1 Introduction

Obesity and diabetes are both multifactorial global epidemics of significant concern and are associated with several macro-and microvascular health disorders, including type 2 diabetes mellitus (T2DM), dyslipidemia, hypertension, and increased visceral adiposity (Han et al., 2017). The unhealthy changes in lifestyle patterns and dietary shifts to highly processed foods in industrialized countries have led to a significant increase in the incidence of obesity which poses a significant public health burden (Hruby and Hu, 2015). Excessive accumulation of adipose tissue in morbid obesity compromises the balance of pro-and anti-inflammatory adipokines secretion, leading to hyperinsulinemia, insulin resistance, and other obesity-related disorders (Czech, 2017).

Insulin resistance (IR) is characterized by decreased glucose absorption in the body to physiologically available insulin levels and can potentiate an array of glucose metabolic and cardiovascular disorders such as impaired glucose tolerance, impaired fasting glucose, and T2DM in both children and adults (Di Pino and Defronzo, 2019).

Asprosin is a centrally acting orexigenic novel hormone recently discovered through neonatal progeroid syndrome, commonly expressed in mature white adipose tissues (Romere et al., 2016). There is a growing interest in asprosin, as recent studies have reported the asprosin influence and regulation on the central nervous system and various other organs. It showed a significant effect on the different signaling pathways of these organs and showed an impact on glucose homeostasis, IR, satiety, and β-cells apoptosis (Duerrschmid et al., 2017; Jung et al., 2019; Lee et al., 2019; Zhang et al., 2019a; Zhang et al., 2019b).

Fibrillin 1 gene (FBN1)-encoded, fasting-induced asprosin targets the liver and facilitates the release of hepatic glucose via the G protein-cAMP-PKA pathway leads to elevated plasma glucose and insulin levels (Duerrschmid et al., 2017; Greenhill, 2016; Romere et al., 2016). During fasting, adipose tissues secrete asprosin, which is recruited to the liver and induces hepatic glucose release into the bloodstream to support and sustain the brain and other organs. Serum asprosin levels rise and decrease acutely with refeeding, indicating circadian rhythm with the dietary state (Duerrschmid et al., 2017; Romere et al., 2016). While much of the clinical and preclinical studies on asprosin revolved around obesity and obesity-related diseases, it is important to acknowledge that asprosin has multifunctional pleiotropic actions, similar to other adipokines since its receptors are located in other tissues such as hepatic, renal, muscle and reproductive tissues (Mazur-Bialy, 2020; Shabir et al., 2021). Furthermore, more studies are needed coming from understudied populations to determine whether the observed actions and associations of asprosin with cardiometabolic indices are consistent, or affected by other variables such as ethnicity.

Hence, the rationale of the current study was to assess serum circulatory asprosin levels and identify the association between serum asprosin levels with IR in addition to other serological parameters in a homogenous Arab population with varying degrees of adiposity and IR.

2 Materials and Methods

3 Results

General clinical and anthropometric characteristics of the participant were illustrated in Table 1. The T2DM/obese group was significantly older than the control and obese groups (p < 0.001). The mean BMI of the control group was significantly lower than that of the T2DM/obese and obese groups (p < 0.001). As expected, the metabolic profile of the T2DM/obese group was significantly worse as compared to the controls and the obese group (Table 1). In the T2DM/obese group, medications were recorded only in 48 (46%) participants, the majority of whom were either on metformin alone or in combination with other T2DM meds.

Table 2 shows the bivariate associations of asprosin with other serological parameters. In all subjects, serum asprosin levels showed a significant positive correlation with BMI (r = 0.22, p < 0.01), whereas with glucose it was inversely associated (r = -0.37, p < 0.01). Furthermore, it was positively associated with adiponectin and resistin in control and T2DM/obese groups (r = 0.33, p < 0.01 and r = 0.56, p < 0.01), (r = 0.46, p < 0.01, r = 0.42, p < 0.01). Serum asprosin levels in obese subjects did not correlate with TG, adiponectin, resistin, IL6, leptin, TNF-α, glucose-insulin, and HOMA-IR. In contrast, a positive correlation was observed between control and T2DM/obese groups (r = -0.37, p < 0.01, r = -0.18, p < 0.01 and r = -0.25, p < 0.01).

As shown in Table 3, the serum levels of asprosin were positively correlated with BMI, adiponectin, and resistin in females (r = 0.23, p < 0.01). A significant inverse correlation between glucose (r = -0.40, p < 0.001), insulin (r = -0.22, p < 0.01) and HOMA-IR (r = -0.28, p < 0.01) were observed. The rest of the parameters were not associated with asprosin. In males, there was a significant positive correlation between adiponectin and resistin with levels of asprosin (r = 0.39, p < 0.01), (r = 0.46, p < 0.01). Both glucose and HOMA-IR showed a significant inverse correlation with asprosin concentrations and no significant correlation with BMI, lipid profile, and leptin.

As intake of oral hypoglycemics was available in 46% of participants in the T2DM/obese group, differences in circulating asprosin levels among those on metformin and those whose medications were unknown were compared in a sub-analysis (Fig. 1). Confirmed metformin users, whether as a monotherapy or in combination, had significantly lower asprosin levels than non-metformin users but on other T2Dm medications (p < 0.001). Adjustments for age and BMI were not done since no differences were seen in the stratified groups.

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Fig. 1

Significant difference in Asprosin levels of age- and BMI-matched T2DM/obese participants on metformin versus other T2DM medications.

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Lastly, Table 4 shows the multiple linear regression analysis using asprosin as a dependent variable as age, BMI, systolic BP, HDL, adiponectin, resistin, glucose, and insulin as independent variables in the T2DM and obese group. Results indicated that 60.5% variation in log asprosin could be explained by this set of independent variables. Furthermore, glucose and insulin were independently and inversely associated with asprosin, while adiponectin was independently and positively associated with asprosin. Backward stepwise regression was also conducted with the same set of variables, which resulted in the inclusion of only glucose, insulin, and adiponectin as the most important predictors of asprosin with an adjusted R-square of 61.3%.

4 Discussion

The current study assessed for the first time the differences and associations of circulating asprosin levels in a homogenous Arab population with varying degrees of obesity and IR. Numerous studies have linked asprosin with different health issues such as polycystic ovarian syndrome (PCOS) (Alan et al., 2019), childhood obesity (Wang et al., 2020), angina pectoris (Acara et al., 2018), glucose dysregulation Wang et al., 2018), and malignancy (Kocaman and Artaş, 2020). Asprosin has also been shown to favorably increase/decrease after exercise (Ko et al., 2019).

Our study found significantly higher serum asprosin levels in obese subjects than controls and T2DM/obese subjects. Yet, BMI was not a significant predictor of asprosin. The pathophysiological function of increased asprosin in obesity remains unclear (Duerrschmid et al., 2017), and findings from other studies are inconsistent. A previous study reported by Wang et al. observed that obese subjects had increased asprosin levels, and these levels significantly decreased after bariatric surgery (Wang et al., 2019). They also speculated that asprosin could have more complex roles than mere modulation of appetite and glucose regulation (Wang et al., 2019). Studies on obese children also showed that asprosin positively correlates with obesity (Sünnetçi Silistre and Hatipoğl, 2020; Wang et al., 2020).

In contrast, Long et al. (Long et al., 2019) reported that asprosin levels were inversely related to BMI and children. The inconsistencies in outcome may be partially due to differences in assays used since the lack of standardization remains a major issue in replicating studies of new biomarkers, or that asprosin’s role is complex and unknown factors need to be accounted for added clarity and reliability (Long et al., 2019). Ugur and Aydin suggested that asprosin could be a novel biomarker for obesity, at least for adults, as their study outcomes showed a parallel increase in asprosin levels with BMI among the underweight, normal, overweight, and obese individuals (Ugur and Aydin, 2019). Another recent study also demonstrated a significant association between BMI and asprosin among newly diagnosed subjects with diabetes (Naiemian et al., 2020). The association of BMI with asprosin, maybe indirect, since BMI’s effects are more apparent in adipokines which can either enhance (e.g., adiponectin) or impair (e.g., resistin, IL-1β and TNF) insulin sensitivity (Andrade-Oliveira et al., 2015; Booth et al., 2016), which, in turn, may influence asprosin levels (Romere et al., 2016).

Correlation analysis in the current study revealed a significant inverse association between circulatory asprosin and fasting glucose, insulin, HOMA-IR, and a positive association with adiponectin and resistin in all except obese subjects. Several adipokines such as adiponectin, resistin, hepcidin, and other inflammatory cytokines, etc., are secreted by adipose tissue that functions systematically (endocrine) and acts locally (autocrine/paracrine) to regulate insulin sensitivity, immune response, cardiovascular function, and many other physiological processes (Andrade-Oliveira et al., 2015). Although numerous studies have reported elevated asprosin levels in T2DM subjects (Wang et al., 2018; Zhang et al., 2019a; Zhang et al., 2019b; Zhang et al., 2020), the present study showed an inverse association with glycemic parameters in T2DM subjects. In contrast, Zhang et al. reported no association between the asprosin levels and parameters of glucose metabolism in participants of both the T2DM and normal glucose tolerance groups (Zhang et al., 2020). The contradictory findings may be attributed to the duration of T2DM as well as medications, as dysregulation of asprosin secretion might be affected by these factors (Zhang et al., 2019a; Zhang et al., 2019b). Another study speculated that, at the onset of T2DM, this dysregulation might intensify and even influence the asprosin response to variation in glucose levels contributing to the compromised relationship in previously diagnosed T2DM subjects between circulatory asprosin levels and glucose metabolism parameters (Zhang et al., 2020).

It has been demonstrated that the effects of asprosin on glucose homeostasis are confined to hepatic production with no significant influence on insulin levels or sensitivity (Hoffmann et al., 2020). In two hyperinsulinemic-euglycemic clamp studies focused on loss and gain of asprosin function, Romere et al. reported no insulin sensitivity change. Moreover, immunologic (anti-asprosin antibody) or genetic loss (NPS mice and patients) of asprosin function was correlated with reduced glucose and insulin (Duerrschmid et al., 2017; Romere et al., 2016).

Adiponectin is the most abundant adipokine that plays a crucial role in obesity- and age-related diseases, with high concentrations being protective against T2DM, insulin resistance, atherosclerosis (Liu et al, 2019). In contrast, its low concentration raises the likelihood of insulin-resistance disorders (Al-Attas et al., 2012; Sabico et al., 2019). In contrast, elevated resistin levels are associated with IR, initiation, and development of T2DM (Emamalipour et al., 2019). Besides, it also shows a connecting link between IR and obesity (Chen et al., 2002). Our results revealed a positive correlation between asprosin levels and adiponectin in T2DM and control subjects, which was consistent with the previous results reported by Weicek et al. (Wiecek et al., 2018). Releasing inflammatory adipokines is associated with the activation of inflammatory pathways that induce insulin action impairment by interfering with insulin signaling, leading to IR (Emamalipour et al., 2019). However, an inverse association was found between asprosin and adiponectin in the subjects diagnosed with non-alcoholic fatty liver disease (Ke et al., 2020). Susceptibility to diabetes is influenced by ethnicity so findings from other studies using other ethnic groups may not necessarily be true for this group.

Lastly, the significantly lower asprosin levels in the T2DM/obese group as compared to the nonT2DM/obese group demonstrated that asprosin is more sensitive to changes in insulin resistance rather than adiposity. This is further confirmed in the stepwise linear regression analysis revealing that the significant predictors of asprosin are known markers of glycemia independent of all parameters, including anthropometry. The non-significant difference in asprosin levels of controls and T2DM/obese can be partially explained by the use of metformin and other oral hypoglycemics, which in the present study showed significantly lower asprosin levels than other T2DM/obese subjects with unknown history of oral hypoglycemic intake. In a recent study by Gozel and Kilinc (Gozel and Kilinc, 2020), newly diagnosed T2DM subjects had significantly higher plasma asprosin levels than controls at baseline independent of BMI. However, a significant decrease in asprosin was observed and levels became immediately comparable to controls within 3 months of metformin treatment. Metformin’s action is primarily to decrease hepatic glucose production, while asprosin promotes it (Gozel and Kilinc, 2020). Orexigenic asprosin exerts its inhibitory effects in proopiomelanocortin- (POMC) (Duerrschmid et al., 2017), while anorexigenic metformin inhibits neuropeptide Y (NPY)/agouti-related protein (AgRP) (Kalsbeek et al., 2020). Both POMC and NPY/AgRP neurons regulate the feeding control center in the hypothalamus (Kalsbeek et al., 2020). The different pathways of metformin and asprosin in the regulation of appetite suggest that metformin use may be inhibitory to asprosin but that the metformin-induced asprosin suppression alone may not affect BMI, given that the functionality of POMC and NPY/AgRP neurons are known to be defective in T2DM (Kalsbeek et al., 2020).

The authors acknowledge certain limitations. The cross-sectional study design cannot prove causality. While the incomplete data on medications in the T2DM/obese group may partially explain the difference between its levels versus the obese group, other factors that affect asprosin such as physical activity, diet and body fat mass which affects asprosin production were missing. Lastly, only a few participants diligently filled out the medications portion of the questionnaire, hence the small sample size in the sub-analysis on metformin These limitations should be strongly considered can in future investigations on asprosin.

5 Conclusions

In conclusion, our findings collectively suggest that asprosin may have a complex function in metabolism but may act as a biomarker in insulin-resistance-related diseases, with particular promise for monitoring response to treatment. The lack of significant associations with inflammatory markers needs further exploration. Further studies are also needed to explore the therapeutic role of asprosin in insulin-resistance-related disorders as well as the effects of different anti-T2DM medications on circulating asprosin levels.