Dossier: Diabetes: Basic Research and Clinical Approach

Effects of a statin group drug, pravastatin, on the insulin resistancein patients with metabolic syndrome

Feyzullah Güçlü a, Bilgin Özmen b,*, Zeliha Hekimsoy b, Cengiz Kirmaz a

a Department of Internal Medicine, Faculty of Medicine, Celal Bayar University, Manisa, Turkeyb Division of Endocrinology of Internal Medicine, Faculty of Medicine, Celal Bayar University, Manisa, Turkey

Received 4 May 2004

Available online 13 October 2004

Abstract

Background. – In West of Scotland Coronary Prevention Study (WOSCOPS), development of type 2 diabetes mellitus (DM) was found todecrease by 30% in pravastatin-treated patients. In the study, it is suggested that pleiotropic effects of pravastatin may be responsible too aswell as its lipid lowering effect.

Objective. – The aim of this study was to assess the effects of pravastatin treatment on the insulin resistance in patients with metabolicsyndrome with impaired glucose tolerance (IGT), by Homeostasis Model Assessment (HOMA) test, insulin sensitivity indices and glucosehalf activation time (glucose t1/2).

Methods. – Study population consisted of 25 women who were diagnosed with metabolic syndrome. At baseline and 10 weeks after the20 mg/daily tablet pravastatin treatment, waist/hip circumference, body weight and arterial blood pressure measurements, plasma glucose,total cholesterol, triglyceride, high density lipoprotein (HDL)-cholesterol, transaminases, glycosylated haemoglobin (A1C) and insulin levelmeasurements were obtained along with HOMA test and insulin tolerance test after 12 h of fasting. Insulin sensitivity indices and glucoset1/2 were assessed.

Results. – After the treatment, a statistically significant decrease was observed in arterial blood pressure values (P < 0.0001). While plasmatotal cholesterol, low density lipoprotein (LDL)-cholesterol, and triglyceride levels were found to decrease significantly and HDL-cholesterollevels increased significantly, a decrease in baseline insulin levels, an increase in insulin sensitivity levels were observed along with andecrease in glucose t1/2. Related to the improvement in aforementioned parameters, statistically significant decreases were noted in HOMA,postprandial and fasting glucose levels and A1C values (P < 0.0001).

Conclusion. – Our study suggests that using pravastatin in the dyslipidemia treatment of metabolic syndrome with IGT may be an effectiveapproach by its advantageous effects on insulin resistance. Based on this result, it is possible to say that this can be a risk lowering treatmentapproach for the development of type 2 DM.© 2004 Elsevier SAS. All rights reserved.

Keywords: Insulin resistance; Metabolic syndrome; Pravastatin; Hyperlipidemia; HOMA-IR

1. Introduction

Metabolic syndrome patients are at increased risk for devel-oping cardiovascular morbidity and mortality [1]. The increas-ing prevalence of the metabolic syndrome in various asymp-tomatic populations has been well documented, however,limited information is available about the prevalence in mani-fest atherosclerotic vascular disease patients [2].

Metabolic syndrome is a disorder in which insulin resis-tance is the main component of the pathogenetic mechanism.In 1988, Reaven [3], upon observing the more than coinci-dental existence of obesity, diabetes, hypertension, hyperlipi-demia and atherosclerotic coronary diseases concomittantlyin a single patient, suggested that these are caused by a singlemetabolic disorder. On the basis of this conclusion, he definedthe “insulin resistance syndrome” (syndrome X) which con-sists of insulin resistance, hyperinsulinemia, obesity, glucoseintolerance, hypertriglyceridemia, reduced high density lipo-protein (HDL)-cholesterol level, hypertension and coronaryarterial diseases, prothrombotic state (e.g., high fibrinogen or

* Corresponding author. Plevne Bulvarı No. 14, D. 9, Alsancak, Izmir35220, Turkey.

E-mail address: bilozmen@yahoo.com (B. Özmen).

Biomedicine & Pharmacotherapy 58 (2004) 614–618

http://france.elsevier.com/direct/BIOPHA/

0753-3322/$ - see front matter © 2004 Elsevier SAS. All rights reserved.doi:10.1016/j.biopha.2004.09.005

plasminogen activator inhibitor [–1] (PAI-1) in the blood),proinflammatory state (e.g., elevated high-sensitivityC-reactive protein (h-CRP) in the blood) and polcystic ova-rian syndrome [3–5].

Insulin resistance is defined as a decrease in endogenous(native) and/or exogenous insulin action. In other words, animpaired response to a specific insulin dose [3]. Many heredi-tary and acquired factors lead to an advance decrease in bio-logical response of insulin by preventing the insulin bindingto the receptors in target tissues or by impairing the receptorsignaling pathways [3,6]. In order to meet the increased action,an excess insulin secretion occurs. Mild-moderate insulinresistance, a common clinical case, leads to impaired glucosetolerance (IGT), type 2 diabetes mellitus (DM), hypertensionand early atherosclerosis [7].

All these clinical features that occur related to insulin resis-tance are significant mortality and morbidity factors. Giventhese facts, new approaches in the treatment of insulin resis-tance may prevent these diseases and also contribute to thetreatment of such diseases.

In West of Scotland Coronary Prevention Study(WOSCOPS), development of type 2 DM was found todecrease by 30% in pravastatin-treated patients [8]. In thisstudy, it is suggested that anti-inflammatory and endothelialeffects of pravastatin may be responsible as well as its lipidlowering effect.

We aimed to detect the effects of pravastatin treatment oninsulin resistance in cases having metabolic syndrome withIGT is assessed by Homeostasis Model Assessment (HOMA)test, insulin sensitivity indices (ISI) and glucose half activa-tion time (glucose t1/2).

2. Materials and methods

2.1. Subject

Our study consisted of 25 cases that met the ATP III crite-ria of metabolic syndrome [5] and thus diagnosed with meta-bolic syndrome between January 2002 and March 2003 inthe Department of Endocrinology and General Internal Medi-cine out-patient clinic of Celal Bayar University Medical Fac-ulty. All the patients were women with an average age of55.56 ± 8.26 (min: 41, max: 68). Additional exclusion crite-ria that all selected patients met were:• being previously diagnosed with type 2 DM (fasting blood

glucose ≥ 126/mg/dl or 2 h OGTT plasma glu-cose ≥ 200 mg/dl);

• having a normal lipid profile (total cholesterol, triglycer-ide, low density lipoprotein (LDL)-cholesterol);

• taking obesity treatment within last two months (diet ormedical);

• attending regular physical program or weight loss of morethan 3% within the last 6 months;

• having obesity due to endocrinologic diseases (hypothy-roid, cushing syndrome, etc.);

• being on drugs that may affect insulin resistance; forexample, taking an angiotensin converting enzyme (ACE)inhibitor or angiotensin receptor blocker group drugs;

• cases with acute coronary diseases;• patients on hormone replacement treatment (HRT) or those

using selective estrogen receptor modulator (SERM);• presence of infection, severe physical or psychological

trauma on the day of insulin tolerance test or any recentday, as these may affect the result of the test;

• those who do not comply with the pravastatin treatment.Informed consent for the described investigations was

obtained from all patients. Approval for the study was givenby the ethics committee of our hospital.

2.2. Study design

At the initial visit, waist/hip circumference, body weightand arterial blood pressure measurements and total choles-terol, HDL-cholesterol, LDL-cholesterol, triglyceride, fast-ing glucose levels, postprandial glucose levels, liver functiontests, glycosylated haemoglobin (A1C) and baseline insulinlevel measurements tests were obtained from the patients cho-sen according to the metabolic syndrome diagnostic criteriaof ATP III [5]. HOMA, ISI and glucose t1/2 of the patientswere calculated. Pravastatin treatment (20 mg once daily atbedtime) was initiated in these patients. This treatment wascontinued until second visit, 10 weeks later. Aforementionedparameters were measured once again.

Plasma glucose level, total cholesterol, triglyceride, HDL-cholesterol, liver function tests and A1C measurements wereanalysed at Celal Bayar University, Medical Faculty Biochem-istry Laboratory, using an automatic analyzer (DiagnosticMerck-Mega-2000 equipment). LDL-cholesterol levels werecalculated by the Friedewald equation [9].

Serum insulin levels were assayed by radioimmunoassay(RIA) method. Commercial kits of DPC (Diagnostic Prod-ucts Corporation, Los Angeles, USA) were used for the mea-surements.

2.3. Assessment of insulin tolerance test

Following the tension arterial, weight, waist/hip measure-ments of the patients obtained after 12 h fasting and 30–45 minrest, they were instructed to lie in supine position on theexamination bed and 22 G needle was used for venous access.Blood glucose measurement was obtained at –5 and 0 minfollowed by infusion of crystallized insulin IV at a rate of0.1 unit/kg in the other arm. Blood glucose level measure-ments were obtained at 1, 2, 3, 5, 7, 10, 15 and 20 min.Hypoglycemic symptoms were monitored closely during thetest. During these observations, no serious hypoglycemicsymptom was observed except, mild sweat, tachycardia andstarvation feeling towards the end of the test. At the end of20 min, 500 ml 5% dextrose serum was infused at 150 ml/hfor 2 or 3 h depending on the condition of the patient. Singledose (before bed time) 10 weeks 20 mg Pravastatin(pravachol™-Bristol-Myers Squibb) treatment was initiated.

615F. Güçlü et al. / Biomedicine & Pharmacotherapy 58 (2004) 614–618

2.4. Assessment of the results and statistical analysis

Baseline insulin values, glucose t1/2 and dG values weretaken into account in statistical analysis. dG was calculatedby subtracting the 0 min blood glucose value from 20 minblood glucose level. G0 is the 0 min blood glucose level. Insu-lin sensitivity indices was calculated as (ISI) = dG/G0.

Glucose t1/2 of the patients is the value that correspondsto the half of the G1 value in scatterplot graphics SPSS ver-sion 10. SPSS Version 10 was used for the assessment of allthe statistical analysis. After calculating the average post- andpre-treatment values, “paired student’s t-test” was used forthe statistical analysis. P values less than 0.05 were acceptedas statistically significant. All data were expressed as ±SD.

3. Results

Twenty-five patients that met the inclusion criteria com-pleted the study. When the pre- and post-treatment param-eters of the patients were compared, a statistically signifi-cance decrease was found in total cholesterol, LDL-cholesterol and triglyceride levels (P < 0.0001), while therewas a statistically significant increase in HDL-cholesterol lev-els (P < 0.0001) (Table 1).

When the seventh report of the Joint National Committee(JNC VII) was taken into account and tension arterial valuesof the patients were evaluated, it was noted that 28% is pre-hypertensive, 48% is stage-1 hypertensive and 24% is nor-motensive. Following the treatment, a statistically significantdecrease was observed in the tension arterial values of thecontrols (P < 0.0001) (Table 1).

Besides an increase in baseline insulin levels (Table 1), astatistically significant difference was identified between theincrease in ISI and decrease in glucose t1/2) (P < 0.0001)(Table 1 and Fig. 1). Related to the improvement in afore-mentioned parameters, statistically significant decreases werefound in HOMA (Table 1 and Fig. 1), fasting and postpran-dial glucose and A1C values (P < 0.0001) (Table 1).

4. Discussion

In the last several years, there has been a decided shift inthe focus of lipid trials from populations with high LDL cho-lesterol to populations with a more modest LDL cholesteroland the dyslipidemia that is characteristic of DM and meta-bolic syndrome [10].

Statins predominantly result in substantial LDL choles-terol lowering but generally also produce favorable, albeitsmaller, changes in triglycerides and HDL cholesterol. Withstatin treatment in either the 4S [11], the CARE [12] or HPS[13], the changes in blood lipids and apoproteins were simi-lar for subgroups with and without diabetes.

Today, when factors such as nourishment habits and sed-entary life are taken into account, obesity is a serious healthproblem which threatens life in a growing concern, becauseserious diseases such as hypertension, stroke, DM, dyslipi-demia and atherosclerosis obesity are significant mortalityand morbidity factors [12].

In our study, after a 20 mg tablet 10 weeks pravastatintreatment, an improvement was observed in arterial tensionvalues of the cases of whose majority was stage 1 hyperten-sive at initial visits. Studies on pravastatin demonstrated adecrease in cardiac reactivity against angiotensin II and nore-pinephrine after 10–12 weeks treatment [14]. As a result, animprovement was observed in tension arterial values by prav-astatin treatment. These results are in consistency with ourstudy. In our study, when the post-treatment lipid profiles ofthe patients were evaluated, a decrease was noted in total cho-lesterol, LDL-cholesterol, triglyceride levels while there wasan increase in HDL-cholesterol levels. Thus, pravastatinimproved the lipid levels. Previous studies indicated that prav-astatin provides an improvement in endothelial dysfunctionrelated to its antioxidant effects while providing a statisti-cally significant decrease in lipid levels especially in LDL-cholesterol levels [15]. Studies have demonstrated thatimprovement in lipid profile related to using pravastatin, evenonly the decrease in LDL-cholesterol levels, is efficient forthe development of endothelial-dependent vasodilation[16,17]. These events can be explained by an increase in nitric

Table 1Pre- and post-treatment parameters of our patients. SBP, systolic blood pressure; DBP, diastolic blood pressure; ISI, insulin sensitivity indices; HOMA, Homeos-tasis Model Assessment. All data were expressed as ±SD

Pre-treatment Post-treatment PTotal cholesterol 233.68 ± 20.02 196.32 ± 7.50 <0.0001Triglyceride 181.92 ± 54.04 161.12 ± 46.15 <0.0001HDL-C 45.08 ± 7.93 47.04 ± 7.39 <0.0001LDL-C 152.08 ± 25.06 117.40 ± 10.46 <0.0001SBP 129.88 ± 16.23 122.40 ± 15.08 <0.0001DBP 76.88 ± 14.58 66.80 ± 14.06 <0.0001Basaline insulin 15.98 ± 4.54 8.92 ± 3.23 <0.0001Glucose t1/2 41.10 ± 10.9295 27.452 ± 5.7048 <0.0001ISI 0.3267 ± 7.21E–02 0.3929 ± 0.00642 <0.0001HOMA 4.48 ± 1.47 2.03 ± 0.78 <0.0001Fasting glucose 112.36 ± 8.76 91.52 ± 6.18 <0.0001Postprandial glucose 148.24 ± 7.03 123.04 ± 9.15 <0.0001A1C 5.58 ± 0.44 5.14 ± 0.39 <0.0001

616 F. Güçlü et al. / Biomedicine & Pharmacotherapy 58 (2004) 614–618

oxide release related to the improvement in endothelial func-tion [17]. Animal studies demonstrated an increase in endot-helial NO release following mevastatin usage [18]. It wasshown in similar studies that tissue plasminogen (t-pa), exces-sive PAI-I and endothelial-I secretion were inhibited as wellas an increase in NO secretion due to statin use [19,20].Vasodilation occurs as a result of these mechanisms. This situ-ation explains the antihypertensive efficacy related to the

improvement in lipid profile, as we have found out in ourstudy too. However, what is ideal for proving the antihyper-tensive activity adequately is performing the studies by moni-toring the ambulatory blood pressure. However, as we didnot aim to determine the antihypertensive activity, we did notmonitor the ambulatory blood pressures of the patients.

In our study, a decrease in baseline insulin levels, anincrease in insulin sensitive indices and again a decrease inglucose t1/2 were noted. Significant increases were identi-fied in HOMA, fasting and proglabin blood glucose and A1Cvalues related to the improvement in these parameters. It hasbeen proved in the literature that high blood lipid and lipo-protein levels increase the risk of diabetes [21,22]. There existfew studies on the usage of the drugs that change the bloodlipid profile and have anti-inflammatory effects in metabolicsyndrome [22,23]. It has been long known that an increase inserum triglyceride levels in metabolic syndrome increases therisk of impaired glucose tolerance [22]. In our study, serumtriglyceride levels were found to decrease by pravastatin treat-ment. The decrease noted in fasting glucose, postprandial glu-cose, HOMA,A1C levels could have been caused by the alter-ation in plasma triglyceride levels. However, insulin resistanceon its own cannot be seen as an improving factor. It shouldnot be forgotten that fibric acid derivatives increase the trig-lyceride levels more compared to statins [24]. Another pointto remember in this regard is that there exist a inverse linearcorrelation between HDL-cholesterol and insulin resistancein the previous studies [25]. At the end of 10 weeks, controlsrevealed an increase in HDL-cholesterol levels of the patientsin our study too. Moreover, low degree inflammatory mark-ers (TNF-a, IL-1, IL-6 and CRP) were shown to reflect type2 DM development risk [22]. Inflammatory cytokines secretedby macrophage and T lenfosits modify the endothelial func-tion, smooth muscle cell proliferation, collagen destructionand thrombosis [26,27]. In experimental models, the decreasein cholesterol levels were accompanied by an increase in thenumber of the inflammatory cells in atherosclerotic plaque[28,29]. This incident stops and even regresses the progres-sion of atherosclerosis. Another important point is that statingroup drugs (pravastatin) may play an important role in reduc-ing insulin resistance related to their anti-inflammatory effects.Studies on pravastatin shows that pravastatin reduces the cir-culating interleukine-6 and TNF-a levels [30]. TNF-a andIL-6 have been known to inhibit the lipose activity of lipo-protein and stimulate the liposis in adipose tissue [31,32].TNF-a lymphoid cell, which is a cytokine originates from fatcell and skeletal muscle, is increased in obese cases. TNF-acauses insulin resistance by reducing the insulin signalingand GLUT-4 expression [33]. It is argued that progressionfrom central obesity towards insulin resistance can be inter-rupted by obtaining a decrease in these cytokines via pravas-tatin treatment. In our study, the increase in insulin resistancewhich was obtained by using pravastatin can be attributed tothe inhibition of the above mentioned proinflammatory cytok-ines, even though not measured.

Given all this information, it has been shown in our studythat using statin in dyslipidemia treatment of metabolic syn-

Fig. 1. Differences in ISI (insulin sensitivity index), HOMA-IR (Homeosta-sis Model Assessment-Insulin Resistance) and glucose t1/2 (glucose activa-tion half time), respectively, a, b, c.

617F. Güçlü et al. / Biomedicine & Pharmacotherapy 58 (2004) 614–618

drome cases is a treatment approach having advantageouseffects on insulin resistance. But longer-term clinical studiesshould be performed with larger numbers of patients to deter-mine the effects of statins on the insulin resistance in thepatients with metabolic syndrome.

References

[1] Lakka HM, Laaksonen DE, Lakka TA. The metabolic syndrome andtotal cardiovascular disease mortality in the middle-aged men. JAMA2002;288:2709–16.

[2] Meigs JB. Epidemiology of metabolic syndrome. Am J Manag Care2002;8(Suppl 11):S283–S292.

[3] Reaven GM. Banting lecture 1988: role of insulin resistance in humandisease. Diabetes 1988;37:1595–607.

[4] Legro RS, Castracane D, Kauffman RP. Detecting insulin resistance inpolycistic ovary syndrome: purpose and pitfalls. Obstet Gynecol Surv2004;59:141–51.

[5] Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndromeamong US adults. Findings from Third National Health and NutritionExamination Survey. JAMA 2002;287:356–9.

[6] Hollenbeck C, Reaven GM. Variations in insülin stimulated glucoseuptake in healthy individuals with normal glucose tolerance. J ClinEndocrinol Metab 1987;64:1169–73.

[7] Bell PM. Clinical significance of insulin resistance. Diabet Med1996;13:504–9.

[8] WOSCOPS Study Group. Screening experience and baseline charac-teristics in the West of Scotland Study. Am J Cardiol 1995;76:485–91.

[9] Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concen-tration of low-density lipoprotein cholesterol in plasma, without useof the preparative ultracentrifuge. Clin Chem 1972;18:499–502.

[10] Robins SJ. Cardiovascular disease with diabetes or the metabolicsyndrome: should sitatins or fibrates be first line lipid therapy? CurrOpin Lipidol 2003;14:575–83.

[11] Hafner SM, Alexander CM, Cook TJ. Reduced coronary events insimvastatin-treated improves prognosis of diabetic patients with coro-nary heart disease: a subgroup analysis of Scandinavian SimvastatinSurvival Study (4S). Diabetes Care 1997;20:614–20.

[12] Goldberg RB, Mellies MJ, Sacks FM. Cardiovascular events and theirreduction with pravastatin in diabetic and glucose-intolernt myocar-dial infarction survivors with average cholesterol levels: subgroupanalyses in the Cholesterol and Recurrent Events (CARE) trial. Cir-culation 1998;98:2513–9.

[13] Robins SJ, Targeting LDL. Cholesterol for therapy: lessons from theveterans affairs HDL intervantion trial. Am J Cardiol 2001;88(12A):19N–23N.

[14] Straznicky NE, Howes LG, Lam W, Louis WJ. Effects of pravastatinon cardiovascular reactivity to norepinephrine and angiotensin II inpatients with hypercholesterolemia and systemic hypertension. Am JCardiol 1995;75:582–6.

[15] Anderson TJ, Meredith IT,Yeung AC, Frei B, Selwyn AP, Ganz P. Theeffect of cholesterol-lowering and antioxidant therapy onendothelium-dependent coronary vasomotion. N Engl J Med 1995;332:488–93.

[16] Tamai O, Matsuoka H, Itabe H, WadaY, Kohno K, Imaizumi T. SingleLDL apheresis improves endothelium-dependent vasodilatation inhypercholesterolemic humans. Circulation 1997;95:76–82.

[17] Mital S, Zhang X, Zhao G, Bernstein RD, Smith CJ, Fulton DL, et al.Simvastatin upregulates coronary vascular endothelial nitric oxideproduction in conscious dogs. Am J Physiol Heart Circ Physiol 2000;279:H2649–H2657.

[18] Alvarez De Sotomayor M, Herrera MD, Marhuenda E, Andriantsito-haina R. Characterization of endothelial factors involved in thevasodilatory effect of simvastatin in aorta and small mesenteric arteryof the rat. Br J Pharmacol 2000;131:1179–87.

[19] KureishiY, Luo Z, Shiojima I, Bialik A, Fulton D, Lefer DJ, et al. TheHMG-CoA reductase inhibitor activates the protein kinase Akt andpromotes angiogenesis in normocholesterolemic animals. Nat Med2000;6:1004–10.

[20] Feron O, Dessy C, Desager JP, Balligand JL. Hydroxy-methylglutaryl-coenzyme A reductase inhibition promotes endothe-lial nitric oxide synthase activation through a decrease in caveolinabundance. Circulation 2001;103:113–8.

[21] Reaven GM. Insulin resistance, hyperinsulinemia, hypertriglyceri-demia and hypertension: parallels between human disease and rodentmodels. Diabetes Care 1991;14:195–202.

[22] Schmidt MI, Duncan BB, Sharrett AR, et al. Markers of inflammationand prediction of diabetes mellitus in adults (Atherosclerosis risk incommunities study): a cohort study. Lancet 1999;353:1649–52.

[23] Haffner SM, Stern MP, Hazuda HP, et al. Cardiovasculer risk factorsin confirmed prediabetic individuals. Dose the clock for coronaryheart disease start ticking before the onset of clinical diabetes. JAMA1990;263:2893–8.

[24] Sane T, Knudsen P, Vuorinen-Markkola H, et al. Decreasing triglyc-eride by gemfibrozil therapy does not affect the glucoregulatory orantilipolytic effect of insulin in non-diabetic subjects with mild hyper-triglyceridemia. Metabolism 1995;44:589–96.

[25] Donahue R, Orchard T, Becker D, et al. Physical activity, insulinsensitivity and the lipoprotein profile in young adults. The BeaverCounty Study. Am J Epidemiol 1988;127:95–103.

[26] Vallance P, Collier J, Bhagat K. Inflection, inflammation andinfarction: dose acute endothelial dysfunction provide a link? Lancet1997;349:1391–2.

[27] Neumann FJ, Marx N, Gawaz M, et al. Induction of cytokine expres-sion in leukocytes by binding of thrombin-stimulated platelets. Circu-lation 1997;95:2358–94.

[28] Shiomi M, Ito T, Tsukada T, et al. Reduction of serum cholesterollevels alters lesional composition of atherosclerotic plaques: effect ofpravastatin sodium on atherosclerosis in mature WHHL rabbits. Arte-rioscler Thromb Vase Biol 1995;15:1938–44.

[29] Williams JK, Sukhova GK, Herrington DM, Libby P. Pravastatin hascholesterol-lowering independent effects on the artery wall of athero-sclerotic monkeys. J Am Coll Cardiol 1998;31:684–91.

[30] Rosenson RS, Tangney CC, Casey LC. Inhibition of proinflammatorycytokine production by pravastatin. Lancet 1999;353:983–4.

[31] Kawakami M, Pekala PH, Lane MD, et al. Lipoprotein lipase suppres-sion in 3T3-L1 cells by an endotoxin-induced mediatör from exudatecells. Proc Natl Acad Sci USA 1982;82:912–6.

[32] Hardardottir I, Grünfeld C, Feingold KR. Effects of endotoxin andcytokines on lipid metabolism. Curr Opin Lipidol 1994;5:207–15.

[33] Uysal KT, Wiesbrock SM, Hotamıslıgil GS. Functional analysis oftumor necrosis factor (TNF) receptors in TNF-alfa mediated insulinresistance in genetic obesity. Endocrinology 1998;139(12):4832–7.

618 F. Güçlü et al. / Biomedicine & Pharmacotherapy 58 (2004) 614–618