Introduction
Diabetes is one of the most common endocrine disorders [1]. The number of patients with diabetes is increasing; it is estimated that it will reach 700 million people by 2045 [2]. High blood sugar in diabetes is associated with complications such as osteoporosis, decreased muscle quality, and cardiovascular diseases [3]. Growing evidence shows that arginase enzyme plays a key role in the complications of diabetes, and modulating this enzyme can be a suitable treatment to reduce the complications of the disease. Arginase is an important enzyme in the urea cycle to convert L-arginine to ornithine and urea. The increase in arginase enzyme expression under high blood sugar conditions may lead to disturbances in nitric oxide production and endothelial function [5]. Recently, it has been reported that activated p38 increases the expression of arginase in diabetic rats. In addition, by using MAP-kinase inhibitors, it has been shown that p38 MAPK is an upstream activator in a signaling cascade that leads to the increase of arginase in high blood sugar conditions [7]. 
Studies have shown that cinnamon enhances the action of insulin and activates the nitric oxide production pathway [14]. On the other hand, aerobic exercise reduces the basal level of p38 activation [20]; in this way, it may prevent the increase of arginase in diabetes. Considering the role of arginase enzyme in high blood sugar and the effect of exercise and cinnamon extract on the upstream protein of these enzymes, the present study aims to assess whether aerobic exercise combined with cinnamon extract can modulate arginase enzyme in diabetes.
Methods
In this study, 35 male Wistar rats aged 8 weeks, after 7 days of adaptation to the new environment, induction of diabetes and adaptation to exercise on a treadmill, were randomly divided into five groups: control (C), diabetic (D), diabetic + supplement (DS), diabetic + exercise (DE) and diabetic + exercise + supplement (DES) based on the weight. Mice became diabetic using nicotinamide and streptozotocin [21]. The aerobic training program was started in a progressive manner. This exercise program was based on Chia et al.’s study and had a moderate intensity [23]. The exercise groups performed running on treadmills at 5 sessions a week for 8 weeks. The rats in DS and DES groups received 200 mg/kg hydroalcoholic cinnamon extract daily by gavage for 8 weeks, and those in DE and D groups received placebo (water) during this period [24]. All rats were anesthetized by intraperitoneal injection of ketamine 48 hours after the last training session. Then, the soleus muscle was isolated and immediately kept at -80° C for assessment. The values of arginase and p38 MAPK were measured by ELISA kits according to the instructions of the manufacturer. Data are reported as Mean±SD. The results of Shapiro-Wilk test showed that the data had a normal distribution. For between-group comparisons, one-way analysis of variance was used, followed by Tukey’s post hoc test. Pearson correlation test was used to assess the relationship between the study variables, considering a significance level of p<0.05.
Results
The mean weight of rats at baseline was not significantly different between the study groups (F=0.948, p=0.45), but after the intervention, the weight of all diabetic rats decreased significantly compared to group C (p=0.000). In addition, the weight of rats in the DS (p=0.02) and DES (p=0.0005) groups had a significant increase compared to group D. Blood glucose changes showed that the blood glucose concentration of diabetic groups was significantly higher than that of group C (p=0.000). In the post-test phase, the glucose concentration of groups DE (p=0.00005), DS (p=0.00005) and DES (p=0.0005) was significantly lower compared to that of group D. Moreover, the blood glucose concentration of DS and DES groups were significantly different (p=0.025), but there was no significant difference between groups DS and DE (p=0.93) and groups DE and DES (p=0.155). Arginase protein levels in groups D (p=0.000), DS (p=0.000) and DE (p=0.000) were significantly higher than in group C. Arginase protein level in the DES group was significantly lower than in groups D (p=0.000), DS (p=0.000) and DE (p=0.000) (Figure 1).



Changes in p38 MAPK protein level showed no significant difference among the groups (F=2.482, p=0.07). There was a significant positive correlation between arginase and blood glucose levels (r=0.547, p=0.000). However, there was no correlation between p38 MAPK and blood glucose levels (r=0.096, p=0.556) and between p38 MAPK and arginase protein levels (r=0.213, p=0.187) .
Discussion
The combination of aerobic exercise and cinnamon extract supplementation can reduce the level of arginase enzyme. Therefore, considering that many complications of diabetes are related to the increase of arginase enzyme, this interventional method can help modulate the complications of diabetes.
Ethical Considerations
Compliance with ethical guidelines
This study obtained its ethical approval from Kurdistan University of Medical Sciences (Code: IR.MUK.REC.1398.5008).
Funding
This study was extracted from a PhD. dissertation of first author in Department of Sport Sciences, Faculty of Literature & Human Sciences, Lorestan University, Khorramabad.

Authors' contributions
Conceptualization, methodology, investigation, resources, writing-original draft preparation, writing-review & editing, visualization, supervision, project administration: Ehsan Hoseininejad and Vahid Valipour Dehnou; Conceptualization, methodology, writing – review & editing, visualization, supervision: Ehsan Ghahramanlou; Software, validation, formal analysis, investigation, resources, data curation, writing – review & editing, visualization: Ali Gorzi.
Conflicts of interest
The authors declared no conflict of interest.

 

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