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Serbian Journal of Management 7 (2) (2012) Serbian Journal of Management NEW MEMBERS OF EDITORIAL BOARD Mladen Velev Faculty of Management Technical University of Sofia 8, St. Kl. Ohridski Blvd bl. 3, office 3237 tel.:(+359 2) 965 2994 fax: (+359 2) 868 5284 Prof. Dr. Mladen Velev is Dean of Faculty of Management, Technical University of Sofia, Bulgaria. He gained a PhD degree in 1989 and was awarded the title of Associate Professor in the scientific field of “Economics and Management” in 199. In 2006 he was granted the title of Full Professor in the scientific field of “Organization and Management of Production”. He teaches the subjects of “Marketing”, “Management of Marketing”, “Marketing Communications”, “Economics of the Enterprise” and others. He has been on specialization courses in England, Wales, Belgium, Germany, France, USA, Russia, Ukraine and other countries. From 2001 to 2011 he was Head of the Department of “Economics, Industrial Engineering and Management” at the Faculty of Management and since 2011 he has been the Dean of the Faculty of Management at the Technical University. He has participated in a great number of scientific research projects, both national and international, in the field of marketing, management and economics of the enterprise. He has also taken part in a number of international educational projects. He has been involved in consultancy work. He has more than 150 scientific publications, which include 17 textbooks and 10 monographs. He is the Editor-in-Chief of the scientific journal of “Industrial Management” published by the Faculty of Management. He is the Chair of the Bulgarian Association of Lecturers in Economics and Management in Industry. active. HIV-infected patients displayed a redistribution of body fat as the percentage of fat on the limb were lower and the percentage of fat in the trunk was higher compared to control subjects. The patients also had disturbances in their lipid metabolism as fasting triglycerides and total-cholesterol levels were higher, and HDL-cholesterol level was lower. In addition, compared to controls, the HIV-infected patients were characterized by peripheral insulin resistance as whole-body insulin-stimulated glucose uptake (Rd) and incremental glucose uptake (Rd basal – Rd clamp) were decreased. Furthermore, the HIV subjects had higher basal endogenous glucose production, lower insulin-mediated suppression of endogenous glucose production (Ra), but no difference in the incremental suppression of endogenous glucose production during the clamp (Ra basal – Ra clamp) as compared to control subjects. Plasma FGF-21 and FGF-21mRNA in muscle Plasma FGF-21 was elevated in the HIV-group compared to healthy controls (70.4656.8 pg/ml vs 109.1671.8 pg/ml, respectively) (P = 0.04) (Figure 1A). FGF-21 mRNA expression in skeletal muscle was increased 8fold in patients with HIV relative to healthy individuals (P,0.0001, parametric statistics, and p = 0.0002 for non-para- metric statistics) (Figure 1B). The association between plasma FGF-21 and muscle FGF-21 did not reach statistical significance (r = 0.32; p = 0.056). Relationships between FGF-21 mRNA, plasma FGF-21 and insulin resistance Muscle FGF-21 mRNA correlated positively to all markers of insulin resistance: fasting insulin (r = 0.57, p = 0.0008), homeostasis model assessment (HOMA) score (r = 0.55, p = 0.001), and insulinAUC (r = 0.38, p = 0.02) (Fig. 1 C–F). To test whether the association between insulin and FGF-21 mRNA in muscle reflect an association with peripheral or hepatic insulin resistance, we performed a euglycemic-hyperinsulinemic clamp with stable isotopes. We found that muscle FGF-21 mRNA was negatively associated with the insulin-mediated glucose-uptake (Figure 1G), but not with hepatic insulin resistance (data not shown). We did not find any association between plasma FGF-21 and parameters of insulin resistance (fasting insulin, plasma glucose, HOMA-IR, glucose AUC, Insulin AUC, Ra or Rd). However, when investigating by group, plasma FGF-21 correlated positive with insulin stimulated glucose-uptake in healthy subjects but not in the HIV patients (r = 0.51, p = 0.049) (data not shown). Previous studies have demonstrated that insulin resistance in patients with HIV-LD are associated with decreased insulinstimulated glycogen synthase (GS) activity [24]. Therefore, we measured GS activity. The GS fractional velocity of % total GS activity was lower in HIV patients compared with healthy controls (2861.3; 3561.6, respectively) in the basal stage. GS fractional velocity is known to correlate positively with the glucose Rd [25]. As high FGF-21 mRNA in muscle is associated with low rate of disappearance of glucose, this could be linked to low GS fractional velocity in muscle. In accordance with this hypothesis, we found that high levels of FGF-21 mRNA in muscle were associated with decreased GS fractional velocity in muscle (Fig. 1H). Relationships between muscle FGF-21 mRNA, and fat distribution and lipids We found a strong negative association between muscle FGF-21 mRNA and the amount of subcutaneous fat (limb fat mass) (r = 20.46; p = 0.0038) and positive association with trunk-limbfat-ratio (r = 0.51; p = 0.001) and triglycerides (r = 0.56; p = 0.0003). FGF-21 mRNA was not associated with total fat mass or total trunk fat (data not shown). Discussion The novelty and the major findings of our study is that we demonstrate for the first time that FGF-21 mRNA expression is increased in skeletal muscle in patients with HIV-LD compared to healthy age-matched men and that muscle FGF-21 mRNA correlates negatively with the rate of insulin-stimulated glucose disappearance (primarily reflecting muscle). Furthermore, increased FGF-21 mRNA expression in muscle is associated with decreased limb fat mass, increased waist-to-hip ratio and increased triglycerides. Only three studies are published on expression of FGF-21 in muscle in humans [10,12,26] and very little is known about the function of muscle FGF-21. Our result is in agreement with a previous study, in which FGF-21 mRNA was found to be increased in muscle from subjects with type 2 diabetes and the expression was increased by hyperinsulinemia [10]. However, this study did not distinguish between hepatic and peripheral insulin sensitivity as we do in the present study. Vienberg et al. [12] also PLOS ONE | 3 March 2013 | Volume 8 | Issue 3 | e55632 Muscle FGF-21,Insulin Resistance and Lipodystrophy Table 1. Baseline characteristics of patients and healthy controls. Age (years) Duration of HIV infection (years) Duration of antiretroviral therapy (years) CD4+ cell (cells/ml) LogHIV-RNA (copies/ml) Antiretroviral use NNRTI-based HAART, PI-based HAART, NNRTI-,PI-based HAART regime, No. Current Thymidine-NRTI use, No. (%) Current PI use, No. (%) Current NNRTI use, No. (%) Physical activity parameters VO2max (LO2/min) Body composition Body-mass index (kg/m2) Weight (kg) Waist (cm) Waist-to.hip ratio Fat mass (kg) Trunk fat mass (kg) Trunk fat percentage (%) Limb fat mass (kg) Limb fat percentage (%) Trunk-to-limb fat ratio Lean mass (kg) Metabolic parameters Total-cholesterol (mmol/L) HDL-C (mmol/L) LDL-C (mmol/L) Triglycerides (mmol/L) Glucose (mmol/L) Insulin (pmol/L) HOMA-IR Insulin sensitivity Rate of appearance (mmol glucose/kg/min) Basal Clamp Delta{ Rate of disappearance (mmol glucose/kg/min) Basal Clamp Delta{ Glucose tolerance Glucose area under the curve (mmol/Lmin) Insulin area under the curve (pmol/Lmin) HIV patients (n = 23) 47.9 (9.5) 15.6 (9.6) 10.3 (4.3) 558 (208) 1.33 (0.12) 12/14/2 11 (47.8) 13 (56.7) 11 (47.8) 2.3 (0.5) 23.7 (2.9) 73.6 (11.2) 93.6 (6.4) 1.01 (0.04) 13.8 (5.3) 9.8 (3.9) 71.2 (6.2) **** 3.5 (1.6)**** 25.1 (6.1) **** 3.09 (1.17)* 57.0 (6.8) 5.5 (0.9)** 1.23 (0.52)* 3.7 (0.9) 2.55(1.43)**** 5.4 (0.6) 52 (25)**** 2.2 (1.4)**** 14.2 (0.49)*** 6.4 (1.8)** 7.8 (2.1) 14.2 (0.49)*** 40.2 (9.9)** 26.02 (10.1)** 826 (200)* 52360 (31017)** Healthy controls (n = 15) 47.5 (6.1) 2.5 (0.6) 23.7 (1.9) 76.9 (7.4) 90 (5.7) 0.94 (0.03) 15.7 (4.4) 8.9 (3.0) 56.1(5.2) 6.2 (1.5) 40.2 (4.9) 1.4 (0.29) 58.2 (5.2) 4.63 (0.64) 1.51 (0.32) 3.3 (0.6) 0.76 (0.24) 5.2 (0.3) 25 (8.9) 0.99 (0.37) 11.8 (2.0) 4.0 (2.5) 7.8 (1.9) 11.8 (2.0) 48.6 (8.4) 36.81 (7.14) 670 (126) 23505 (10598) Data are presented as mean (SD). {Delta, differences between clamp and basal values. HAART, highly active antiretroviral therapy; PI, protease inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non- nucleoside reverse transcriptase inhibitor. HOMA-IR, homeostatic model assessment for insulin resistance, Rate of appearance and disappearance, Rate of appearance and disappearance of glucose during a euglycemic-hyperinsulinemic clamp performed in both HIV patients and healthy controls. *P,0.05; **P,0.01; ***P,0.001, ****P,0.0001 by t-test. doi:10.1371/journal.pone.0055632.t001 PLOS ONE | 4 March 2013 | Volume 8 | Issue 3 | e55632 Muscle FGF-21,Insulin Resistance and Lipodystrophy Figure 1. FGF-21 mRNA are increased in muscle from subjects with HIV-lipodystrophy and correlates to several measurement of insulin resistance. (A) Fasting plasma levels of fibroblast growth factor (FGF) 21 are increased 2-fold in HIV subjects with lipodystrophy compared to healthy men; (B) mRNA expression of FGF-21 are increased 8-fold in muscle biopsies from HIV subjects with lipodystrophy compared to healthy men; (C–F) Plots of FGF-21 mRNA in muscle versus several measurements of insulin resistance: FGF-21 mRNA in muscle are positively correlated to fasting insulin (C), HOMA-IR (D), Area under the curve for insulin during an oral glucose tolerance test (E), Area under the curve for C-peptide during Nan oral glucose tolerance test (F), and negatively correlated to the incremental rate of disappearance of glucose (G), and fractionel velocity of glycogen synthesis (H) in healthy (e) and HIV subjects with lipodystrophy ( ). In the dot plots data for each subjects are given and the line represent means. * P,0.05 and ***P,0.001 for healthy vs HIV-lipodystrophy patients. For plots, linear regression lines, correlations coefficient, and significance levels are given for all subjects. doi:10.1371/journal.pone.0055632.g001 PLOS ONE | 5 March 2013 | Volume 8 | Issue 3 | e55632 Muscle FGF-21,Insulin Resistance and Lipodystrophy find that FGF-21 mRNA was expressed in muscle, but they find no activation of muscle FGF-21 mRNA by a short term high fat overfeeding. In the study by Mashili et al. [26], FGF-21 mRNA was expressed in skeletal muscle, but in the aquatic environment for long-term survival and for transmission to arthropod and mammalian hosts. References 1. Ray K, Marteyn B, Sansonetti PJ, Tang CM. Life on the inside: the intracellular lifestyle of cytosolic bacteria. Nature reviews. 2009; 7(5):333–40. doi: 10.1038/nrmicro2112 PMID: 19369949 2. Kingry LC, Petersen JM. Comparative review of Francisella tularensis and Francisella novicida. Frontiers in cellular and infection microbiology. 2014; 4:35. doi: 10.3389/fcimb.2014.00035 PMID: 24660164 3. 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