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Methodology and Mathematical Modeling

Propionate Challenge Tests Have Limited Value for Investigating Bovine Metabolism^1,2

Department of Animal Science, Michigan State University, East Lansing, MI 48824

³ To whom correspondence should be addressed. E-mail: allenm{at}msu.edu.

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Two experiments were designed to assess the potential utility of the propionate challenge test (PCT) as an index of gluconeogenic capacity. In Expt. 1, the dose-response to jugular propionate infusion was assessed in a duplicated 4 x 4 Latin square experiment with 8 lactating dairy cows. Sodium propionate (4.5 mol/L, pH 7.4) was infused in an intrajugular bolus at 0 (saline), 0.52, 1.04, or 1.56 mmol/kg body weight (BW), and jugular blood was sampled over the following 2 h. Peak propionate concentration in plasma and area under the curve for plasma glucose both increased linearly with increasing propionate dose (P < 0.01). Plasma free fatty acid (FFA) concentration was elevated by all propionate treatments at 20 min postinfusion (P = 0.03), and plasma cortisol concentration tended to increase (P < 0.10) after propionate infusions. Experiment 2 was designed to study the effect of short-term differences in fed state on responses to propionate infusion. Lactating dairy cows (n = 8) were included in a duplicated 4 x 4 Latin square design with a 2 x 2 factorial arrangement of treatments. Sodium propionate (1.04 mmol/kg BW) or saline was infused either before feeding (0900) or 2 h after feeding (1300). Fed cows consumed 4.4 ± 1.4 kg dry matter before the PCT. Although fed cows had a significantly higher preinfusion plasma propionate concentration, fed state did not influence postinfusion changes in plasma propionate, glucose, insulin, glucagon, or FFA concentrations. Liver glycogen concentration decreased significantly after propionate, but not saline infusion (P < 0.05). Short-term differences in fed state do not affect the physiological responses to PCT. However, glucagon release after jugular administration of propionate is likely supraphysiologic, and postinfusion lipolysis and glycogenolysis suggest that stress responses may alter PCT measurements. Although the PCT may help to diagnose liver dysfunction, it is not a useful index with which to assess differences in gluconeogenic capacity.

KEY WORDS: • propionate challenge test • dairy cows • infusion • dose-response • methods

Propionate plays a central role in ruminant metabolism as the primary gluconeogenic precursor in fed animals, and diets for lactating dairy cows must be formulated to provide adequate propionate supply for glucose production. However, excess propionate production may result in decreased feed intake in cows fed highly fermentable diets (1). Therefore, determining the ideal rate and/or amount of propionate absorption from the rumen is of interest to ruminant nutritionists.

Propionate metabolism by the ruminant occurs nearly exclusively in the liver. Once trapped as propionyl-CoA and converted to succinyl-CoA, propionate carbon can be utilized for gluconeogenesis or oxidized. Despite the fact that as much as 85% of propionate is used for glucose production in lactating cows (2), propionate oxidation may play a significant role in the regulation of feed intake. Propionate entry rates likely exceed the capacity of gluconeogenic enzymes in animals fed highly fermentable diets, and excess propionate can be oxidized after conversion to acetyl-CoA (3). The resulting increase in intracellular energy status may lead to satiety and decreased meal size (4).

However, the extent to which propionate uptake exceeds gluconeogenic capacity depends not only on diet characteristics, but also on animal-to-animal variability in the concentration and activity of gluconeogenic enzymes. We hypothesized that higher-producing cows have greater feed intake in part because they have greater gluconeogenic capacity and therefore can absorb greater amounts of propionate before satiety is triggered. Testing this hypothesis, however, requires measurement of gluconeogenic capacity without the confounding effects of differences in meal patterns and level of feed intake.

The propionate challenge test (PCT),⁴ or propionate loading test, is one method by which hepatic function may be assessed with minimal invasiveness. By measuring the rate of propionate disappearance and glucose appearance in blood plasma after propionate infusion, the efficiency of propionate extraction and rate of gluconeogenesis can be estimated. However, there are concerns about both the accuracy of these estimates and the safety of the PCT. Jugular infusions of propionate have resulted in adverse responses including increased respiratory rate, increased heart rate, metabolic alkalosis (5), and even death (6). Even if the long-term health of the animals is not jeopardized by the PCT, researchers must consider whether these physiologic changes might influence measured metabolic responses to the infusion.

Our aims in these experiments were as follows: 1) to determine whether propionate can be infused at a dose that would provide insight into its metabolism, but avoid the negative consequences of its administration; 2) to determine whether short-term differences in fed state alter response variables during the PCT; and 3) to assess the validity of measuring changes in plasma glucose concentration as a proxy for gluconeogenic rate during the PCT.

	MATERIALS AND METHODS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Experimental procedures were approved by the All-University Committee on Animal Use and Care at Michigan State University.

    Experiment 1. Experiment 1 was designed to assess the dose-response to jugular Na propionate infusion and to determine whether a single jugular catheter is adequate for a PCT. Lactating Holstein cows [n = 8; 636 ± 59 kg body weight (BW), 55 ± 4 kg milk yield, and 84 ± 14 d in milk, mean ± SD] were randomly assigned to square and treatment sequence in a replicated 4 x 4 Latin-square design balanced for carry-over effects. Treatments were 0, 0.52, 1.04, and 1.56 mmol Na propionate/kg BW. Cows were housed indoors in tie stalls, fed a total mixed ration once daily at 1100, and milked twice daily in a milking parlor (0530 and 1500). Diet ingredients and nutrient composition are shown in Table 1.

    Experiment 2. Experiment 2 was designed to test the effects of short-term feed withdrawal on PCT results and to assess changes in hepatic glycogen content after propionate infusion. Lactating Holstein cows (n = 8; 726 ± 67 kg BW, 29 ± 4 kg milk yield, and 275 ± 59 d in milk) were randomly assigned to square and treatment sequence in a replicated 4 x 4 Latin-square design balanced for carry-over effects with a 2 x 2 factorial arrangement of treatments. Infusion treatments were 1.04 mmol Na propionate/kg BW or an equal volume of sterile isotonic saline, and cows were either allowed to eat their primary daily meal before the PCT or the PCT was administered before the normal feeding time. Cows were managed as in Expt. 1; diet ingredients and nutrient composition are shown in Table 1.

Two days before the initial infusion for each cow, radiopaque polyurethane catheters (14 gauge x 13 cm, no. 1411, MILA International) were inserted into a single jugular vein. Catheter patency was checked daily throughout the experiment. On test days, unfed cows were blocked from feed at 0900 and PCT were initiated immediately, whereas fed cows were fed as normal at 1100, allowed to eat for 2 h, and then blocked from feed for PCT at 1300. Although feed was available before 0900, little feed was consumed between 0700 and 0900 in either group, and the largest meal of the day occurred immediately after feeding. At treatment initiation, Na propionate (prepared as in Expt. 1) or an equal volume of saline was infused over a period of 2.5–5 min. Blood was sampled and catheters were flushed as in Expt. 1.

Liver biopsies were collected at –5, 35, and 125 min relative to the beginning of each infusion. After local anesthetization with 2% lidocaine hydrochloride, biopsy instruments (14-gauge Vet-Core biopsy needles, Global Veterinary Products) were inserted between the 11th and 12th ribs on a line between the olecranon and the tuber coxae on the right side. Biopsies of 20 mg (n = 5) were collected and immediately (<5 s) frozen in liquid nitrogen; the 100-mg sample was stored at –80°C until further processing.

    Sample handling and analysis. Blood was collected and stored as previously described (7). Plasma propionate concentrations were determined by HPLC according to the method described for ruminal fluid (8). Plasma samples were analyzed using commercial kits to determine concentrations of free fatty acids (FFA; NEFA C-kit, Wako Chemicals), insulin (Coat-A-Count, Diagnostic Products), and glucagon (Glucagon kit GL-32K, Linco Research). Plasma glucose concentration was determined by the glucose oxidase method (Sigma Chemical). In addition, plasma samples from Expt. 1 collected at the –10-, 0-, and 10-min time points were analyzed for cortisol concentration by RIA (Coat-A-Count, Diagnostic Products). Cortisol values are expressed as change from baseline to account for the large animal-to-animal variation in the preinfusion concentrations.

Liver samples were analyzed for glycogen content by a method modified from Andersson et al. (9). After extraction as described, 200 µL of homogenate was incubated with 400 µL of 2 mol/L KOH for 20 min at 70°C. The homogenate solution was cooled to room temperature; 200 µL of 1 mol/L Na₂SO₄ and 1 mL of 95% ethanol were added, and the solution was centrifuged for 5 min at 2000 x g. The precipitate was dried overnight in a fume hood; then, 400 µL of 0.3 mol/L Na acetate buffer (pH 4.8) containing 0.375% amyloglucosidase (Sigma Chemical) was added. The solution was then mixed on a vortex and incubated for 1 h at 55°C. Finally, the glucose concentration of the solution was measured by the glucose oxidase method. Glycogen content was calculated as glucosyl units/g wet tissue weight.

    Statistical analysis. Data from 1 cow period in Expt. 1 and 4 cow periods in Expt. 2 were deleted because catheter patency was lost, providing 31 PCT in Expt. 1 and 28 PCT in Expt. 2 for statistical analysis. To assess the dose response to Na propionate infusion, Expt. 1 data were analyzed using the mixed model procedure of SAS (version 9.0, SAS Institute) according to the following model:

where Y_ijklm is a dependent variable, µ = overall mean, S_i = fixed effect of square (i = 1–2), D_j = fixed effect of dose (j = 1–4), C_k(S_i) = random effect of cow (k = 1–4) nested within square, P_l(S_i) = fixed effect of period (l = 1–4) nested within square, T_m = fixed effect of sample time (m = –10 to 120), DT_im = interaction of dose and sample time, and e_ijklm = residual. A heterogeneous autroregressive [ARH(1)] covariance structure was assigned to the time variable, and residual distributions were checked visually for normality. Denominator df were estimated by the Kenward-Rogers method. Values were log-transformed for analysis and reported means were back-transformed.

The area under the curve (AUC) was calculated by the trapezoidal rule for glucagon, insulin, FFA, and glucose concentrations using the mean of the –10- and 0-min time points as the baseline value for each PCT. Values for AUC and change in cortisol concentration were analyzed using the fit model procedure of JMP (version 5.0, SAS Institute) according to the following models:

where Y_ijkl is a dependent variable, µ = overall mean, S_i = fixed effect of square (i = 1–2), D_j = fixed effect of dose (j = 1–4), C_k(S_i) = random effect of cow (k = 1–4) nested within square, P_l(S_i) = fixed effect of period (l = 1–4) nested within square, and e_ijkl = residual.

where Y_ijklm is a dependent variable, µ = overall mean, S_i = fixed effect of square (i = 1–2), D_j = fixed effect of dose (j = 1–2), F_k = fixed effect of fed state (k = 1–2), C_l(S_i) = random effect of cow (l = 1–4) nested within square, P_m(S_i) = random effect of period (m = 1–4) nested within square, DF_jk = interaction of infusion and fed state, and e_ijklm = residual.

For Expt. 1, the overall effect of propionate administration was tested by comparing all 3 propionate infusions with the saline treatment using an orthogonal contrast. Dose responses were assessed by linear and quadratic contrasts for each variable; the effect of catheter on plasma propionate concentration was also tested with this model by including the fixed effect of catheter in the model. For Expt. 2, liver glycogen data were analyzed by adding fixed effects of sample time (–5, 35, or 125 min) and all 2- and 3-way treatment x time interactions to the model. Propionate concentrations at 10 min postinfusion and glucose AUC values from both experiments were log-transformed for analysis and reported means were back-transformed. For all analyses, treatment effects were declared significant at P < 0.05 and tendencies for treatment effects were declared at P < 0.10, whereas interactions were declared significant at P < 0.10 and tendencies were declared at P < 0.15.

	RESULTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
    Experiment 1. Baseline plasma propionate concentrations did not differ for all treatments (Table 2). Measured propionate concentrations peaked at 10 min after initiation of infusion for all propionate treatments (Fig. 1A), and propionate concentrations at the 10-min time point increased linearly with propionate dose (P < 0.001, Table 2). As expected, plasma propionate concentrations returned to baseline values by 30 min postinfusion for all doses, and only the 1.56 mmol/kg dose elevated propionate concentrations at 20 min postinfusion. Concentrations of plasma glucose increased rapidly after propionate infusion, reaching a maximum between 10 and 20 min and returning to baseline by 120 min after propionate infusion (Fig. 1B). Glucose AUC increased linearly with increasing propionate infusion (P < 0.01, Table 2).

View larger version (18K): [in this window] [in a new window]   FIGURE 1  Effects of propionate infusion dose on plasma concentrations of propionate (A), glucose (B), insulin (C), glucagon (D), and FFA (E) in dairy cattle. Values are least-square means ± SEM, n = 8.

Plasma propionate concentrations from sampling and infusion catheters were compared for samples collected at 10 min postinfusion. Although the values from the 2 catheters were correlated (r = 0.98, P < 0.001, Fig. 2), there was an effect of catheter on measured propionate values (P < 0.001), indicating that values determined from the sampling catheter were higher than those from the infusion catheter.

View larger version (11K): [in this window] [in a new window]   FIGURE 2  Correlation between propionate concentrations in plasma of 8 dairy cattle collected from infusion and sampling catheters after proprionate infusion (slope = 0.78).

View larger version (15K): [in this window] [in a new window]   FIGURE 3  Effect of propionate infusion on liver glycogen concentration in dairy cattle. Values are least-square means ± SEM, n = 7.

	DISCUSSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

Another methodological consideration for the PCT is the importance of test time relative to feeding. Fasting for 6 d has dramatic effects on PCT measurements (11), but potential effects of short-term differences in fed state have not been assessed. Our results in Expt. 2 suggest that results from PCTs conducted before daily feeding are quite similar to those from postfeeding PCTs. Although baseline propionate concentrations increased after 2 h of access to feed, postinfusion PCT measurements were not influenced by short-term fed state.

    Utility of the PCT. Postinfusion changes in plasma propionate and glucose concentrations increased linearly with increasing propionate (Table 2). Linear responses were expected, given that propionate is a potent insulin secretagogue (12) and the primary glucose precursor (13) in ruminants. Although plasma glucagon and FFA responses (Fig. 1D, E) were characteristic of reported PCT results (14,15), the lack of linear responses to an increasing propionate dose suggests that propionate's effects on glucagon secretion and FFA release are either nearly maximal at a dose of 0.52 mmol/kg or are secondary responses to propionate infusion. Postinfusion glucagon responses to the PCT are likely much larger than physiologic responses to propionate taken up via the portal vein. Sano et al. (16) demonstrated dramatic differences in glucagon secretion when propionate was infused via the femoral vein compared with the mesenteric vein in sheep. Because first-pass hepatic extraction of propionate is typically in excess of 80%, <20% of propionate absorbed through the portal vein is available for delivery to extrahepatic tissue, including the pancreas. Supraphysiologic glucagon secretion after peripheral propionate infusion is likely explained by the fact that all of the infused propionate is available for delivery to extrahepatic tissue. The dose-response plot for glucagon (Fig. 1D) suggests that pancreatic glucagon release is maximized by peripheral infusion of 0.52 mmol propionate/kg BW; treatment effects on glucagon AUC were driven primarily by differences in glucagon concentration between 30 and 120 min postinfusion. Decreased glucagon concentrations after 30 min postinfusion were likely secondary responses resulting from the increase in plasma glucose concentration after propionate infusion.

Postinfusion FFA responses were also unusual, because plasma FFA concentrations typically decline during meals at the same time that propionate is being absorbed (1). Although transient, the significant increase in plasma FFA concentrations 20 min after propionate infusion (Fig. 1E) indicates that lipolysis occurred. The delayed increase in FFA concentration also suggests that propionate does not stimulate lipolysis directly. Although glucagon is probably lipolytic in ruminants (17,18), it seems unlikely that glucagon alone could have stimulated lipolysis in this situation because the insulin:glucagon ratio increased after propionate infusion, and insulin would be expected to prevent lipolysis by glucagon. Similarly, the decrease in liver glycogen content after propionate infusion in Expt. 2 (Fig. 3) indicates that glycogenolysis occurred, despite the fact that insulin concentrations remained elevated for the majority of the sampling period.

The most likely cause of postinfusion lipolysis and glycogenolysis is a stress response to propionate infusion. Although cortisol responses to propionate infusion were relatively minor, epinephrine concentrations may have been affected more dramatically. Labored breathing and coughing were observed at all propionate doses, consistent with the dose-independent effects on plasma FFA concentrations. In addition to being the most potent endogenous lipolytic agent in ruminants, epinephrine stimulates glycogenolysis in both muscle and the liver (19). Therefore, we suspect that postinfusion lipolysis and glycogenolysis are caused by a stress-induced release of epinephrine, and not directly by infused propionate. Unfortunately, samples were not handled and stored in a way that allowed for epinephrine analysis in these experiments.

Supraphysiologic increases in plasma glucagon and FFA concentrations after propionate infusion do not, in themselves, negate the use of the PCT as a tool with which to assess gluconeogenic capacity. However, postinfusion glycogenolysis does interfere with the use of plasma glucose concentration as a proxy for gluconeogenic flux. Therefore, we conclude that the PCT is not useful for assessing gluconeogenic capacity.

Propionate challenge tests have been used to assess hepatic function in ruminants for >3 decades, and Na propionate is typically administered at doses of 2.5 or 3.0 mmol/kg BW (11,14,20). Although some mild side effects of propionate infusion were reported (10,11), most studies have not reported adverse consequences (14,20,21). However, infusion of Na propionate at a dose of 3.12 mmol/kg caused tachypnea, coughing, and stupor in our preliminary work (unpublished data); furthermore, metabolic alkalosis (5) and even death (6) were reported by others using similar doses. Decreasing the dose used in the PCT from the typical 3.0 mmol/kg BW to 0.52 mmol/kg did not completely alleviate physiological stress responses, and the cause of such responses is still in question. Koenig et al. (5) expressed concern that the high osmolality of Na propionate solutions used in many studies could cause adverse effects, and in our experiments, we used a solution with relatively high osmolality (4.5 mol/L Na propionate). However, infusion of hypertonic saline (5) did not cause the same problems as propionate infusion, and Schmidely et al. (22) infused a 5.16 mol/L Na propionate solution in goats with no adverse effects reported. Given that breathing irregularities are the primary condition reported during PCTs, it seems more likely that propionate has a direct effect on the lungs. Jugular administration of fatty acids results in delivery of nearly the entire dose to the pulmonary circulation, and such high concentrations of propionate may cause an inflammatory response in the lungs. Although i.v. infusion of oleic acid can cause respiratory distress (23), it is unclear whether propionate can cause a similar effect.

	ACKNOWLEDGMENTS

 
The authors thank R. E. Kreft, M. Kopcha, R. A. Longuski, D. G. Main, Y. Ying, and E. Boterman for their technical assistance.

	FOOTNOTES

 
¹ Presented in part at the American Dairy Science Association annual meeting, July 2005, Cincinnati, OH [Bradford BJ, O'Toole AD, Nash AS, Allen MS. Validation of propionate challenge test methodology (abstract). J. Dairy Sci. 2005; 88(Suppl. 1): 249].

² Supported in part by National Research Initiative Competitive Grant no. 2004-35206-14167 from the U.S. Department of Agriculture Cooperative State Research, Education, and Extension Service (to M.S.A.), a National Science Foundation Graduate Research Fellowship (to B.J.B.), and G.C. and Gwendolyn Graf Memorial Student Enhancement Funds (to A.D.G. and A.S.N.).

⁴ Abbreviations used: AUC, area under the curve; BW, body weight; FFA, free fatty acid; PCT, propionate challenge test.

Manuscript received 8 March 2006. Initial review completed 17 April 2006. Revision accepted 20 April 2006.

	LITERATURE CITED

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5. Koenig GJ, Constable PD, Hull BL, Firkins JL. Limitations and safety hazards of propionate loading test: assessing hepatic function in the dairy cow. Large Anim Pract. 1999;20:24–9.

6. Peters JP. The relationship of vitamin B₁₂ status to B₁₂-associated urinary metabolites and endocrine events associated with infusion of propionate in the dairy cow [MS thesis]. Ithaca, NY: Cornell University; 1978.

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8. Oba M, Allen MS. Effects of corn grain conservation method on feeding behavior and productivity of lactating dairy cows at two dietary starch concentrations. J Dairy Sci. 2003;86:174–83.[Abstract/Free Full Text]

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16. Sano H, Hayakawa S, Takahashi H, Terashima Y. Plasma insulin and glucagon responses to propionate infusion into femoral and mesenteric veins in sheep. J Anim Sci. 1995;73:191–7.[Abstract]

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18. Itoh F, Obara Y, Rose MT, Fuse H. Heat influences on plasma insulin and glucagon in response to secretogogues in non-lactating dairy cows. Domest Anim Endocrinol. 1998;15:499–510.[Medline]

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20. Corse DA, Elliot JM. Propionate utilization by pregnant, lactating, and spontaneously ketotic dairy cows. J Dairy Sci. 1970;53:740–6.[Abstract/Free Full Text]

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22. Schmidely P, Lloret-Pujol M, Bas P, Rouzeau A, Sauvant D. Influence of feed intake and source of dietary carbohydrate on the metabolic response to propionate and glucose challenges in lactating goats. J Dairy Sci. 1999;82:738–46.[Abstract]

23. Gemer M, Dunegan LJ, Lehr JL, Bruner JD, Stetz CW, Don HF, Hayes JA, Drinker PA. Pulmonary insufficiency induced by oleic acid in the sheep: a model for investigation of extracorporeal oxygenation. J Thorac Cardiovasc Surg. 1975;69:793–9.[Abstract]

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