLETF rats 0.86, respectively. Insulin resistance increased more in untreated OLETF rats than in LETO rats. There was a trend of decreased insulin resistance in rosiglitazone-treated OLETF rats compared with untreated OLETF rats (data not shown).
At the 28th week, the FFA concentrations of the LETO and OLETF rat groups were 484.8 ± 77.9 mg/dL and 311.8 ± 76.7 mg/dL, respectively (Fig. 3). At the 40th week, the FFA concen- tration of the LETO rats was 505.3 ± 82.7 mg/dL, that of the untreated OLETF rats was 276.1 ± 18.3 mg/dL and that of the rosiglitazone-treated OLETF rats was 280.1 ± 46.6 mg/dL. At the 40th week, the FFA level was lower in the OLETF group compared to the LETO group. In contrast, a decrease in the FFA level was not observed in the rosiglitazone-treated group Changes in inflammatory cytokines
Serum TNF-α concentrations at the 40th week were 261.9 ± 8.3 pg/mL in the LETO rats, 613.5 ± 64.3 pg/mL in the untreat- ed OLETF rats, and 282.1 ± 11.84 pg/mL in the rosiglitazone- treated OLETF rats (Fig. 4). The TNF-α concentration of the OLETF rat group was significantly increased compared with that of the LETO rat group at the 40th week. In the OLETF rat group, TNF-α secretion was significantly decreased by rosigli- For IL-1β at the 40th week, the mean concentration in the LETO rat group was significantly lower than that in the un- treated OLETF rat group (125.6 ± 7.9 pg/mL vs. 189.8 ± 30.6 pg/mL, respectively). The IL-1β concentration of the rosiglita- zone-treated OLETF rat group at the 40th week, was 137.8 ± 5.7 pg/mL, which was significantly lower than that of the un- For IL-6 at the 40th week, the mean concentration in the LETO rat group was significantly lower than that of the un- treated OLETF rat group (261.8 ± 19.5 pg/mL vs. 906.5 ± 49.1 pg/mL, respectively). The rosiglitazone-treated rats had signif- icantly lower IL-6 levels (709.1 ± 61.2 pg/mL) compared with Changes of inflammatory cytokine gene expression in Fig. 4. Changes in inflammatory cytokine levels in Long-Ev-
skeletal muscle
ans Tokushima Otsuka (LETO) and Otsuka Long-Evans Toku- shima Fatty (OLETF) rats. Tumor-necrosis factor (TNF)-α, in- The gene expression of inflammatory cytokines in the OLETF terleukin (IL)-1β, IL-6 levels in sera of LETO or OLETF rats rat group was higher than that of the LETO rat group (Fig. 5). were measured by enzyme-linked immunosorbent assay at 28 Cytokine gene expression was lower in the rosiglitazone-treat- and 40 weeks. Values are represented as the mean ± standard ed OLETF rat group than in the untreated OLETF rat group, deviation. ROSI, rosiglitazone. aP < 0.05 and bP < 0.001 as although the difference was not statistical y significant.
Fig. 5. Changes in inflammatory cytokine gene expression in Long-Evans Tokushima Otsuka (LETO) and Otsuka Long-Evans
Tokushima Fatty (OLETF) rats. The expression of Tumor-necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 mRNA in skeletal muscle tissues of LETO and OLETF mice were determined by RT-PCR at 40 weeks. There are no significant differences between the groups. This is a representative figure from three independent experiments. ROSI is an abbreviation for rosiglitazone.
Fig. 6. Changes in levels of in-
Changes in inflammatory signal molecules expression
rats was shown to increase compared with that in the OLETF To investigate the effects of rosiglitazone administration on rats. The phosphorylation of ERK1/2 was lowered by rosiglita-the inflammatory pathway, expression of signaling molecules zone treatment in OLETF rats (Fig. 6A). In addition, for NF-in ERK1/2 MAPK and NF-κB pathways was examined in skel- κB, there was an increase in the expression of the NF-κB p65 etal muscle tissue of LETO and OLETF rats by Western blot subunit in the nucleus in OLETF rats, and this was decreased (Fig. 6). The phosphorylation of ERK1/2 MAPK of the LETO by administration of rosiglitazone (Fig. 6B).
Anti-inflammation of rosiglitazone in OLETF rats DISCUSSION
it is known to bind with PPAR-γ selectively in adipose tissue, muscle tissue and liver tissue, which are the target organs of Skeletal muscle mainly uses glucose as an energy fuel. Insulin insulin action. It accelerates gene expression of glucose trans-resistance of muscle, caused by accumulation of fatty acid and porter (GLUT)-1, GLUT-4 and activates differentiation of adi-reduced expression of glucose transporter, plays a significant pose tissue and inhibits expression of TNF-α, hepatic glucoki-role in the pathogenesis of type 2 diabetes. Normal muscle tis- nase. Final y, it improves insulin resistance and recovers glucose sues are not involved in the inflammatory process, except for homeostasis in the human body. In this experiment, we found in the condition of muscle atrophy, which is seen in cachexia that rosiglitazone plays a role in reducing glucose and insulin or chronic inflammation of muscles. Human leukocyte anti- levels among various biochemical markers. We observed an gen (HLA) class Ι, HLA class ΙΙ and secretion of inflammatory improvement in insulin resistance, although there was not an cytokine increase when a proinflammatory stimulus is given increase in insulin secretion ability. Rosiglitazone-treated OLETF to normal muscle tissues [15]. TNF-α mRNA expression after rats gained their weight gradual y until the 40th week, while delivery was higher in gestational diabetes patients than in pa- untreated OLETF rats lost weight after the 40th week, which is tients with normal glucose tolerance, and this was also related considered to be a negative side effect of rosiglitazone.
to insulin resistance [16]. The inflammatory process was ob- It is known that TZDs have an anti-inflammatory effect served in the skeletal muscle of diabetes patients, in whom chron- through inhibition of the transcription process in the inflam- ic systemic inflammation is known to be present. However, the mation pathway. PPAR-γ expression was abundantly found in degree of inflammation of skeletal muscle in relation to insulin adipose tissue, macrophages and endothelial cel s of blood resistance in diabetes has never been shown. An increase in vessels and it was also reported that TZDs decrease NF-κB ex-adipose tissue caused by obesity activates the JNK and NF-κB pression at colonic epithelial cel s in inflammatory bowel dis-pathway, and also induces inflammation in liver through se- ease [20]. However, its anti-inflammatory effect on skeletal mus- cretion of several inflammatory cytokines. This phenomenon is cle, which is the target organ of insulin action, has not been clar-known to contribute to hyperglycemia through inappropriate ified yet. It is known that rosiglitazone has an effect on several inhibition of gluconeogenesis in liver [4]. Our hypothesis was inflammatory pathways, such as STAT, AP-1, and NF-κB [21]. that increased inflammation in skeletal muscle tissues of dia- Rosiglitazone inhibits inflammatory cytokine secretion at mono- betes patients contributes to increases in insulin resistance in cytes and macrophages by interruption of NF-κB in these inflam-type 2 diabetes, just as there is inflammation in liver tissues in matory pathways [11-13]. In our study, at the 40th week, in-diabetes patients. Then, we examined inflammation markers flammatory cytokines (TNF-α, IL-1β and IL-6) were reduced in skeletal muscle tissue and plasma in OLETF rats, which is significantly in rosiglitazone-treated OLETF rats in compari-an animal model of type 2 diabetes.
son to untreated OLETF rats. The expression of inflammatory In this experiment, at the 40th week, gene expression of in- cytokine mRNA (TNF-α, IL-1β and IL-6) was found to be de- flammatory cytokines (TNF-α, IL-1β and IL-6) and expres- creased in rosiglitazone-treated OLETF rats. The inflammato- sion of ERK1/2 MAPK and NF-κB in the gastrocnemius mus- ry pathways of ERK/MAPK and NF-κB were inhibited at skele- cle was increased in OLETF rats compared to LETO rats. In- tal muscle of rosiglitazone-treated OLETF rats. This study result creased expression of the transcriptional factors of inflamma- shows that rosiglitazone, which increases the expression of tory pathways such as ERK1/2 MAPK and IκB/NF-κB in the glucose transporters and to decrease the accumulation of lip-nucleus is known to be involved in the pathogenesis of insulin ids at skeletal muscle [22,23], also interrupts the expression of resistance in skeletal muscle. There have been other studies inflammatory cytokine (TNF-α, IL-1β and IL-6) mRNA and that observed activation of NF-κB caused by reduction of in- thus contributes to the inhibition of inflammatory pathway of hibitor of κBβ (IκB) at skeletal muscle of type 2 diabetes pa- ERK/MAPK and NF-κB at skeletal muscle [24,25]. However, tients is related with insulin resistance [17]. Activation of NF- there is still doubt that only inhibition of NF-κB pathway at κB in adipose tissue, which is caused by TNF-α stimulus, in- skeletal muscle is sufficient to improve insulin resistance in the duces insulin resistance through inhibition of insulin signaling whole body, because a previous study showed an opposite result [18,19].
based on an experiment with muscle-specific IKK2 (IκB kinase) The mode of action of TZD has not verified completely, but knockout mice [26]. The anti-inflammatory effect of rosiglita- zone on insulin resistance must be studied more extensively from hepatic activation of IKK-beta and NF-kappaB. Nat Med through the measurement of GLUT-4 expression, glucose re- ceptor and IRS-1 in the skeletal muscle of OLETF rats. In ad- 5. Winkler G, Salamon F, Harmos G, Salamon D, Speer G, Szek- dition, it is necessary to investigate whether Rel translocation, eres O, Hajos P, Kovacs M, Simon K, Cseh K. Elevated serum Rel DNA binding and IκBα degradation, which are considered tumor necrosis factor-alpha concentrations and bioactivity in to be involved in the pathogenetic mechanisms that inhibits type 2 diabetics and patients with android type obesity. Diabe- NF-κB pathway, are related to the anti-inflammatory effect of 6. Mishima Y, Kuyama A, Tada A, Takahashi K, Ishioka T, Kibata In this experiment, we did not observe improvement in FFA M. Relationship between serum tumor necrosis factor-alpha level, which is a well-known effect of rosiglitazone in other tis- and insulin resistance in obese men with type 2 diabetes melli- sues. Although the weight of OLETF rats increased, the FFA tus. Diabetes Res Clin Pract 2001;52:119-23.
level did not increase in the OLETF rats compared to the LETO 7. Saghizadeh M, Ong JM, Garvey WT, Henry RR, Kern PA. The rats between the 28th and 40th week. Thus, we were unable to expression of TNF alpha by human muscle: relationship to in- detect an improvement in lipids. However, the anti-inflamma- sulin resistance. J Clin Invest 1996;97:1111-6.
tory effect of rosiglitazone was observed. It has already been 8. Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, shown that low dose rosiglitazone exerts an anti-inflammatory Spiegelman BM. IRS-1-mediated inhibition of insulin receptor effect independently of improvements in lipid and insulin re- tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science 1996;271:665-8.
In this study, we observed the relationship between changes 9. Plomgaard P, Bouzakri K, Krogh-Madsen R, Mit endorfer B, in skeletal muscle inflammation and chronic inflammation in Zierath JR, Pedersen BK. Tumor necrosis factor-alpha induces hyperglycemic status. Rosiglitazone directly inhibited the in- skeletal muscle insulin resistance in healthy human subjects flammatory process in the skeletal muscle in our rat model, via inhibition of Akt substrate 160 phosphorylation. Diabetes which is considered to be a component of the pathogenesis of insulin resistance in skeletal muscle. These effects might help 10. Bouzakri K, Zierath JR. MAP4K4 gene silencing in human to improve insulin resistance, not only in skeletal muscle, but skeletal muscle prevents tumor necrosis factor-alpha-induced insulin resistance. J Biol Chem 2007;282:7783-9.
11. Jiang C, Ting AT, Seed B. PPAR-gamma agonists inhibit pro- ACKNOWLEDGEMENT
duction of monocyte inflammatory cytokines. Nature 1998; 391:82-6.
This study was supported by a grant of the Korean Diabetes 12. Ricote M, Li AC, Wil son TM, Kel y CJ, Glass CK. The peroxi-Association (2008) and was funded by Ulsan University Hospi- some proliferator-activated receptor-gamma is a negative reg- tal (Biomedical Research Center Promotion Fund, UUH- ulator of macrophage activation. Nature 1998;391:79-82.
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Deutschsprachige Übersetzung der frei zugänglichen (open access) Originalarbeit: Graessel E, Stemmer R, Eichenseer B, Pickel S, Donath C, Kornhuber J, Luttenberger K: Non-pharmacological, multicomponent group therapy in patients with degenerative dementia: a 12-months randomized, controlled trial. BMC Medicine 9 (2011) 129 Eine nicht-medikamentöse, multimodale Gruppentherapie für Patie

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