Higher baseline irisin concentrations are associated with greater reductions in glycemia and insulinemia after weight loss in obese subjects

OPEN Citation: Nutrition & Diabetes (2014) 4, e110; doi:10.1038/nutd.2014.7 & 2014 Macmillan Publishers Limited All rights reserved 2044-4052/14 www.nature.com/nutd SHORT COMMUNICATION Higher baseline irisin concentrations are associated with greater reductions in glycemia and insulinemia after weight loss in obese subjects P Lopez-Legarrea1,2, R de la Iglesia1, AB Crujeiras3,4,5, M Pardo3,4, FF Casanueva4, MA Zulet1,3 and JA Martinez1,3 Irisin is assumed to be a relevant link between muscle and weight maintenance as well as to mediate exercise benefits on health. The aim of this study was to assess the possible associations between irisin levels and glucose homeostasis in obese subjects with metabolic syndrome (MetS) following an energy-restricted treatment. Ninety-six adults with excessive body weight and MetS features underwent a hypocaloric dietary pattern for 8 weeks, within the RESMENA randomized controlled trial (www.clinicaltrials.gov; NCT01087086). After the intervention, dietary restriction significantly reduced body weight and evidenced a dietary-induced decrease in circulating levels of irisin in parallel with improvements on glucose homeostasis markers. Interestingly, participants with higher irisin values at baseline (above the median) showed a greater reduction on glucose (P ¼ 0.022) and insulin (P ¼ 0.021) concentrations as well as on the homeostasis model assessment index (P ¼ 0.008) and triglycerides (P ¼ 0.006) after the dietary intervention, compared with those presenting low-irisin baseline values (below the median). Interestingly, a positive correlation between irisin and carbohydrate intake was found at the end of the experimental period. In conclusion, irisin appears to be involved in glucose metabolism regulation after a dietary-induced weight loss. Nutrition & Diabetes (2014) 4, e110; doi:10.1038/nutd.2014.7; published online 24 February 2014 INTRODUCTION Obesity is a worldwide health burden, accompanied by a number of comorbidities including glucose intolerance, insulin resistance and type 2 diabetes.1 In this context, the myokine irisin,2 which is a cleavage product of the type I membrane protein fibronectin type III domain-containing 5, has been hypothesized as a target to counteract obesity and type 2 diabetes.3,4 Irisin is expressed in the muscle and the adipose tissue and has been associated with adiposity and body weight in animals5,6 and humans.7,8 However, the precise role and underlying mechanisms concerning irisin actions and signaling pathways remain incompletely understood. The aim of this research was to assess changes on circulating irisin concentrations in obese subjects presenting metabolic syndrome (MetS) features after a treatment designed to lose weight and to analyze the potential relationships of this myokine with glucose homeostasis after dieting. MATERIALS AND METHODS Study protocol This research reports the findings of the 8-week intervention period of the RESMENA randomized intervention trial (www.clinicaltrials.gov; NCT01087086), which was conducted following the CONSORT 2010 criteria. A full list of inclusion criteria, as well as a complete description of the study methodology can be found in earlier publications.9,10 Briefly, participants were randomized into two intervention groups, with the same energy restriction (–30% E), but differing mainly in the carbohydrate/ protein ratio and meal frequency: control group supplying 55% E from 1 CHO and 15% E from proteins within a 3–5 meals per day pattern, and RESMENA group providing 40% E from CHO and 30% E from proteins within a 7 meals per day plan. Subjects Ninety-six adults (mean age ¼ 50 years old; range 21–70 years old) with excessive body weight (mean body mass index ¼ 35.9 kg m–2; range 26.9–49.4 kg m–2) suffering MetS according to the International Diabetes Federation criteria completed the intervention period. All the participants gave a written informed consent to participate as approved by the Ethics Committee of the University of Navarra (065/2009) and in accordance with the Declaration of Helsinki. Participant’s dietary intake was assessed by means of 48-h weighed records at baseline and at the end of the intervention and further analyzed using the DIAL software (Alce Ingenieria, Madrid, Spain). Subjects were asked to maintain their usual activity levels during the study, which was monitored at the beginning and endpoint with a validated 24-h physical activity questionnaire.9 Anthropometric measurements and body composition determinations were performed, as described elsewhere.9 Overnight fasting plasma levels of glucose and triglycerides were measured in an autoanalyzer Pentra C-200 (HORIBA ABX, Madrid, Spain) with specific kits from this company. Insulin concentrations were determined with an enzyme-linked immunosorbent assay kit (Mercodia, Uppsala, Sweden) in a Triturus autoanalyzer (Grifols SA, Barcelona, Spain) and the homeostasis model (homeostatic model assessment-insulin resistance (HOMA-IR)) was applied to estimate insulin resistance. Irisin plasma levels were determined using a commercial enzyme-linked immunosorbent assay kit following the manufacturer’s instructions (Irisin ELISA kit EK-067–52; Phoenix Pharmaceuticals, Inc., Burlingame, CA, USA), Department of Nutrition, Food Science and Physiology, University of Navarra, Pamplona, Spain; 2Faculty of Health Science, Universidad Autonoma de Chile, Santiago, Chile; CIBERObn, Carlos III Health Institute, Madrid, Spain; 4Laboratory of Molecular and Cellular Endocrinology, Health Research Institute (IDIS), University of Santiago Hospital Complex (CHUS) and Santiago de Compostela University (USC), Santiago de Compostela, Spain and 5Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain. Correspondence: Professor JA Martinez, Department of Nutrition, Food Science and Physiology, University of Navarra, C/Irunlarrea 1, Pamplona 31008, Spain. E-mail: Received 5 September 2013; revised 4 January 2014; accepted 18 January 2014 3 Irisin and glucose homeostasis P Lopez-Legarrea et al 2 on a spectrophotometric reader at a wavelength of 450 nm (Versamax Microplate Reader, East Falmouth, MA, USA). This test provided a range of detection of 0.066–1024 ng ml–1 and exhibited a coefficient of variation of 6–10% inter- and intra-assay. The samples were kept at  80 1C and were analyzed immediately after the experiment was ended. Statistical analysis The sample size of this secondary analysis was calculated for an a ¼ 0.05 and a power of 80% based on the waist circumference reduction, as described elsewhere.9 Normality distributions of the measured variables were determined according to the Shapiro–Wilk test. Irisin plasma levels were not normally distributed, but based on the sample size (n460) a parametric test was performed. Indeed, after analysis with a log transformation of irisin values the statistical outcomes were maintained. 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