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Arquivo Brasileiro de Medicina Veterinária e Zootecnia

On-line version ISSN 1678-4162

Arq. Bras. Med. Vet. Zootec. vol.69 no.2 Belo Horizonte Mar./Apr. 2017

http://dx.doi.org/10.1590/1678-4162-8453 

Medicina Veterinária

Combinação de butafosfan e cianocobalamina no metabolismo da glicose em vacas leiteiras após o parto

Combined of butaphosphan and cyanocobalamin on the glucose metabolism of dairy cows after calving

V.C. Tabeleão1 

E. Schwegler1 

R.A. Pereira1 

A.R.T. Krause1 

P. Montagner1 

J.O. Feijó1 

A. Schneider1 

E. Schmitt1 

C.C. Brauner1 

V.R. Rabassa1 

F.A.B. Del Pino1 

M.N. Corrêa*  1 

1Universidade Federal de Pelotas ˗ Pelotas, RS

RESUMO

A hipótese deste estudo é de que o uso da combinação de butafosfan e cianocobalamina pode melhorar a resistência periférica à insulina, aumentar a quantidade de glicose disponível para a glândula mamária e a produção de leite. Assim, o objetivo foi investigar os efeitos combinados de butafosfan e cianocobalamina sobre o metabolismo da glicose em vacas leiteiras no período pós-parto. Vinte e uma vacas leiteiras foram divididas em dois grupos: grupo controle (CON, n= 11), que recebeu cinco aplicações de solução salina (20mL / animal 0,9% NaCl), e grupo Catosal(r) (ABC, n= 10), que recebeu cinco aplicações de 20mL de uma solução contendo as substâncias butafosfan e cianocobalamina (B12 Catosal(r), 100mg da substância butafosfan e 50µg de cianocobalamina por mL). As aplicações foram realizadas por via intramuscular, nos dias sete, 12, 17, 22 e 27 pós-parto. As amostras de sangue foram coletadas para a avaliação das concentrações plasmáticas de fósforo, glicose, ácidos graxos não esterificados (AGNE), albumina, aspartato aminotransferase (AST) e creatina quinase (CK). Nos dias oito e 28 pós-parto, os animais foram pesados e submetidos aos testes de tolerância à glicose e à insulina. O tratamento promoveu perda de peso (ABC 40,4kg, CON 10,73kg, P<0,05) e aumento da AST (ABC 62,92 ±3,31U/L, CON 53,11±3,49 U / L, P<0,05) e dos níveis de CK (ABC 134,09± 19,08U / L, CON 79,43 ± 18,27U / L). Os grupos não diferiram quanto ao metabolismo (área sob a curva) da glicose nos dias oito e 28, porém os animais tratados tiveram um aumento na glicemia (P<0,05) no dia 28 pós-parto (97,54 ± 8,54mg / dL), após a administração de insulina, em comparação ao dia oito (83,01 ± 8,54mg / dL). Assim, pode-se concluir que a combinação de butafosfan e cianocobalamina melhora a adaptação do metabolismo da glicose em vacas leiteiras no início da lactação.

Palavras-chave: metabolismo energético; fósforo orgânico; resistência à insulina; vacas leiteiras

ABSTRACT

The hypothesis of this study is that the combined use of butaphosphan and cyanocobalamin could enhance peripheral insulin resistance, increasing the amount of glucose available for the mammary gland and milk production. Thus, our aim was to investigate the combined effects of butaphosphan and cyanocobalamin on the glucose metabolism in dairy cows during the postpartum period. Twenty one dairy cows were divided into two groups: Control Group (CON, n= 11), that received 5 injections of saline solution (20mL/animal 0.9 % NaCl), and Catosal group (ABC, n= 10) which received 5 injections of 20mL of a Butafosfan and Cyanocobalamin solution (Catosal(r) B12, 100mg of Butafosfan and 50µg Cyanocobalamin for mL). The injections were performed by intramuscular route, on days 7, 12, 17, 22 and 27 postpartum. Blood samples were taken on these days to evaluate plasma concentrations of phosphorus, glucose, non-esterified fatty acids (NEFA), albumin, aspartate aminotransferase (AST) and creatine kinase (CK). On days 8 and 28 postpartum, the animals were weighted and subjected to the glucose tolerance and insulin challenge tests. The treatment promoted weight loss (ABC 40.4kg, CON 10.73kg, P< 0.05) and increased AST (ABC 62.92 ±3.31U/L, CON 53.11 ±3.49U/L, P< 0.05) and CK levels (ABC 134.09 ±19.08U/L, CON 79.43 ±18.27U/L). Glucose metabolism (area under the curve) did not differ (P> 0.05) among groups on days 8 and 28; however, ABC animals showed higher serum glucose levels (P< 0.05) after insulin administration on day 28 postpartum (97.54 ±8.54mg/dL) when compared to day 8 (83.01 ±8.54mg/dL). It could be concluded that the combined use of butaphosphan and cyanocobalamin interferes positively with the adaptation of glucose metabolism in dairy cows in early lactation.

Keywords: energetic metabolism; organic phosphorus; insulin resistance; dairy cows

INTRODUCTION

The use of different strategies has contributed to the generation of dairy cows with higher production capacity, and, consequently, higher metabolic demands (Patton et al., 2007). These demands are mainly due to the synthesis of colostrum in the prepartum period as well as the synthesis of milk in the postpartum, causing metabolic changes in homeostatic and adaptive processes that characterize this transition period, in addition, low dry matter intake (DMI) increases negative energy balance (NEB) and then exacerbates metabolic alterations (Castaneda-Gutierrez et al., 2009).

Milk production, which increases in the first weeks postpartum, also increases the demand for glucose by the mammary gland, which requires 72 g glucose per liter of milk produced (Mattmiller et al., 2011). Some studies have demonstrated that milk production is positively correlated with peripheral insulin resistance, therefore the greater the genetic merit of the herd, the higher the milk production and the higher the insulin resistance and, therefore, the lower the glucose metabolism by peripheral tissues (Chagas et al., 2009, Zhang et al., 2013).

This peripheral insulin resistance is characterized by a decrease in the entry of glucose into the cell, which may be due to a lower expression of insulin receptors (Tsuruzoe et al., 2001) or to the lower insulin production by the pancreas (Ning et al., 2011). As a result, peripheral tissues use different compounds as energy sources, as the non-esterified fatty acids (NEFA), which are provided by adipose tissue (Ning et al., 2011) or amino acids arising from plasma and/or muscle proteins (De Koster and Opsomer, 2013) which are primarily intended for hepatic gluconeogenesis (Pires et al., 2013).

The combined use of butaphosphan, organic source of phosphorus, and cyanocobalamin, which contributes to the gluconeogenesis (Kreipe et al., 2011) has proven to have an effect on milk production and the NEB of cows (Pereira et al., 2013). Furthermore, this association decreases the expression of hepatic enzyme, which act on the metabolism of fatty acids, and increases the expression of the β-oxidation enzyme route (Kreipe et al., 2011). Therefore, the hypothesis of this study is that combined use of butaphosphan and cyanocobalamin could enhance peripheral insulin resistance, increase the amount of glucose available for the mammary gland and increase milk production. Therefore, the aim of this study was to investigate the combined effects of butaphosphan and cyanocobalamin on the glucose metabolism in dairy cows after calving.

MATERIAL AND METHODS

This study was approved by the Ethics Committee on Animal Experimentation at University Federal of Pelotas, registered under number 23110.

The experiment was conducted on a dairy farm in southern Brazil (32º 16 'S, 52 67º 32' E) in a semi-extensive production system (pasture based with concentrate supplementation after milking). Twenty one Holstein dairy cows between 2 and 4 lactations and with no clinical signals of health disorders during previous lactation were divided into two groups: Control Group (CON, n= 11), that received 5 injections of saline solution (20mL/animal 0.9% NaCl), and Catosal group (ABC, n= 10) which received 5 injections of 20mL of a solution of Butafosfan and Cyanocobalamin (Catosal(r) B12, 100mg of Butafosfan and 50µg Cyanocobalamin for mL). The injections were performed by intramuscular route, on days 7, 12, 17, 22 and 27 postpartum. The average weight of the selected cows at the beginning of the experiment was 588.43 ±57.3kg. The body condition score (BCS) varied between 2 and 3.5 (7.14% with score 2; 35.71% with score 2.5; 35.71% with score 3, and 21.43% with score 3.5), on a scale of 1 to 5 (Wildman et al., 1982). The cows were milked twice a day (at 5a.m. and at 5p.m.). The ingredient composition of postpartum diets for dairy cows is observed in Tab. 1. Between the two milking procedures, cows had ad libitum access to water and pasture, which consisted of forage sorghum. Milk production was recorded daily by the ALPRO(r) Windows software (DeLaval, Kansas City, Mo, USA).

Table 1.  Ingredient composition of postpartum diets for dairy cows 

Ingredients Amount (kg)
Forage sorghum Ad libitum
Haylage 15.000
Wheatbran 1.500
Soybeanbran 2.400
Rice bran 2.880
Groundcorn 3.000
Groundsorghum 2.130
Mineral Supplements 0.110
Urea 0.090
Sodiumbicarbonate 0.190
Calciticlimestone 0.190
Salt 0.002

Blood samples were taken on days of treatment administration (days 7, 12, 17, 22 and 27 postpartum), after milking, before the injection and before feeding. Samples were placed into two tubes - tube 1, containing 10% EDTA and glycolysis pathway inhibitor (12% potassium fluoride), and tube 2, containing only blood. The samples were then centrifuged at 1800xg for 15min and frozen at -20ºC for subsequent biochemical analyzes, except glucose determination, which was done immediately.

The metabolites evaluated were plasma glucose, phosphorus, albumin, aspartate aminotransferase (AST) and creatine kinase (CK) by using commercial kits (Labtest(r) Diagnóstica S.A., Brazil). The plasma concentration of non-esterified fatty acids (NEFA) was obtained by using a commercial kit (Wako NEFA-HR, Wako Chemicals, USA(r)) and was performed according to the micromethod (Ballou et al., 2009) by using a plate reader (Thermo Plate(r) TP-Reader, São Paulo, Brazil): All the other metabolites were analyzed by colorimetric reaction by Visible Light Spectrophotometer (CELM SB 190(r), CompanhiaEquipadora de LaboratóriosModernos - CELM, Brazil).

On days 8 and 28 postpartum, the animals were weighed and subjected to jugular vein catheterization immediately after milking and before feed supplementation in order to perform the glucose tolerance and insulin challenge tests. The glucose tolerance test was done by considering as a time zero the glucose infusion, and the glucose levels at -5, 0, 15, 30, 45 and 60 minutes after administration were used to determine the area under the curve (AUC).

To calculate the AUC for glucose, the area of the trapezoid formed between two subsequent samplings was used (Regnault et al., 2004), taking into consideration changes in relation to the baseline level of each individual (Area= (Value Collection 1 - Average of the two baseline collections + Value Collection 2 - Average of the two baseline collections) * Interval between collections/2). The glucose metabolic rate (δ) was defined as the speed of its metabolization (natural log iT(15 min) - natural log fT(60 min)/fTf difference(60 min)-iT(15 min)) * 100, where iT means initial time and fT means final time. The time required for glucose to reach half the initial concentration was defined as its half-life rate (T1/2 min= 100* (0,693/δ) (Chagas et al., 2009). Sixty minutes after glucose infusion, 0.1 UI/kg body weight insulin was applied, and the glucose disappearance rate was calculated by determining glycemia at 60, 65, 70, 75, 90, 120, 150 and 180min after glucose infusion.

The data were analyzed by considering animals as experimental units. All variables were subjected to the test of normality by the Shapiro-Wilk test (P> 0.90) through the UNIVARIATE Procedure. The variables were compared using the MIXED MODEL procedure, and the approach to determine the degrees of freedom in the denominator was performed by Satterthwaite for tests of fixed effects. The analyses of glucose application and the pre and post insulin application periods, serum, mean serum glucose, phosphorus, AST, CK and NEFA levels, body weight and milk production were compared between treatments, as well as the time of collection and their interaction (Littell et al., 1998) by means of analysis of variance with repeated measures. The autoregressive covariance structure provided the best fit for the analyses according to Akaike's information criterion. However, the first collection was considered as a covariate to make up for initial differences between treatments, being thus included in blood metabolite profiles in the statistical model, except for CK activity, which showed non normal distribution and was consequently analyzed by the nonparametric test by the NPAR1WAY procedure and a one-way classification. In addition, the animals were considered as random effects within treatments. The analyses of the half-life and metabolism rates, area under the curve of glucose and daily weight gain of the animals were individually compared between treatments by means of analysis of variance. The results were presented as mean ± standard error of the mean (SEM). All statistical analyses were performed using the SAS software (Littell et al., 1998; SAS version 9.1- SAS(r) Institute Inc., Cary, NC, USA, 2009). Differences were considered significant when P< 0.05.

RESULTS

The half-life, metabolism and AUC glucose rates, which were determined between 0 and 60 minutes (GTT0-60min,Tab. 2) on days 8 and 28 postpartum did not differ (P> 0.05) between treatments. Nevertheless, the insulin challenge showed an interaction between group and collection (P= .02) in plasma glucose levels after insulin administration (between 60 and 180 minutes) in the ABC (Figure 1d); on day 8 postpartum, the mean glucose levels (83.01 ±8.54mg/dL) were lower than those on day 28 postpartum (97.54 ±8.54mg/dL). The trend, however, was not observed in the CON (P> 0.05) (Figure 1b). In spite of this, mean plasma glucose levels did not differ between treatments and collections (P>0.05) on application days (Table 3). As to the period before insulin administration, no differences were observed between treatments, collections and their interactions (P> 0.05) (Figure 1).

The body weight (Table 3) of the animals in the ABC was lower (P= 0.0046) on day 28, when compared to their weight on day 8. Also, differences between groups on day 28 were observed (P=0.0433). Thus, the average daily weight gain (kg) (Table 3) was lower (P=0.0088) for ABC animals when compared to the CON. As to milk production (Table 3), differences between collections were observed (P= 0.03), though there were no significant differences between groups, or in the group - collection interaction. Plasma levels of phosphorus, albumin and NEFA (Table 3) obtained during treatment did not differ (P>0.05) between groups, collections and their interactions. However, CK and AST activities were higher in the ABC (P= 0.04 and P=0.05, respectively) when compared to the CON, but there were no significant differences between the collections and the group - collection interaction (P> 0.05).

Table 2 Effects of the use of butaphosphan and cyanocobalamin combination on the glucose tolerance test (GTT0-60min), half-life rate, metabolism rate and area under the curve (AUC) of dairy cows 

Parameters Treatment1 P2
CON1 ABC2
GTT D83
Glucose half-life rate (%) 58.4 ± 6.71 61.9±7.04 0.73
Metabolism rate (min) 1.3 ± 0.14 1.3 ± 0.15 0.95
Glucose AUC5 0 - 60 mg/dL 7225.1 ± 284.03 6719.2 ±297.89 0.23
GTT D284
Glucose half-life rate (%) 61.2 ±7.98 64.9 ±8.37 0.75
Metabolism rate (min) 1.3±0.19 1.2 ±0.20 0.61
Glucose AUC5 0 - 60 mg/dL 7068.4 ± 472.61 6973.4 ±495.67 0.89

1CON = Control Group (n=11; NaCl 0.9%; 20mL/animal) and ABC = Catosal Group (n=10; 20mL Catosal(r) B12/animal per application); 2Probability value; 3GTT D8 = Glucose Tolerance Test 8 days potpartum; 4GTT D28 = Glucose Tolerance Test 28 days postpartum.; 5AUC = Area under the Curve.

Table 3 Average daily weight gain (ADG) (kg), milk production (kg), blood concentration of NEFA (mmol/L), phosphorus (mg/dL), glucose (mg/dL), albumin (g/L), AST (U/L) and CK (U/L) of animals treated with butaphosphan and cyanocobalamin combination after calving 

Parameters Treatment1 P2
COM ABC Group Collection Group*Collection
Performance
ADG3 (kg) 0.5b ± 0.6 -2.0a ±0.6 <0.01
Milkproduction (kg/day) 24.5 ± 2.0 29.6 ± 2.4 0.13 0.03 0.54
Biochemical
NEFA4 (mmol/L) 0.2 ± 0.04 0.3 ± 0.04 0.16 0.15 0.51
Phosphorus (mg/dL) 8.8 ± 1.52 7.5 ± 2.14 0.63 0.48 0.85
Glucose (mg/dL) 68.1 ± 6.10 80.5 ± 5.10 0.14 0.27 0.43
Albumin (g/L) 21.0 ± 1.4 20.9 ± 1.4 0.33 0.13 0.44
Aspartate aminotransferase (U/L) 53.1b ± 3.49 62.9a ± 3.31 0.05 0.16 0.97
Creatine kinase (U/L) 79.4b ± 18.2 134.1a ± 19.1 0.04

1CON = Control Group (n=11; NaCl 0.9%; 20mL/animal) and ABC = Catosal Group (n=10; 20mL Catosal(r) B12/animal per application); Collection (time): collection of blood samples on days 7, 12, 17, 22 and 27 postpartum, realized after milking, before the injection and before the feeding; 2Probability value; 3ADG = Average Daily Gain (From day 8 to 28 postpartum); 4NEFA = Non-esterified Fatty Acid;† = Not applicable; a,b Values within a row with different superscripts differ significantly at P<0.05.

Figure 1.  Mean plasma glucose levels (mg/dL) of dairy cows submitted to successive applications of butaphosphan and cyanocobalamine. Mean glucose levels in the control group (CON n=11; NaCl 0.9%; 20mL /animal) prior to insulin application (a); Mean plasma glucose levels (mg/dL) in the catosal group (ABC n=10; 20mL Catosal(r) B12/animal perapplication) prior to insulin application (b); Mean plasma glucose levels (mg/dL) in the control group (CON n=11; NaCl 0.9%; 20mL/animal) after insulin injection (c); Mean plasma glucose levels (mg/dL) in the Catosal group (ABC n=10; 20mL Catosal(r) B12/animal per application) after insulin application (d). 

DISCUSSION

The higher CK (P= 0.04) and AST (P= 0.05) activities - the former muscle tissue specific and the latter found both in liver and muscle tissues (Shpigel et al., 2003) - observed in the ABC suggests greater muscle catabolism in the treated animals (Tab.3) as contrasted with the CON, which gained weight during the experimental period. Still, a previous study investigating a similar treatment, found no changes in the muscle and lipid deposition of the animals, once the evaluation method used was BCS (Pereira et al., 2013). This methodology shows low sensitivity to detect small body weight variations, besides being subjective and demanding many observations (Loker et al., 2013, Pires et al., 2013).

Furthermore, the weight loss may result from a reduction in the glucose supply to the skeletal muscle due to a reduced expression of insulin receptors, which are necessary for the internalization of insulin through glucose transporter type 4 (GLUT4) (Duehlmeier et al., 2013, Zhang et al., 2013). This decrease in receptor expression has been demonstrated by other studies as being a physiological mechanism (Bell and Bauman, 1997, Kerestes et al., 2009) which aims to decrease glucose use by peripheral tissues and increase its availability to the mammary gland (Bell and Bauman, 1997, Mattmiller et al., 2011). This also increases the availability of amino acids for gluconeogenesis (Roche et al., 2009, Koster and Opsomer, 2013), promoting the conversion of methylmalonyl-CoA into succiny-CoA by methylmalonyl-CoA mutase, which is cyanocobalanin-dependent. This is an important route for the entry of propionate into the Krebs Cycle to synthesize energy (Furll et al., 2010). This adaptive mechanism (Roche et al., 2009) could be observed in the treated animals (Fig.1) which, after insulin administration, showed a decreased glucose metabolism at the end of the treatment (28 days postpartum) when compared to the beginning (8 days postpartum).

Therefore, the weight loss and muscle catabolism observed in ABC cows may be related to the high energy demand generated by an increased milk production (Roche et al., 2006, Chagas et al., 2009), which was 5.2kg/day higher for the ABC animals (Table 3). This may have resulted from the synthesis of lactose, which occurs from glucose. The former is responsible for 50% of the osmotic pressure, partially determining the milk volume (Boutinaud et al., 2008). Besides, this was not the central hypothesis of this study, other authors have already demonstrated an increase in the production of dairy cows supplemented with 5 doses of 1000mg butaphosphan and 0.5mg cyanocobalamin (Pereira et al., 2013), or 3 doses of 10mg butaphosphan and 0.05mg cyanocobalamin/kg body weight (Kreipe et al., 2011).

No differences were detected in GTT0-60min half-life and glucose degradation rates and area under the curve (Tab. 2). These results suggest that the homeostatic mechanisms of glucose metabolism, which are mediated by endogenous insulin (Balogh et al., 2009) were not altered by the successive associated doses of butaphosphan and cyanocobalamin, thus keeping a constant transport speed of plasma into the cells (Duehlmeier et al., 2013).

Similarly, plasma levels of the other metabolites evaluated were not altered by supplementation. This can be attributed to either the low butaphosphan plasma half-life, once it can be detected in the urine flow 116 minutes after intravenous application (Veterinary..., 2000) or to its use in the phosphorylation of proteins that act on energy metabolism pathways (Grunberg et al., 2009). The same trend was observed for albumin levels, thus demonstrating that the hepatic conditions of protein anabolism and catabolism, as well as the supply of dietary protein (Raggio et al., 2007), were similar for both groups, being suitable for the transition period but lower than those of cows over 100 days of lactation (Alberghina et al., 2011). Likewise, NEFA, which measures the intensity of lipolysis in the adipose tissue (Patton et al., 2007, Rocco and McNamara, 2013), showed molar equivalence between groups, signaling that there were no lipolysis differences between treatments.

CONCLUSIONS

Combined use of butaphosphan and cyanocobalamin has the ability to enhance the adaptive physiological processes of the glucose metabolism, as well as influence the rate of muscle protein metabolism in dairy cows, which integrate the transition period. In summary, the metaphylatic injection of butaphosphan and cyanocobalamine interferes in the glucosemetabolism in dairy cows during the negative energy balance period.

ACKNOWLEDGMENTS

The authors thank Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) for the financial support.

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Received: May 23, 2015; Accepted: June 28, 2016

*Autor para correspondência (corresponding author) E-mail: marcio.nunescorrea@gmail.com

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