Altered Interleukin-10 Signaling in Skeletal Muscle Regulates Obesity-Mediated Inflammation and Insulin Resistance

Dagdeviren, Sezin,Jung, Dae Young,Lee, Eunjung,Friedline, Randall H.,Noh, Hye Lim,Kim, Jong Hun,Patel, Payal R.,Tsitsilianos, Nicholas,Tsitsilianos, Andrew V.,Tran, Duy A.,Tsougranis, George H.,Kearns American Society for Microbiology 2016 Molecular and cellular biology Vol.36 No.23

<P>Skeletal muscle insulin resistance is a major characteristic of obesity and type 2 diabetes. Although obesity-mediated inflammation is causally associated with insulin resistance, the underlying mechanism is unclear. Here, we examined the effects of chronic obesity in mice with muscle-specific overexpression of interleukin-10 (M-IL10). After 16 weeks of a high-fat diet (HFD), M-IL10 mice became markedly obese but showed improved insulin action compared to that of wild-type mice, which was largely due to increased glucose metabolism and reduced inflammation in skeletal muscle. Since leptin regulates inflammation, the beneficial effects of interleukin-10 (IL-10) were further examined in leptin-deficient ob/ob mice. Muscle-specific overexpression of IL-10 in ob/ob mice (MCK-IL10(ob/ob)) did not affect spontaneous obesity, but MCK-IL10(ob/ob) mice showed increased glucose turnover compared to that in ob/ob mice. Last, mice with muscle-specific ablation of IL-10 receptor (M-IL10R(-/-)) were generated to determine whether IL-10 signaling in skeletal muscle is involved in IL-10 effects on glucose metabolism. After an HFD, M-IL10R(-/-) mice developed insulin resistance with reduced glucose metabolism compared to that in wild-type mice. Overall, these results demonstrate IL-10 effects to attenuate obesity-mediated inflammation and improve insulin sensitivity in skeletal muscle, and our findings implicate a potential therapeutic role of anti-inflammatory cytokines in treating insulin resistance and type 2 diabetes.</P>

IL-10 prevents aging-associated inflammation and insulin resistance in skeletal muscle

Dagdeviren, Sezin,Jung, Dae Young,Friedline, Randall H.,Noh, Hye Lim,Kim, Jong Hun,Patel, Payal R.,Tsitsilianos, Nicholas,Inashima, Kunikazu,Tran, Duy A.,Hu, Xiaodi,Loubato, Marilia M.,Craige, Siobhan The Federation of American Societies for Experimen 2017 The FASEB Journal Vol.31 No.2

<P>Altered energy balance and insulin resistance are important characteristics of aging. Skeletal muscle is a major site of glucose disposal, and the role of aging-associated inflammation in skeletal muscle insulin resistance remains unclear. To investigate, we examined glucose metabolism in 18-mo-old transgenic mice with muscle-specific overexpression of IL-10 (M-IL10) and in wild-type mice during hyperinsulinemic-euglycemic clamping. Despite similar fat mass and energy balance, M-IL10 mice were protected from aging-associated insulin resistance with significant increases in glucose infusion rates, whole-body glucose turnover, and skeletal muscle glucose uptake (similar to 60%; P < 0.05), as compared to age-matched WT mice. This protective effect was associated with decreased muscle inflammation, but no changes in adipose tissue inflammation in aging M-IL10 mice. These results demonstrate the importance of skeletal muscle inflammation in aging-mediated insulin resistance, and our findings further implicate a potential therapeutic role of anti-inflammatory cytokine in the treatment of aging-mediated insulin resistance.</P>

Shear stresses below the rectangular foundations subjected to biaxial bending

Dagdeviren, Ugur Techno-Press 2016 Geomechanics & engineering Vol.10 No.2

Soils are subjected to additional stresses due to the loads transferred by the foundations of the buildings. The distribution of stress in soil has great importance in geotechnical engineering projects such as stress, settlement and liquefaction analyses. The purpose of this study is to examine the shear stresses on horizontal plane below the rectangular foundations subjected to biaxial bending on an elastic soil. In this study, closed-form analytical solutions for shear stresses in x and y directions were obtained from Boussinesq's stress equations. The expressions of analytical solutions were simplified by defining the shear stress influence values ($I_1$, $I_2$, $I_3$), and solution charts were presented for obtaining these values. For some special loading conditions, the expressions for shear stresses in the soil below the corners of a rectangular foundation were also given. In addition, a computer program was developed to calculate the shear stress increment at any point below the rectangular foundations. A numerical example for illustrating the use of the presented solution charts was given and, finally, shear stress isobars were obtained for the same example by a developed computer program. The shear stress expressions obtained in this work can be used to determine monotonic and cyclic behavior of soils below rectangular foundations subjected to biaxial bending.

An Evaluation of Patient Satisfaction in Turkey with the EUROPEP Instrument

Nezih Dagdeviren,Zekeriya Akturk 연세대학교의과대학 2004 Yonsei medical journal Vol.45 No.1

Seeking to understand patient perspectives is an important step in the efforts to improve the quality of health care. Developed by the EQuiP Task Force on Patient Evaluations of General Practice Care, the EUROPEP instrument aims to collect information on patient evaluations of general practice care. In order to expose the current state of patient satisfaction and make international comparisons, a study was conducted with relevant data collected from Turkey. The Turkish version of the EUROPEP instrument was administered to 1160 patients in six different Turkish cities. Thirty-three medical practices were included in the study. In every practice, a minimum of 30 adult patients who visited the practice for a consultation were consecutively included. The results were compared with previous values from European countries. “Helping you understand the importance of following his or her advice”, “Getting through to the practice on the telephone”, and “Providing quick services for urgent health problems” were evaluated best (76.7%, 76.3%, and 76.2%, ‘good or excellent’ ratings, respectively) and “Helping to deal with emotional problems related to the health status” was rated the worst (60.2%, ‘good or excellent’). Other areas which had low ratings were: “Waiting time in the waiting room” (63.0%), “Quick relief of symptoms” (61.3%), and “Involving patients in decisions about medical care” (61.3%). Patient evaluations can help to educate medical staff about their achievements as well as their failures, assisting them to be more responsive to their patients' needs. In order to get the best benefit from EUROPEP, national benchmarking should be started to enable national and international comparisons.

Thin Film Receiver Materials for Deterministic Assembly by Transfer Printing

Kim, Tae-il,Kim, Mo Joon,Jung, Yei Hwan,Jang, Hyejin,Dagdeviren, Canan,Pao, Hsuan An,Cho, Sang June,Carlson, Andrew,Yu, Ki Jun,Ameen, Abid,Chung, Hyun-joong,Jin, Sung Hun,Ma, Zhenqiang,Rogers, John A. American Chemical Society 2014 Chemistry of materials Vol.26 No.11

<P>We present a specially designed materials chemistry that provides ultrathin adhesive layers with persistent tacky surfaces in solid, nonflowable forms for use in transfer printing and related approaches to materials and micro/nanostructure assembly. The material can be photocured after assembly, to yield a robust and highly transparent coating that is also thermally and electrically stable, for applications in electronics, optoelectronics, and other areas of interest.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/cmatex/2014/cmatex.2014.26.issue-11/cm501002b/production/images/medium/cm-2014-01002b_0007.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/cm501002b'>ACS Electronic Supporting Info</A></P>

Genetic ablation of lymphocytes and cytokine signaling in nonobese diabetic mice prevents diet-induced obesity and insulin resistance

Friedline, Randall H.,Ko, Hwi Jin,Jung, Dae Young,Lee, Yongjin,Bortell, Rita,Dagdeviren, Sezin,Patel, Payal R.,Hu, Xiaodi,Inashima, Kunikazu,Kearns, Caitlyn,Tsitsilianos, Nicholas,Shafiq, Umber,Shultz The Federation of American Societies for Experimen 2016 The FASEB Journal Vol.30 No.3

<P>Obesity is characterized by a dysregulated immune system, which may causally associate with insulin resistance and type 2 diabetes. Despite widespread use of nonobese diabetic (NOD) mice, NOD with severe combined immunodeficiency (scid) mutation (SCID) mice, and SCID bearing a null mutation in the IL-2 common chain receptor (NSG) mice as animal models of human diseases including type 1 diabetes, the underlying metabolic effects of a genetically altered immune system are poorly understood. For this, we performed a comprehensive metabolic characterization of these mice fed chow or after 6 wk of a high-fat diet. We found that NOD mice had similar to 50% less fat mass and were 2-fold more insulin sensitive, as measured by hyperinsulinemic-euglycemic clamp, than C57BL/6 wild-type mice. SCID mice were also more insulin sensitive with increased muscle glucose metabolism and resistant to diet-induced obesity due to increased energy expenditure (similar to 10%) and physical activity (similar to 40%) as measured by metabolic cages. NSG mice were completely protected from diet-induced obesity and insulin resistance with significant increases in glucose metabolism in peripheral organs. Our findings demonstrate an important role of genetic background, lymphocytes, and cytokine signaling in diet-induced obesity and insulin resistance.</P>

Endoplasmic reticulum chaperone GRP78 regulates macrophage function and insulin resistance in diet‐induced obesity

Kim, Jong Hun,Lee, Eunjung,Friedline, Randall H.,Suk, Sujin,Jung, Dae Young,Dagdeviren, Sezin,Hu, Xiaodi,Inashima, Kunikazu,Noh, Hye Lim,Kwon, Jung Yeon,Nambu, Aya,Huh, Jun R.,Han, Myoung Sook,Davis, Federation of American Society for Experimental Bi 2018 The FASEB Journal Vol.32 No.4

<P>Obesity-mediated inflammation is a major cause of insulin resistance, and macrophages play an important role in this process. The 78-kDa glucose-regulated protein (GRP78) is a major endoplasmic reticulum chaperone that modulates unfolded protein response (UPR), and mice with GRP78 heterozygosity were resistant to diet-induced obesity. Here, we show that mice with macrophage-selective ablation of GRP78 (Lyz-GRP78(-/-)) are protected from skeletal muscle insulin resistance without changes in obesity compared with wild-type mice after 9 wk of high-fat diet. GRP78-deficient macrophages demonstrated adapted UPR with up-regulation of activating transcription factor (ATF)-4 and M2-polarization markers. Diet-induced adipose tissue inflammation was reduced, and bone marrow-derived macrophages from Lyz-GRP78(-/-) mice demonstrated a selective increase in IL-6 expression. Serum IL-13 levels were elevated by >4-fold in Lyz-GRP78(-/-) mice, and IL-6 stimulated the myocyte expression of IL-13 and IL-13 receptor. Lastly, recombinant IL-13 acutely increased glucose metabolism in Lyz-GRP78(-/-) mice. Taken together, our data indicate that GRP78 deficiency activates UPR by increasing ATF-4, and promotes M2-polarization of macrophages with a selective increase in IL-6 secretion. Macrophage-derived IL-6 stimulates the myocyte expression of IL-13 and regulates muscle glucose metabolism in a paracrine manner. Thus, our findings identify a novel crosstalk between macrophages and skeletal muscle in the modulation of obesity-mediated insulin resistance.</P>