Table 1.

Characteristics of the included human studies

Author Year, (Reference)	Participants and number	Study design	aim	Main Outcomes
Karaca et al. 2018 [11]	29 type 1 and 30 type 2 diabetic patients and a control group of 23 healthy subjects	cross-sectional study	to measure levels of spexin in lean type 1 diabetic patients and its relevance to glycemic parameters without the presence of obesity or insulin resistance	spexin levels: - significantly lower in patients with diabetes than in control subjects - not correlated with glycemic parameters, lipids, BMI, cortisol levels and thyroid stimulating hormone - no association between age and spexin levels in Regression models - no association with spexin levels within each group in Regression models including cortisol, BMI, HbA1c
Lin et al. 2018 [30]	68 healthy adult women aged are in a wide range (minimum: 23; median: 38.5; maximum: 64	cross-sectional study	the relationship between circulating spexin levels and age and to study their interaction effects on body mass index (BMI), fasting glucose, and -lipids	Serum spexin levels: - significantly correlated with age, BMI, fasting glucose and TG - independently predict the risk of high BMI and high fasting glucose - No interaction effects of spexin and age on BMI and fasting glucose
Lin et al. 2018 [30]	91 healthy adults)age of 18–65 years(	Cross sectional	Association between spexin and bile acid metabolism.	serum spexin: - negatively correlated with TBA and TC levels,serum levels of GCDCA or TCDCA
Al-Daghi et al. 2018 [12]	102 Saudi pregnant women (63 non-GDM and 39 GDM	prospective study	to determine whether circulating spexin (SPX) is modified during the course of pregnancy and whether it is affected by the presence of glucose intolerance, i.e., Gestational Diabetes Mellitus (GDM)	In GDM patients, SPX levels: - increased significantly after 6-months, in parallel with a borderline significant increase in glucose In non-GDM patients SPX levels: - decreased from baseline to 6-months and this change was not associated with changes in glucose levels. Change in glucose from baseline to 6-months was positively associated with change in SPX in GDM patients only
Al-Daghri et al. 2018 [12]	124 participants (41 males and 83 females; aged 42.4 ± 10.3 y) (MetS group) and 136 (21 male and 115 females; aged 33.1 ± 8.7 y) (non-MetS group)	cross-sectional study	to determine whether circulating levels of spexin (SPX) is associated with components of metabolic syndrome (MetS)	SPX levels - significantly lower in participants with MetSvs. non-MetS - associated with MetS only in women with Stratification according to sex. - this significance was lost after adjustment for age and BMI
Al-Daghri et al. 2018 [12]	N = 117 (n = 63 women with gestational diabetes mellitus (GDM) N = 54 without GDM)	Cross-sectional study.	Relationship between sepxin and glucose hemostasis, lipid profile and inflammatory factors in GDM	levels of SPX: - not significantly different in pregnant women with and without GDM. - positive associations with total cholesterol, LDL-cholesterol, 25(OH)D, and IL1b. - modest associations with glucose and HOMA in all subjects
Kumar et al. 2018 [9]	(12 girls with severe obesity; age = 16.7 ± 1.5 years; BMI = 51.6 ± 2.9 kg/m 2).	Longitudinal study	effect of Roux-en-Y gastric bypass (RYGB) surgery on endogenous spexin concentration and various risk factors of type 2 diabetes and cardiovascular disease in youth with severe obesity.	Serum spexin - increased at 6 months after surgery and stabilized afterward - correlated negatively with: homeostatic model assessment insulin resistance, HOMA - correlated positively with: high molecular weight adiponectin. - The change in spexin, from baseline to 6 months after surgery, inversely correlated with: the corresponding change in BMI - the 6-month changes in spexin and HOMA-IR, inversely correlated even after adjusting for the change in BMI
Kolodziejski et al. 2018 [8]	healthy female (n = 15, meanBMI 22.50 ± 0.58) and obese patients (n = 15, mean BMI 40.23 ± 1.31)	cross-sectional study	Relationship between sepxin and KISS with obesity and glucose hemostasis	Serum spexin and KISS - significantly lower in obese patients compared to non-obese. - SPX negatively correlated with:BMI, HOMA-IR, insulin, glucagon,active ghrelin and leptin - positively correlated with: serum levels of obestatin, GLP-1 and adiponectin and orexin-A
Kumar et al. 2018 [9]	N = 19 adolescents with obesity Mean ages = 15.8 ± 1.7 years)	Cross-sectional study	Relationship between sepxin and adiposity and inflammatory hormones	Spexin inversely related with leptin. the odds of having ‘low spexin and high leptin’ in participants with higher hs-CRP (≥ 3 mg/L) were 12.25 times higher than those of participants with lowerhs-CRP (<3 mg/L).
Hodges et al. 2017 [16]	12healthy normal weight and 10 obese adolescents mean age = 16 years 12obese with T2DM	Cross sectional	Relationship between spexin and obesity	Spexin was not significantly correlated with any of the body composition, fitness, or blood biochemical measurements
Kumar et al. 2016 [6]	51 obese and18 normal weight; Mean age = 15.3 ± 0.26. N = 69	cross-sectional study	Relationship between sepxin and weight and cardio-metabolic hormones	Spexin levels: - were significantly lower in obese vs normal-weight children, - not correlate with other adipokines and/or insulin and glucose levels.
Gu et al. 2015 [14]	121 subjects with T2DM and 105 healthy individuals 12 healthy volunteers (aged: 52.8 ± 9.2 years with BMI: 23.3 ± 1.8 kg/m2) including 5 males and 7 females	Cross sectional	to examine circulating spexin levels after glucose load in T2DM patients.	- Serum spexin level: significantly lower inT2DM - significant negative correlation: between spexin and FBG, HbA1c, TG and LDL-C - During the OGTT: - negative correlation of blood glucose with spexin - spexin exhibited a progressive and significant decrease from time 0 to 60 min and returned gradually to the basal values at 180 min

- Abbreviation: TBA: total bile acid, GCDCA:glycocheno-deoxycholate, TCDCA:tauro-chenodeoxycholate, SPX: spexin, GDM: Gestational diabetes mellitus, MetS:Metabolic syndrome, KISS:kisspeptin, HOMA-IR: Homeostatic Model Assessment of Insulin Resistance, OGTT:oral glucose tolerance test