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Effect of yerba mate (Ilex paraguariensis) extract on the metabolism of diabetic rats
Biomedicine & Pharmacotherapy 105 (2018) 370–376
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Effect of yerba mate (Ilex paraguariensis) extract on the metabolism of diabetic rats
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Débora Santos Rocha , Lucas Casagrande, Jorge Felipe Argenta Model, Jordana Tres dos Santos, Ana Lúcia Hoefel, Luiz Carlos Kucharski Physiology Department, Federal University of Rio Grande do Sul, Sarmento Leite, 500, 90050-170, Porto Alegre, Rio Grande do Sul, Brazil
A R T I C LE I N FO
A B S T R A C T
Keywords: Diabetes Ilex paraguariensis Liver Metabolism Muscle
The relationship between metabolic disturbances and clinical events related to diabetes is well known. Yerba mate has presented a potential use as preventive and therapeutic agent on diabetes. The aim of this study was to evaluate the effect of yerba mate on different tissues of diabetic rats, focusing on energetic metabolism. Diabetes was induced by streptozotocin, followed by daily yerba mate treatment. After 30 days, the animals were euthanized to evaluate metabolic parameters on liver, adipose tissue, muscle and serum. The results showed mate treatment promoted a decrease in retroperitoneal adipose tissue in healthy animals. Muscle weight returned to control levels in diabetic rats treated with mate. There was improvement on serum glucose, creatinine, urea and total protein levels associated with mate treatment. Muscle parameters, such as glucose uptake and carbon dioxide production, were improved by mate treatment to control levels. The results evidenced the beneficial actions mate can have on metabolic disturbances of diabetes.
1. Introduction Yerba mate (Ilex paraguariensis) belongs to Aquifoleaceae family and is a native species from South America. Its leaves and stems are used to prepare a tea-like beverage widely consumed by the local population. Studies have shown that yerba mate has potential properties, performing improvements on oxidative imbalance and lipid metabolism [1,2]. These properties are mainly related to its bioactive fractions, represented by methylxanthines, saponins and polyphenols. Large quantities of phenolic compounds been found in yerba mate [3]. This fraction has been presenting protective effect against oxidative damage to lipids and DNA [1]. The lipid peroxidation, particularly in blood vessels, is mitigated by treatment with mate in face of high-fat diet [4,5]. Alkaloids, such as xanthines and methylxanthines, represented by caffeine and theobromine, are also found in yerba mate [6,7]. According to Yamada et al. [8], the stimulating action of caffeine is related to the activation of sympathetic autonomic nervous system. Also, Pang et al. [9] observed decrease in caloric intake and inflammatory markers, and an increase in signaling molecules of satiety (leptin).
Saponins also comprise one of I. paraguariensis’ fractions [10]. Resende et al. [11] investigated its specific action in vivo, demonstrating that this fraction has effects on lipid metabolism. Indeed, they found increase in fecal excretion of lipids and, at the same time, stimulation of adipogenesis in adipose tissue. Metabolic unbalance events have their association with diabetes already described: change in sympathetic nervous system response, oxidative stress, metabolic syndrome, dyslipidemia and atherosclerosis. According to the World Health Organization (WHO), the overall prevalence of diabetes mellitus was estimated in 9% in 2014 and rising [12]. So, faced the alarming prevalence of diabetes and the potential use of I. paraguariensis’ extract as additional therapy. The aim of this study was to evaluate the muscle and liver metabolism of diabetic rats after treatment with yerba mate. 2. Materials and methods 2.1. Animals and experimental design Male Wistar rats (8 weeks old) were divided into four groups:
Abbreviations: C group, Control group; CM group, Control with treatment group; D group, diabetes group; DM group, diabetes with treatment group; STZ, streptozotocin; RAT, retroperitoneal adipose tissue; EAT, epidydimal adipose tissue; SM, soleus muscle; L, liver; 14C, carbon-14; KRB, Krebs Ringer bicabornate; [U-14C]-glucose, uniformly labeled carbon-14 glucose; [14C-2-DG], 2-deoxi-D-[1-14C]-glucose; GLP-1, similar to glucagon peptide; PEPCK, phosphoenolpyruvate carboxykinase enzyme; ApoA-I, apolipoprotein A1 structure; AST, aspartate aminotransferase; ALT, alanine aminostransferase; HMG-CoA, 3-hidroxi-3-methyl-glutaril-CoA reductase; GLUT, glucose transporter ⁎ Corresponding author. E-mail addresses: [email protected] (D.S. Rocha), [email protected] (L. Casagrande), [email protected] (J.F.A. Model), [email protected] (J.T. dos Santos), [email protected] (A.L. Hoefel), [email protected] (L.C. Kucharski). https://doi.org/10.1016/j.biopha.2018.05.132 Received 10 January 2018; Received in revised form 28 May 2018; Accepted 28 May 2018 0753-3322/ © 2018 Published by Elsevier Masson SAS.
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To glycogen content, samples were placed into KOH 30% (w/v) solution and boiled for 15 min. Ethanol (96°GL) was added for glycogen precipitation and the samples were washed two times. Data described as nmol 14C glucose converted to glycogen per g of tissue per hour. Lipid content was measured adding chloroform:methanol (2:1, v/v), followed by extraction performed according to Folch et al. [14]. Results expressed as nmol 14C glucose converted to lipid per g of tissue per hour.
control (C), control treated with mate (CM), diabetes (D) and diabetes treated with mate (DM) (nine individuals per group). The diabetic groups (D and DM) received Streptozotocin (STZ) (65 mg/kg) in citrate Buffer (0.1 M, pH 4,5) intraperitoneally. Control groups (C and CM) received vehicle. Hyperglycemia was confirmed in diabetic individuals (above 250 mg/dL). 2.2. Plant materials and aqueous extract preparing Yerba mate was obtained from commercial market (Ervateira Barão de Cotegipe, RS, Brazil/ Lot /12/14/3), heated up to 80 °C (70 g/L of water), left for 15 min, filtered, cooled and offered as tea immediately after being prepared. The treatment was performed for 30 days. All groups received 1 L of aqueous extract (70 g/L) for ad libitum consumption, and DM group received it diluted three times (23,3 g/L), since diabetic individuals tend to ingest it about three times more than controls when ad libitum consuming.
2.6. Determination of glycogen, triacylglycerol and cholesterol liver concentrations
2.3. Euthanasia and tissue proceedings
2.7. Glucose uptake
Tissues were collected and processed according to specific protocols. Morphometric parameters were expressed as tissue index (tissue weight / body weight): retroperitoneal adipose tissue (RAT), epidydimal adipose tissue (EAT), soleus muscle (SM), and liver (L). All euthanasia proceedings were approved by the Research Ethics Committee (protocol number: 09-055) and performed in the Physiology Department (Federal University of Rio Grande do Sul). Serum parameters were determined using commercial kits (Labtest ®, Minas Gerais, Brazil). Insulin levels were assayed using ELISA kit (Millipore ®).
Soleus muscle was incubated (37 °C/1 h) into tubes containing KRB (pH 7.4) and 0.1 μCi of 2-deoxi-D-[1-14C]-glucose (14C-2-DG) (55 mCi/ mmol, Amersham). Tissue was disrupted in distilled water, then samples from incubation medium and tissue fluid were collected. Results expressed as dpm/ml of tissue fluid per g of tissue divided by dpm/ml of incubation medium (T/M ratio).
2.4.
Glycogen content was measured through KOH (30%) solution boiling, alcoholic precipitation, washing, HCl (4 M) boiling, and glucose detection by colorimetric kit (Labtest®). Determination of hepatic triacylglycerol was enzymatically assessed using colorimetric kits (Labtest), and the cholesterol was measured according to Folch et al. [14].
2.8. Statistical analyses Data expressed as mean and standard deviation (SD). Differences among groups were tested by two-way ANOVA and Bonferroni post hoc test (Prism® software, 6 edition). Values of p < 0.05 were considered significant. Nonparametric data were tested by Kruskal Wallis (KW) and Dunn’s post hoc, data expressed as median and 25/75 interquartile range (IQR).
14
C glucose incorporation into carbon dioxide (14CO2)
The 14C glucose incorporation into 14CO2 was performed according to Torres et al. [13]. Tissues were incubated at 37 °C for 60 min in Krebs–Ringer buffer (KRB, pH 7.4), 0.1 μCi [U-14C] glucose (55 mCi/ mmol, Amersham, Little Chalfont, UK), and glucose 5 mM. To capture the 14CO2, a 3 MM-Whatman paper were placed above the incubation medium (14CO2 wells). The oxidation assay was stopped by trichloracetic acid 50% (v/v) into tissue well, and NaOH (2.0 M) into the 14 CO2 wells. The paper contents were transferred liquid scintillation mixture and the radioactivity was measured (1209 Liquid Scintillation Counter). Results expressed as nmol of 14C glucose incorporated into CO2 per g of tissue per hour. 2.5.
3. Results and discussion 3.1. Morphometry Regarding the mate treatment, a reduction in the retroperitoneal adipose tissue weight, but not in epididymal adipose tissue, was observed in control group (Table 1). Lafontan [15] and Mauriege et al. [16] described peculiarities and different responses that fat depots can display according to the number and type of catecholamines’ receptors. This heterogeneity could explain the observed effect probably through the lipolytic action of methylxanthines and saponins. There were no effects related to treatment in diabetic group (DM). Resende et al. [11], showed that the fraction rich in methylxanthines was able to improve the lipid profile and increase lipolysis in
14
C-glucose incorporation into glycogen and lipid assay
Samples from 14C glucose incorporation into 14CO2 assay were used to glycogen and lipid production measurement. Radioactivity was assessed in scintillation liquid mixture. Table 1 Morphometric parameters on Yerba Mate treated diabetic rats. Parameter
Experimental Group C
ANOVA CM
Body weight (g) RAT Index *104
406.8 ± 36.37 75.46 ± 15.35
EAT Index *104 L Index *102 SM Index *103
9.70 ± 1.49 3.33 ± 0.36 0.91 ± 0.17
a a a,b
a a
D
410.2 ± 24.84 62.25 ± 10.85 8.86 ± 1.20 3.27 ± 0.13 1.01 ± 0.06
a
DM
273.7 ± 26.58 6.29 ± 1.96 c
b
a
3.37 ± 1.40 4.03 ± 0.27 0.87 ± 0.27
a a,b
b b b
b
277.9 ± 34.29 7.84 ± 4.58 c 3.91 ± 1.87 4.12 ± 0.14 1.12 ± 0.20
b b a
b
# (P < 0.0001) # (P < 0.0001) & (P = 0.0347) # (P < 0.0001) # (P < 0.0001) # (P = 0.0070)
Two-way ANOVA and Bonferroni post hoc. Sources of variation are represented as model (#), treatment (*) and model-treatment interaction (&). Data expressed by mean and standard deviation (SD). Same letters indicate equivalence. p < 0.05 considered significant. n = 9 per group. RAT, retroperitoneal adipose tissue; EAT, epidydimal adipose tissue; SM, soleus muscle; L, liver. 371
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adipose tissue, an important tissue for capturing glucose when it is aimed at lowering glycemic levels. This action on GLUT-4 can be the explanation the results of decreased glycemia in diabetic rats treated with yerba mate. Thus, direct effect on insulin-dependent glucose transport may also be a key point of action of the bioactive compounds of the yerba mate Thus, through the activity of the mate’s extract in these important points of absorption and metabolization of carbohydrates, the hyperglycemia seems to be attenuated. These outcomes emphasize mate could present clinical importance as adjuvant treatment to diabetes, improving the effectivity of pharmacological therapy and minimizing its adverse effects.
adipose tissue, which confirms the lipolytic action of methylxanthines from mate. Hussein et al. [17] reported anorexigenic effects caused by similar to glucagon peptide (GLP-1) and leptin, compounds involved in satiety behaviour and reduction of food intake after treatment with polyphenols and saponin fractions. Studies using crude yerba mate extract were able to intervene in lipid metabolism, such as differentiation of pre-adipocytes in mature adipocytes [18]. Additionally, mate extract has effect in dissacaridases’ activity and pancreatic lipase in vitro [19]. Other papers also describe the ability of increase satiety signalling molecules in hyperlipidemic mice treated with mate, in addition to decreasing weight gain and caloric intake [20]. Apparently, this extract has effect on body fat depots through diverse ways, including food intake behavior, gastrointestinal absorption, adipocytes differentiation and adipose tissue lipolysis. Thus, this demonstrates its potential action on this important risk factor for cardiovascular and metabolic diseases.
3.3. Lipid profile STZ increased serum triglycerides, cholesterol and LDL, and decreased HDL-cholesterol. However, DM group presented no benefits on lipid profile. The literature describes beneficial results of mate consumption, with an increase of HDL-c fraction and reduction of other lipid profile components [17,25]. Menini et al. [26] observed preservation of paraxonase 1, an antioxidant enzyme carried by HDL-c, and of apolipoprotein A1 structure (apoA-I), also related to the structure of HDL-c. These discrepancies can be related to methodological differences regarding the presence of high-fat diet and treatment time.
3.2. Serum parameters The DM group showed lower blood glucose values in comparison to the D group, although still considered high, but insulin levels failed to improve (Table 2). Pereira et al. [19] evaluated in vitro effect of mate, and described the inhibition of disaccharidases present in intestinal brush border after acute treatment, which probably decreases the disaccharides degradation and thus attenuates the glycemic peak in postprandial period. In alloxan-induced diabetes model, Oliveira et al. [21] observed decrease in intestinal glucose transporter expression upon treatment with yerba mate, similar to the effect described by Resende et al. [22], improving the control of blood glucose levels. Still, Miranda et al. [23] observed a decrease in mRNA levels of phosphoenolpyruvate carboxykinase enzyme (PEPCK), significantly activated in diabetes, leading to return of these mRNAs to basal levels. This pathway is critically important to glucose production during fasting periods, however, in diabetes, thanks to the lack of insulin action, they are increased leading to hyperglycemia. Other drugs have already been shown to have effect on insulin-dependent glucose uptake in particular by acting on mechanisms of gene transcription and translation of proteins involved in glucose transporter-4 (GLUT-4) signaling [24]. According to the authors, human adipocytes treated with Calcineurin inhibitors decrease glucose uptake, but the mechanisms must still be investigated. In other words, there is still a need to elucidate the action of drugs on the uptake of glucose into
3.4. Urea and creatinine Diabetic rats presented increased urea and decreased creatinine. This could represent the intense activity of protein catabolism, and possible kidney damage. Creatinine levels are clinically used for renal function evaluation, however, in this work, this was hampered by the intense muscle mass loss in diabetics, which significantly interferes with creatinine levels. While in normal individuals this substance remains stable, when there is loss of muscle mass, creatinine levels drop, as depicted in these results. It is thus possible that decreasing insulin levels led to intense muscular proteolysis and, consequently, muscle mass loss [27]. Diabetic rats treated with mate showed decreased urea and increased levels of creatinine. Silva et al. [28] did not find changes in muscle protein synthesis, however their experiment involved healthy rats (no diabetes). The increase of muscle weight in diabetic rats after treatment with mate (Table 1) indicates muscle mass recovery and can be associated with the increase in creatinine levels.
Table 2 Serum parameters on Yerba-Mate treated diabetic rats. Parameter
Experimental Group C
ANOVA /KW test CM
a
124.9 ± 14.55
D a
626.4 ± 78.73
DM c
548.2 ± 40.84b
Glucose (mg/dL)
119.3 ± 8.585
Insulin (ng/mL) Triglycerides (mg/dL) Cholesterol (mg/dL) HDL-cholesterol (mg/dL) LDL (mg/dL) Urea (mg/dL)
1.54 ± 0.715a 110.0 ± 38.14a 128.0 ± 23.26a 4.858 ± 0.494a 101.2 ± 20.23 70.61 ± 16.09a
1.36 ± 0.751a 80.16 ± 22.26a 133.8 ± 24.39a 4.853 ± 0.438a 112.9 ± 24.34 83.51 ± 15.15a,b
0.33 ± 0.042b 358.0 ± 101.1b 218.8 ± 58.98b 4.206 ± 0.463a,b 104.4 ± 41.41 100.7 ± 17.81b
0.42 ± 0.086b 353.7 ± 222.2b 214.3 ± 40.33b 3.864 ± 0.585b 139.8 ± 26.00 89.21 ± 13.00a,b
Creatinin (mg/dL)
0.181 ± 0.029a,b
0.218 ± 0.041b
0.140 ± 0.042a
0.210 ± 0.025b
AST (U/L) ALT (U/L)
205.2 (183.3/222.6) 100.4 (76.38/161.5)a
244.4 (209.5/296.8) 113.5 (104.8/165.9)a
157.1 (128.8/253.2) 122.2 (104.8/353.6)a
353.6 (181.2/473.6) 205.2 (139.7/445.2)b
# (P < 0.0001) *(P = 0.0219) &(P = 0.0090) #(P < 0.0001) #(P < 0.0001) #(P < 0.0001) #(P < 0.0001) NS #(P < 0.0001) & (P = 0.0257) #(P = 0.0462) *(P = 0.0001) No (P = 0.1260) Yes (P = 0.0112)
Two-way ANOVA and Bonferroni post hoc or Kruskal Wallis (KW) and Dunn’s post hoc. The source of variation is represented as model (#), treatment (*) and modeltreatment interaction (&). To nonparametric data “yes” describes difference among groups. Parametric data expressed by mean and standard deviation (SD) or median and 25–75 interquartile range (IQR). Same letters indicate equivalence. p < 0.05 considered significant. n = 9 per group. 372
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Fig. 1. Hepatic metabolism on Yerba-Mate treated diabetic rats. The hepatic metabolism was observed as triglycerides (a), cholesterol (b) and glycogen content; CO2 (c), glycogen (d) and lipid (e) production from glucose. Data expressed by mean and standard deviation (SD). Same letters indicate equivalence. p < 0.05 considered significant. n = 8–9 each experimental group.
3.5. Liver transaminases
3.6. Liver metabolism
After yerba mate treatment, the CM group exhibited no differences in liver transaminases related to the C group. However, the DM group presented increased AST levels in relation to CM group and increased levels of ALT in relation to all other groups. Pittler, Schmidt and Ernst [29] described the use of yerba mate in laboratory animals as safe. However just DM group showed differences in liver transaminases. The results of Vozarova et al. [30], suggest a specific increase in ALT, but not AST, as an indicator of liver response to insulin inefficiency, a condition characteristically associated with diabetes, observed in results of DM group. Apparently, diabetes and yerba mate intake together lead to liver overload after 30 days of treatment.
Diabetes caused increase in liver index in D and DM groups (Table 1). Das et al. [31] described streptozotocin promotes changes in hepatic architecture., explained by the deposition of triglyceride (steatosis) [31]. In liver metabolism, the glucose oxidation (Fig. 1C), glycogen synthesis (Fig. 1D) and glycogen concentration (Fig. 1F) showed significant variation on diabetes. The first two parameters being increased and the third, diminished. However, mate treatment did not alter glucose oxidation (Fig. 1C), glycogen synthesis (Fig. 1D), nor glycogen concentration (Fig. 1F). Increased CO2 production and conversion to glycogen from glucose in diabetics can be understood as compensation to expressive catabolism state. The hepatic glucose uptake via GLUT-2 is independent of 373
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healthy individuals. Furthermore, the levels of protection indicative against redox imbalance substances increased in individuals consuming mate tea. Thus, the muscle protection observed in the present study could also be attributed to antioxidant molecules (total polyphenols) of yerba mate, preventing the damage by diabetes. The stimulating action of xanthines involves sympathetic nervous system, increasing the release and, consequently, the action of catecholamines [8]. Catecholamines activate catabolic pathways, such as lipolysis, but preserve muscle tissue from proteolysis [34]. This is in line with the results described here, that showed decrease in retroperitoneal adipose tissue index, but muscle mass preservation. The possibilities include, phosphodiesterase (PDE) inhibition, calcium mobilization from sarcoplasmic reticulum, facilitating skeletal muscle function [40,41]. However, the yerba mate’s protection of muscle tissue in diabetes has not yet been well described, emphasizing the need for confirmation of data here presented, and further elucidation of involved mechanisms, even if caffeine already had shown properties in muscle. Since untreated diabetic individuals tend to degrade energetic sources, including proteins, their muscle tissue could present expressive loss in mass. These improvements on muscle tissue metabolism and mass brought a surprisingly suggestion of I. paraguariensis as an adjuvant therapy to diabetic individuals, preventing muscle metabolism harm and helping on muscle energy sources maintenance. Lastly, the use of this extract as muscle protective agent must be verified in other circumstances: cancer cachexia, aging, muscle atrophy, emphasizing the importance of these outcomes to muscle metabolism research. Lastly, considering the studies in progress in cancer area and the need to ensure the safety of this extract consumption under various aspects, another point to evaluate is the carcinogenic risk to the digestive tract in yerba mate consumers. Studies point out that there is an increased risk of cancer development, but it is a crucial factor to be observed, the temperature of the extract’s consumption. The local population, especially in cooler frequency regions, generally consumes it hot. Thus, studies have shown that the temperature of the aqueous extract preparation increases the carcinogenic compounds generation [42], besides the direct hot water damage in the digestive tract, that also exposes the tissue to a harmful condition [43,44].
insulin’s action, and hepatic glucose are proportional directly to blood concentrations, which can increase the use of glucose for glycogen and CO2 production. Nonetheless, it is important to remember that insulin is critical to liver energy pathways, playing role on enzymes involved in preventing gluconeogenesis and stimulating energy reserves synthesis. Consequently, additional studies are still needed, beyond the examination energy synthesis and degradation pathways, for example, the activity of glycogen synthase and glycogen phosphorylase enzymes. Lipid synthesis (Fig. 1E), triglycerides (Fig. 1A) and cholesterol tissue concentrations (Fig. 1B) were also evaluated. Diabetic rats showed increased lipid synthesis, unchanged triglycerides and diminished cholesterol. Only hepatic cholesterol levels increased and returned to the controls values. Hyperglycemia result in increased acetyl-CoA levels, leading to increased lipid synthesis from glucose, although liver cholesterol levels were reduced in diabetics. Hepatic cholesterol synthesis can be regulated by several factors. Circulating levels of cholesterol may produce a negative feedback in 3-hidroxi-3-methyl-glutaril-CoA (HMG-CoA) reductase enzyme, as an effort to decrease blood levels. Glucagon displays inhibitory effects on the same enzyme, while insulin has stimulatory action. Therefore, in insulin’s absence, the action of HMG-CoA reductase is low and, consequently, low levels of liver cholesterol can be observed [32]. The variation of articles granted us better understanding of such effects and improved the evaluation of hepatic metabolism Hepatic cholesterol levels returned to controls values after treatment. The methylxanthines may be responsible for this effect, causing release of catecholamines [8], which act on cholesterol synthesis through HMG-CoA reductase stimulation in normal rats [33]. This explains the increase found in diabetic rats treated with mate, stimulating the hepatic cholesterol synthesis pathway. Nevertheless, this ability to influence cholesterol synthesis should still be investigated. 3.7. Muscle metabolism Proteolytic activity appears in diabetes pathogenesis and entails, in long term, loss of muscle mass. In this study, no statistical difference was observed between diabetes and control groups, which could suggest that proteolysis activity was not significant yet after 30 days of diabetes in rats. However, DM group showed muscle gain (Table 1). The muscle metabolism was assessed through glucose uptake (Fig. 2B), CO2 production (Fig. 2A) and glycogen synthesis (Fig. 2C). The diabetic muscle tissue showed greater ability to uptake (per gram of tissue) and convert glucose to CO2. As already reported in literature, diabetic individuals have decreased glucose uptake (in whole tissue) by insulin resistance, in addition to decrease in glycolytic pathway that normally accompanies CO2 production [34]. As noted in these results, the effects were not apparently confirmed. The muscle needs insulin to increase glucose uptake, through glucose transporter-4 (GLUT-4) and use it to CO2 produce. However, the presence of GLUT-1 can ensure basal uptake. Some articles discuss GLUT-4 decreased expression, but not GLUT-1, during diabetes [35]. Therefore, changes in uptake capacity over time remain uncertain. Mogyorosi & Ziyadeh [36] described increasing of GLUT-1 in response to hyperglycemia in vitro. Thus, the increased uptake appears to involve elevated CO2 formation from glucose, and probably related to GLUT-1 transporter activity after 30 days of diabetes. That was evidenced lower values of CO2 production and glucose uptake presented by the DM, equal to control groups. This likely occurs through improvement of hiperglycemia, described earlier, interfering with skeletal muscle metabolism [37]. Nevertheless, this aspect could also be elucidated by other parameters evaluation, such as lipid oxidation, and analysis of activation process of these outcomes in skeletal muscle [38]. Other studies have also verified the benefit of yerba mate on the skeletal muscle [39]. According to the authors, mate tea was able to accelerate muscle recovery, especially up to 24 h post workout in
4. Concluding remarks The results showed mate treatment promoted a decrease in retroperitoneal adipose tissue in healthy animals and an improvement on serum glucose, creatinine, urea and total protein levels in diabetic rats. Further, muscle parameters, such as weight, glucose uptake and carbon dioxide production, return to control levels after 30 days of treatment. Further studies are needed to address the safety of yerba mate, not only as a protective agent to healthy individuals, but also as an auxiliary therapy for diabetic individuals. The results presented here elucidate some properties of its aqueous extract using metabolic approach, something that has been evaluated by few authors so far. The action in muscle tissue, particularly, should be expanded, given the potential benefits evidenced in these results. Finally, the elucidation of specific properties of mate compounds is still required and will be of great assistance in detailing mechanisms involved in the outcomes observed. Conflicts of interest Authors declare no conflict of interest. Author contributions D.S.R conducted all experiment, analyzed data and wrote the manuscript. L.C. was involved in animal treatment. J.F.A.M, J.T.S, A.L.H performed euthanasia and tissue proceeding. L.C.K. was involved in conceptual advices and coordination. 374
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Fig. 2. Muscle metabolism on Yerba-Mate treated diabetic rats. The muscle metabolism was observed as CO2 (a) and glycogen (c) production from glucose and glucose uptake (b). Data are expressed by mean and standard deviation (SD). Same letters indicate equivalence. p < 0.05 considered significant. n = 8–9 each experimental group.
Acknowledgments
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Effect of yerba mate (Ilex paraguariensis) extract on the metabolism of diabetic rats
T
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Débora Santos Rocha , Lucas Casagrande, Jorge Felipe Argenta Model, Jordana Tres dos Santos, Ana Lúcia Hoefel, Luiz Carlos Kucharski Physiology Department, Federal University of Rio Grande do Sul, Sarmento Leite, 500, 90050-170, Porto Alegre, Rio Grande do Sul, Brazil
A R T I C LE I N FO
A B S T R A C T
Keywords: Diabetes Ilex paraguariensis Liver Metabolism Muscle
The relationship between metabolic disturbances and clinical events related to diabetes is well known. Yerba mate has presented a potential use as preventive and therapeutic agent on diabetes. The aim of this study was to evaluate the effect of yerba mate on different tissues of diabetic rats, focusing on energetic metabolism. Diabetes was induced by streptozotocin, followed by daily yerba mate treatment. After 30 days, the animals were euthanized to evaluate metabolic parameters on liver, adipose tissue, muscle and serum. The results showed mate treatment promoted a decrease in retroperitoneal adipose tissue in healthy animals. Muscle weight returned to control levels in diabetic rats treated with mate. There was improvement on serum glucose, creatinine, urea and total protein levels associated with mate treatment. Muscle parameters, such as glucose uptake and carbon dioxide production, were improved by mate treatment to control levels. The results evidenced the beneficial actions mate can have on metabolic disturbances of diabetes.
1. Introduction Yerba mate (Ilex paraguariensis) belongs to Aquifoleaceae family and is a native species from South America. Its leaves and stems are used to prepare a tea-like beverage widely consumed by the local population. Studies have shown that yerba mate has potential properties, performing improvements on oxidative imbalance and lipid metabolism [1,2]. These properties are mainly related to its bioactive fractions, represented by methylxanthines, saponins and polyphenols. Large quantities of phenolic compounds been found in yerba mate [3]. This fraction has been presenting protective effect against oxidative damage to lipids and DNA [1]. The lipid peroxidation, particularly in blood vessels, is mitigated by treatment with mate in face of high-fat diet [4,5]. Alkaloids, such as xanthines and methylxanthines, represented by caffeine and theobromine, are also found in yerba mate [6,7]. According to Yamada et al. [8], the stimulating action of caffeine is related to the activation of sympathetic autonomic nervous system. Also, Pang et al. [9] observed decrease in caloric intake and inflammatory markers, and an increase in signaling molecules of satiety (leptin).
Saponins also comprise one of I. paraguariensis’ fractions [10]. Resende et al. [11] investigated its specific action in vivo, demonstrating that this fraction has effects on lipid metabolism. Indeed, they found increase in fecal excretion of lipids and, at the same time, stimulation of adipogenesis in adipose tissue. Metabolic unbalance events have their association with diabetes already described: change in sympathetic nervous system response, oxidative stress, metabolic syndrome, dyslipidemia and atherosclerosis. According to the World Health Organization (WHO), the overall prevalence of diabetes mellitus was estimated in 9% in 2014 and rising [12]. So, faced the alarming prevalence of diabetes and the potential use of I. paraguariensis’ extract as additional therapy. The aim of this study was to evaluate the muscle and liver metabolism of diabetic rats after treatment with yerba mate. 2. Materials and methods 2.1. Animals and experimental design Male Wistar rats (8 weeks old) were divided into four groups:
Abbreviations: C group, Control group; CM group, Control with treatment group; D group, diabetes group; DM group, diabetes with treatment group; STZ, streptozotocin; RAT, retroperitoneal adipose tissue; EAT, epidydimal adipose tissue; SM, soleus muscle; L, liver; 14C, carbon-14; KRB, Krebs Ringer bicabornate; [U-14C]-glucose, uniformly labeled carbon-14 glucose; [14C-2-DG], 2-deoxi-D-[1-14C]-glucose; GLP-1, similar to glucagon peptide; PEPCK, phosphoenolpyruvate carboxykinase enzyme; ApoA-I, apolipoprotein A1 structure; AST, aspartate aminotransferase; ALT, alanine aminostransferase; HMG-CoA, 3-hidroxi-3-methyl-glutaril-CoA reductase; GLUT, glucose transporter ⁎ Corresponding author. E-mail addresses: [email protected] (D.S. Rocha), [email protected] (L. Casagrande), [email protected] (J.F.A. Model), [email protected] (J.T. dos Santos), [email protected] (A.L. Hoefel), [email protected] (L.C. Kucharski). https://doi.org/10.1016/j.biopha.2018.05.132 Received 10 January 2018; Received in revised form 28 May 2018; Accepted 28 May 2018 0753-3322/ © 2018 Published by Elsevier Masson SAS.
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To glycogen content, samples were placed into KOH 30% (w/v) solution and boiled for 15 min. Ethanol (96°GL) was added for glycogen precipitation and the samples were washed two times. Data described as nmol 14C glucose converted to glycogen per g of tissue per hour. Lipid content was measured adding chloroform:methanol (2:1, v/v), followed by extraction performed according to Folch et al. [14]. Results expressed as nmol 14C glucose converted to lipid per g of tissue per hour.
control (C), control treated with mate (CM), diabetes (D) and diabetes treated with mate (DM) (nine individuals per group). The diabetic groups (D and DM) received Streptozotocin (STZ) (65 mg/kg) in citrate Buffer (0.1 M, pH 4,5) intraperitoneally. Control groups (C and CM) received vehicle. Hyperglycemia was confirmed in diabetic individuals (above 250 mg/dL). 2.2. Plant materials and aqueous extract preparing Yerba mate was obtained from commercial market (Ervateira Barão de Cotegipe, RS, Brazil/ Lot /12/14/3), heated up to 80 °C (70 g/L of water), left for 15 min, filtered, cooled and offered as tea immediately after being prepared. The treatment was performed for 30 days. All groups received 1 L of aqueous extract (70 g/L) for ad libitum consumption, and DM group received it diluted three times (23,3 g/L), since diabetic individuals tend to ingest it about three times more than controls when ad libitum consuming.
2.6. Determination of glycogen, triacylglycerol and cholesterol liver concentrations
2.3. Euthanasia and tissue proceedings
2.7. Glucose uptake
Tissues were collected and processed according to specific protocols. Morphometric parameters were expressed as tissue index (tissue weight / body weight): retroperitoneal adipose tissue (RAT), epidydimal adipose tissue (EAT), soleus muscle (SM), and liver (L). All euthanasia proceedings were approved by the Research Ethics Committee (protocol number: 09-055) and performed in the Physiology Department (Federal University of Rio Grande do Sul). Serum parameters were determined using commercial kits (Labtest ®, Minas Gerais, Brazil). Insulin levels were assayed using ELISA kit (Millipore ®).
Soleus muscle was incubated (37 °C/1 h) into tubes containing KRB (pH 7.4) and 0.1 μCi of 2-deoxi-D-[1-14C]-glucose (14C-2-DG) (55 mCi/ mmol, Amersham). Tissue was disrupted in distilled water, then samples from incubation medium and tissue fluid were collected. Results expressed as dpm/ml of tissue fluid per g of tissue divided by dpm/ml of incubation medium (T/M ratio).
2.4.
Glycogen content was measured through KOH (30%) solution boiling, alcoholic precipitation, washing, HCl (4 M) boiling, and glucose detection by colorimetric kit (Labtest®). Determination of hepatic triacylglycerol was enzymatically assessed using colorimetric kits (Labtest), and the cholesterol was measured according to Folch et al. [14].
2.8. Statistical analyses Data expressed as mean and standard deviation (SD). Differences among groups were tested by two-way ANOVA and Bonferroni post hoc test (Prism® software, 6 edition). Values of p < 0.05 were considered significant. Nonparametric data were tested by Kruskal Wallis (KW) and Dunn’s post hoc, data expressed as median and 25/75 interquartile range (IQR).
14
C glucose incorporation into carbon dioxide (14CO2)
The 14C glucose incorporation into 14CO2 was performed according to Torres et al. [13]. Tissues were incubated at 37 °C for 60 min in Krebs–Ringer buffer (KRB, pH 7.4), 0.1 μCi [U-14C] glucose (55 mCi/ mmol, Amersham, Little Chalfont, UK), and glucose 5 mM. To capture the 14CO2, a 3 MM-Whatman paper were placed above the incubation medium (14CO2 wells). The oxidation assay was stopped by trichloracetic acid 50% (v/v) into tissue well, and NaOH (2.0 M) into the 14 CO2 wells. The paper contents were transferred liquid scintillation mixture and the radioactivity was measured (1209 Liquid Scintillation Counter). Results expressed as nmol of 14C glucose incorporated into CO2 per g of tissue per hour. 2.5.
3. Results and discussion 3.1. Morphometry Regarding the mate treatment, a reduction in the retroperitoneal adipose tissue weight, but not in epididymal adipose tissue, was observed in control group (Table 1). Lafontan [15] and Mauriege et al. [16] described peculiarities and different responses that fat depots can display according to the number and type of catecholamines’ receptors. This heterogeneity could explain the observed effect probably through the lipolytic action of methylxanthines and saponins. There were no effects related to treatment in diabetic group (DM). Resende et al. [11], showed that the fraction rich in methylxanthines was able to improve the lipid profile and increase lipolysis in
14
C-glucose incorporation into glycogen and lipid assay
Samples from 14C glucose incorporation into 14CO2 assay were used to glycogen and lipid production measurement. Radioactivity was assessed in scintillation liquid mixture. Table 1 Morphometric parameters on Yerba Mate treated diabetic rats. Parameter
Experimental Group C
ANOVA CM
Body weight (g) RAT Index *104
406.8 ± 36.37 75.46 ± 15.35
EAT Index *104 L Index *102 SM Index *103
9.70 ± 1.49 3.33 ± 0.36 0.91 ± 0.17
a a a,b
a a
D
410.2 ± 24.84 62.25 ± 10.85 8.86 ± 1.20 3.27 ± 0.13 1.01 ± 0.06
a
DM
273.7 ± 26.58 6.29 ± 1.96 c
b
a
3.37 ± 1.40 4.03 ± 0.27 0.87 ± 0.27
a a,b
b b b
b
277.9 ± 34.29 7.84 ± 4.58 c 3.91 ± 1.87 4.12 ± 0.14 1.12 ± 0.20
b b a
b
# (P < 0.0001) # (P < 0.0001) & (P = 0.0347) # (P < 0.0001) # (P < 0.0001) # (P = 0.0070)
Two-way ANOVA and Bonferroni post hoc. Sources of variation are represented as model (#), treatment (*) and model-treatment interaction (&). Data expressed by mean and standard deviation (SD). Same letters indicate equivalence. p < 0.05 considered significant. n = 9 per group. RAT, retroperitoneal adipose tissue; EAT, epidydimal adipose tissue; SM, soleus muscle; L, liver. 371
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adipose tissue, an important tissue for capturing glucose when it is aimed at lowering glycemic levels. This action on GLUT-4 can be the explanation the results of decreased glycemia in diabetic rats treated with yerba mate. Thus, direct effect on insulin-dependent glucose transport may also be a key point of action of the bioactive compounds of the yerba mate Thus, through the activity of the mate’s extract in these important points of absorption and metabolization of carbohydrates, the hyperglycemia seems to be attenuated. These outcomes emphasize mate could present clinical importance as adjuvant treatment to diabetes, improving the effectivity of pharmacological therapy and minimizing its adverse effects.
adipose tissue, which confirms the lipolytic action of methylxanthines from mate. Hussein et al. [17] reported anorexigenic effects caused by similar to glucagon peptide (GLP-1) and leptin, compounds involved in satiety behaviour and reduction of food intake after treatment with polyphenols and saponin fractions. Studies using crude yerba mate extract were able to intervene in lipid metabolism, such as differentiation of pre-adipocytes in mature adipocytes [18]. Additionally, mate extract has effect in dissacaridases’ activity and pancreatic lipase in vitro [19]. Other papers also describe the ability of increase satiety signalling molecules in hyperlipidemic mice treated with mate, in addition to decreasing weight gain and caloric intake [20]. Apparently, this extract has effect on body fat depots through diverse ways, including food intake behavior, gastrointestinal absorption, adipocytes differentiation and adipose tissue lipolysis. Thus, this demonstrates its potential action on this important risk factor for cardiovascular and metabolic diseases.
3.3. Lipid profile STZ increased serum triglycerides, cholesterol and LDL, and decreased HDL-cholesterol. However, DM group presented no benefits on lipid profile. The literature describes beneficial results of mate consumption, with an increase of HDL-c fraction and reduction of other lipid profile components [17,25]. Menini et al. [26] observed preservation of paraxonase 1, an antioxidant enzyme carried by HDL-c, and of apolipoprotein A1 structure (apoA-I), also related to the structure of HDL-c. These discrepancies can be related to methodological differences regarding the presence of high-fat diet and treatment time.
3.2. Serum parameters The DM group showed lower blood glucose values in comparison to the D group, although still considered high, but insulin levels failed to improve (Table 2). Pereira et al. [19] evaluated in vitro effect of mate, and described the inhibition of disaccharidases present in intestinal brush border after acute treatment, which probably decreases the disaccharides degradation and thus attenuates the glycemic peak in postprandial period. In alloxan-induced diabetes model, Oliveira et al. [21] observed decrease in intestinal glucose transporter expression upon treatment with yerba mate, similar to the effect described by Resende et al. [22], improving the control of blood glucose levels. Still, Miranda et al. [23] observed a decrease in mRNA levels of phosphoenolpyruvate carboxykinase enzyme (PEPCK), significantly activated in diabetes, leading to return of these mRNAs to basal levels. This pathway is critically important to glucose production during fasting periods, however, in diabetes, thanks to the lack of insulin action, they are increased leading to hyperglycemia. Other drugs have already been shown to have effect on insulin-dependent glucose uptake in particular by acting on mechanisms of gene transcription and translation of proteins involved in glucose transporter-4 (GLUT-4) signaling [24]. According to the authors, human adipocytes treated with Calcineurin inhibitors decrease glucose uptake, but the mechanisms must still be investigated. In other words, there is still a need to elucidate the action of drugs on the uptake of glucose into
3.4. Urea and creatinine Diabetic rats presented increased urea and decreased creatinine. This could represent the intense activity of protein catabolism, and possible kidney damage. Creatinine levels are clinically used for renal function evaluation, however, in this work, this was hampered by the intense muscle mass loss in diabetics, which significantly interferes with creatinine levels. While in normal individuals this substance remains stable, when there is loss of muscle mass, creatinine levels drop, as depicted in these results. It is thus possible that decreasing insulin levels led to intense muscular proteolysis and, consequently, muscle mass loss [27]. Diabetic rats treated with mate showed decreased urea and increased levels of creatinine. Silva et al. [28] did not find changes in muscle protein synthesis, however their experiment involved healthy rats (no diabetes). The increase of muscle weight in diabetic rats after treatment with mate (Table 1) indicates muscle mass recovery and can be associated with the increase in creatinine levels.
Table 2 Serum parameters on Yerba-Mate treated diabetic rats. Parameter
Experimental Group C
ANOVA /KW test CM
a
124.9 ± 14.55
D a
626.4 ± 78.73
DM c
548.2 ± 40.84b
Glucose (mg/dL)
119.3 ± 8.585
Insulin (ng/mL) Triglycerides (mg/dL) Cholesterol (mg/dL) HDL-cholesterol (mg/dL) LDL (mg/dL) Urea (mg/dL)
1.54 ± 0.715a 110.0 ± 38.14a 128.0 ± 23.26a 4.858 ± 0.494a 101.2 ± 20.23 70.61 ± 16.09a
1.36 ± 0.751a 80.16 ± 22.26a 133.8 ± 24.39a 4.853 ± 0.438a 112.9 ± 24.34 83.51 ± 15.15a,b
0.33 ± 0.042b 358.0 ± 101.1b 218.8 ± 58.98b 4.206 ± 0.463a,b 104.4 ± 41.41 100.7 ± 17.81b
0.42 ± 0.086b 353.7 ± 222.2b 214.3 ± 40.33b 3.864 ± 0.585b 139.8 ± 26.00 89.21 ± 13.00a,b
Creatinin (mg/dL)
0.181 ± 0.029a,b
0.218 ± 0.041b
0.140 ± 0.042a
0.210 ± 0.025b
AST (U/L) ALT (U/L)
205.2 (183.3/222.6) 100.4 (76.38/161.5)a
244.4 (209.5/296.8) 113.5 (104.8/165.9)a
157.1 (128.8/253.2) 122.2 (104.8/353.6)a
353.6 (181.2/473.6) 205.2 (139.7/445.2)b
# (P < 0.0001) *(P = 0.0219) &(P = 0.0090) #(P < 0.0001) #(P < 0.0001) #(P < 0.0001) #(P < 0.0001) NS #(P < 0.0001) & (P = 0.0257) #(P = 0.0462) *(P = 0.0001) No (P = 0.1260) Yes (P = 0.0112)
Two-way ANOVA and Bonferroni post hoc or Kruskal Wallis (KW) and Dunn’s post hoc. The source of variation is represented as model (#), treatment (*) and modeltreatment interaction (&). To nonparametric data “yes” describes difference among groups. Parametric data expressed by mean and standard deviation (SD) or median and 25–75 interquartile range (IQR). Same letters indicate equivalence. p < 0.05 considered significant. n = 9 per group. 372
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Fig. 1. Hepatic metabolism on Yerba-Mate treated diabetic rats. The hepatic metabolism was observed as triglycerides (a), cholesterol (b) and glycogen content; CO2 (c), glycogen (d) and lipid (e) production from glucose. Data expressed by mean and standard deviation (SD). Same letters indicate equivalence. p < 0.05 considered significant. n = 8–9 each experimental group.
3.5. Liver transaminases
3.6. Liver metabolism
After yerba mate treatment, the CM group exhibited no differences in liver transaminases related to the C group. However, the DM group presented increased AST levels in relation to CM group and increased levels of ALT in relation to all other groups. Pittler, Schmidt and Ernst [29] described the use of yerba mate in laboratory animals as safe. However just DM group showed differences in liver transaminases. The results of Vozarova et al. [30], suggest a specific increase in ALT, but not AST, as an indicator of liver response to insulin inefficiency, a condition characteristically associated with diabetes, observed in results of DM group. Apparently, diabetes and yerba mate intake together lead to liver overload after 30 days of treatment.
Diabetes caused increase in liver index in D and DM groups (Table 1). Das et al. [31] described streptozotocin promotes changes in hepatic architecture., explained by the deposition of triglyceride (steatosis) [31]. In liver metabolism, the glucose oxidation (Fig. 1C), glycogen synthesis (Fig. 1D) and glycogen concentration (Fig. 1F) showed significant variation on diabetes. The first two parameters being increased and the third, diminished. However, mate treatment did not alter glucose oxidation (Fig. 1C), glycogen synthesis (Fig. 1D), nor glycogen concentration (Fig. 1F). Increased CO2 production and conversion to glycogen from glucose in diabetics can be understood as compensation to expressive catabolism state. The hepatic glucose uptake via GLUT-2 is independent of 373
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healthy individuals. Furthermore, the levels of protection indicative against redox imbalance substances increased in individuals consuming mate tea. Thus, the muscle protection observed in the present study could also be attributed to antioxidant molecules (total polyphenols) of yerba mate, preventing the damage by diabetes. The stimulating action of xanthines involves sympathetic nervous system, increasing the release and, consequently, the action of catecholamines [8]. Catecholamines activate catabolic pathways, such as lipolysis, but preserve muscle tissue from proteolysis [34]. This is in line with the results described here, that showed decrease in retroperitoneal adipose tissue index, but muscle mass preservation. The possibilities include, phosphodiesterase (PDE) inhibition, calcium mobilization from sarcoplasmic reticulum, facilitating skeletal muscle function [40,41]. However, the yerba mate’s protection of muscle tissue in diabetes has not yet been well described, emphasizing the need for confirmation of data here presented, and further elucidation of involved mechanisms, even if caffeine already had shown properties in muscle. Since untreated diabetic individuals tend to degrade energetic sources, including proteins, their muscle tissue could present expressive loss in mass. These improvements on muscle tissue metabolism and mass brought a surprisingly suggestion of I. paraguariensis as an adjuvant therapy to diabetic individuals, preventing muscle metabolism harm and helping on muscle energy sources maintenance. Lastly, the use of this extract as muscle protective agent must be verified in other circumstances: cancer cachexia, aging, muscle atrophy, emphasizing the importance of these outcomes to muscle metabolism research. Lastly, considering the studies in progress in cancer area and the need to ensure the safety of this extract consumption under various aspects, another point to evaluate is the carcinogenic risk to the digestive tract in yerba mate consumers. Studies point out that there is an increased risk of cancer development, but it is a crucial factor to be observed, the temperature of the extract’s consumption. The local population, especially in cooler frequency regions, generally consumes it hot. Thus, studies have shown that the temperature of the aqueous extract preparation increases the carcinogenic compounds generation [42], besides the direct hot water damage in the digestive tract, that also exposes the tissue to a harmful condition [43,44].
insulin’s action, and hepatic glucose are proportional directly to blood concentrations, which can increase the use of glucose for glycogen and CO2 production. Nonetheless, it is important to remember that insulin is critical to liver energy pathways, playing role on enzymes involved in preventing gluconeogenesis and stimulating energy reserves synthesis. Consequently, additional studies are still needed, beyond the examination energy synthesis and degradation pathways, for example, the activity of glycogen synthase and glycogen phosphorylase enzymes. Lipid synthesis (Fig. 1E), triglycerides (Fig. 1A) and cholesterol tissue concentrations (Fig. 1B) were also evaluated. Diabetic rats showed increased lipid synthesis, unchanged triglycerides and diminished cholesterol. Only hepatic cholesterol levels increased and returned to the controls values. Hyperglycemia result in increased acetyl-CoA levels, leading to increased lipid synthesis from glucose, although liver cholesterol levels were reduced in diabetics. Hepatic cholesterol synthesis can be regulated by several factors. Circulating levels of cholesterol may produce a negative feedback in 3-hidroxi-3-methyl-glutaril-CoA (HMG-CoA) reductase enzyme, as an effort to decrease blood levels. Glucagon displays inhibitory effects on the same enzyme, while insulin has stimulatory action. Therefore, in insulin’s absence, the action of HMG-CoA reductase is low and, consequently, low levels of liver cholesterol can be observed [32]. The variation of articles granted us better understanding of such effects and improved the evaluation of hepatic metabolism Hepatic cholesterol levels returned to controls values after treatment. The methylxanthines may be responsible for this effect, causing release of catecholamines [8], which act on cholesterol synthesis through HMG-CoA reductase stimulation in normal rats [33]. This explains the increase found in diabetic rats treated with mate, stimulating the hepatic cholesterol synthesis pathway. Nevertheless, this ability to influence cholesterol synthesis should still be investigated. 3.7. Muscle metabolism Proteolytic activity appears in diabetes pathogenesis and entails, in long term, loss of muscle mass. In this study, no statistical difference was observed between diabetes and control groups, which could suggest that proteolysis activity was not significant yet after 30 days of diabetes in rats. However, DM group showed muscle gain (Table 1). The muscle metabolism was assessed through glucose uptake (Fig. 2B), CO2 production (Fig. 2A) and glycogen synthesis (Fig. 2C). The diabetic muscle tissue showed greater ability to uptake (per gram of tissue) and convert glucose to CO2. As already reported in literature, diabetic individuals have decreased glucose uptake (in whole tissue) by insulin resistance, in addition to decrease in glycolytic pathway that normally accompanies CO2 production [34]. As noted in these results, the effects were not apparently confirmed. The muscle needs insulin to increase glucose uptake, through glucose transporter-4 (GLUT-4) and use it to CO2 produce. However, the presence of GLUT-1 can ensure basal uptake. Some articles discuss GLUT-4 decreased expression, but not GLUT-1, during diabetes [35]. Therefore, changes in uptake capacity over time remain uncertain. Mogyorosi & Ziyadeh [36] described increasing of GLUT-1 in response to hyperglycemia in vitro. Thus, the increased uptake appears to involve elevated CO2 formation from glucose, and probably related to GLUT-1 transporter activity after 30 days of diabetes. That was evidenced lower values of CO2 production and glucose uptake presented by the DM, equal to control groups. This likely occurs through improvement of hiperglycemia, described earlier, interfering with skeletal muscle metabolism [37]. Nevertheless, this aspect could also be elucidated by other parameters evaluation, such as lipid oxidation, and analysis of activation process of these outcomes in skeletal muscle [38]. Other studies have also verified the benefit of yerba mate on the skeletal muscle [39]. According to the authors, mate tea was able to accelerate muscle recovery, especially up to 24 h post workout in
4. Concluding remarks The results showed mate treatment promoted a decrease in retroperitoneal adipose tissue in healthy animals and an improvement on serum glucose, creatinine, urea and total protein levels in diabetic rats. Further, muscle parameters, such as weight, glucose uptake and carbon dioxide production, return to control levels after 30 days of treatment. Further studies are needed to address the safety of yerba mate, not only as a protective agent to healthy individuals, but also as an auxiliary therapy for diabetic individuals. The results presented here elucidate some properties of its aqueous extract using metabolic approach, something that has been evaluated by few authors so far. The action in muscle tissue, particularly, should be expanded, given the potential benefits evidenced in these results. Finally, the elucidation of specific properties of mate compounds is still required and will be of great assistance in detailing mechanisms involved in the outcomes observed. Conflicts of interest Authors declare no conflict of interest. Author contributions D.S.R conducted all experiment, analyzed data and wrote the manuscript. L.C. was involved in animal treatment. J.F.A.M, J.T.S, A.L.H performed euthanasia and tissue proceeding. L.C.K. was involved in conceptual advices and coordination. 374
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Fig. 2. Muscle metabolism on Yerba-Mate treated diabetic rats. The muscle metabolism was observed as CO2 (a) and glycogen (c) production from glucose and glucose uptake (b). Data are expressed by mean and standard deviation (SD). Same letters indicate equivalence. p < 0.05 considered significant. n = 8–9 each experimental group.
Acknowledgments
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