1 SCIENTIFIC REPORTS | (2019) 9:9454 | https://doi.org/10.1038/s41598-019-46006-0 www.nature.com/scientificreports Favorable Changes in Fasting Glucose in a 6-month Self- Monitored Lifestyle Modifcation Programme Inversely Afects Spexin Levels in Females with Prediabetes Nasser M. Al-Daghri 1 , Kaiser Wani 1 , Sobhy M. Yakout 1 , Hazim Al-Hazmi 1 , Osama E. Amer 1 , Syed Danish Hussain 1 , Shaun Sabico 1 , Mohammed Ghouse Ahmed Ansari 1 , Sara Al-Musharaf 2 , Amal M. Alenad 1 , Majed S. Alokail 1 & Mario Clerici 1,3,4 Spexin (SPX) is a novel peptide thought to have a role in various metabolic regulations. Given its presumed body-weight regulatory functions, we aimed to determine whether lifestyle intervention programs on weight loss and fasting glucose (FG) improvement among people with impaired glucose regulation also alter levels of circulating SPX. A total of 160 Saudi adult males and females with prediabetes were randomly selected from a larger cohort (N = 294) who underwent a 6-month lifestyle modifcation program to improve their glycemic status. Participants were split into two groups based on diferences in glucose levels post-intervention, with the frst 50% (improved group) having the most signifcant reduction in FG. SPX was measured at baseline and after 6 months. Changes in SPX was signifcant only in the improved group [baseline: median (Q1–Q3) of 164 pg/ml (136–227) vs follow-up: 176 pg/ml (146–285); p < 0.01]. When stratifed by sex, the signifcant increase was observed only in females [159 pg/ml (127–252) vs 182.5 (152,369.1); p < 0.01]. Furthermore, SPX levels showed a signifcant inverse association with FG (β = -0.22, p = 0.003) even after adjustment with age and BMI, again only in females. Circulating SPX levels increase over time in people with prediabetes, particularly women who responded favorably in a 6-month lifestyle intervention program. Whether an unknown mechanism regulating the sexual disparity seen in SPX levels post-intervention exists should be further investigated using a larger sample size. Spexin (SPX) is a newly identifed neuropeptide with emerging roles in many metabolic processes such as sati- ety, pubertal growth and reproduction 1,2 . Discovered through bioinformatics approach using Markov model screening 3 , SPX consists of 14 amino acids and belongs to spexin/galanin/kisspeptin gene family 4 . SPX is widely expressed in a number of rat tissues such as liver, testis, ovary, adrenal gland, etc., making it a promising bio- marker in pathological disorders such as the metabolic syndrome, diabetes and others 5 . SPX studies in animal models like fsh and rodents revealed its role in various metabolic regulations. In 2014, Walewski et. al. showed that SPX regulates satiety in mice, possibly by inhibiting the uptake of long chain fatty acids into hepatocytes and adipocytes, resulting in weight loss 6 . Similar results confrmed the role of SPX as a regulator of fatty acid uptake in adipocytes and hepatocytes in fsh 7 and mice models 8 , respectively. Teir results 1 Chair for Biomarkers of Chronic Diseases, Department of Biochemistry, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia. 2 College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia. 3 Department of Physiopathology and Transplantation, University of Milan, via F.lli Cervi 93, Segrate, 20090, Milan, Italy. 4 IRCCS Fondazione Don Carlo Gnocchi ONLUS, Milan, 20148, Italy. Correspondence and requests for materials should be addressed to N.M.A.-D. (email: aldaghri2011@gmail.com) Received: 21 January 2019 Accepted: 21 June 2019 Published: xx xx xxxx OPEN