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Effect of insulin administration before weaning on reproductive performance in feed-restricted primiparous sows
Animal Reproduction Science 51 Ž1998. 119–129
Effect of insulin administration before weaning on reproductive performance in feed-restricted primiparous sows H. Quesnel ) , A. Prunier Station de Recherches Porcines, Institut National de la Recherche Agronomique, 35590 Saint-Gilles, France Accepted 10 January 1998
Abstract The objective of this study was to determine whether exogenous insulin administration in late lactation can improve reproductive performance of feed-restricted primiparous sows. A total of 24 pure Large White gilts were assigned at farrowing to one of the three following experimental groups. Control sows ŽCTRL. were fed on a plane of nutrition close to ad libitum and received 6 kg food dayy1. Restricted saline-treated ŽRS. and insulin-treated ŽRI. sows received only 4 kg food dayy1. Sows from RI group received 0.4 IU insulin per kg of live weight once daily during the 5-day pre-weaning period, whereas CTRL and RS sows received saline injections as a sham treatment. Litters Ž8–10 piglets. were weaned at 23.5 " 1 days post-partum. Blood samples were collected 2 days before ŽDay W y 2. and after weaning ŽDay W q 2.. Restricted sows RS and RI lost significantly more weight than CTRL sows Ž25 kg and 32 kg, respectively, vs. 10 kg. and more fat Ž5.3 mm and 4.7 mm, respectively, vs. 2.2 mm.. During insulin treatment, daily litter weight gain was lower in RI than in RS and CTRL groups Ž P - 0.05.. On Day W y 2, insulin concentration was higher, while that of glucose was lower in RI than in RS and CTRL sows Ž P - 0.05.. Concentrations of NEFA and IGF-I were similar in the three groups of sows. On Day W q 2, concentrations of FSH and oestradiol-17b did not differ significantly between females of the different groups. Weaning-to-oestrus interval and ovulation rate were similar in CTRL, RS and RI females Ž5.7, 5.9 and 5.6 days; 19.2, 20.7 and 22.1 corpora lutea, respectively.. We concluded that insulin administration during late lactation to feed-restricted primiparous sows did not
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Corresponding author. Tel.: q33 299 28 72 49; fax: q33 299 28 50 80; e-mail: [email protected]. 0378-4320r98r$19.00 q 1998 Elsevier Science B.V. All rights reserved. PII S 0 3 7 8 - 4 3 2 0 Ž 9 8 . 0 0 0 6 1 - X
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H. Quesnel, A. Prunierr Animal Reproduction Science 51 (1998) 119–129
improve weaning-to-oestrus interval and post-weaning ovulation rate, but was likely to decrease milk production. q 1998 Elsevier Science B.V. Keywords: Pig, reproductive performance; Lactation; Metabolic state; Reproductive performance; Insulin
1. Introduction Energy balance during lactation influences the interval from weaning to oestrus in sows ŽReese et al., 1984; Koketsu et al., 1996; Zak et al., 1997. and ovulation rate in cyclic and weaned sows ŽCox et al., 1987; Zak et al., 1997.. In a previous experiment with primiparous sows, we observed that restricting feed intake during lactation induced a decrease in LH pulsatility and ovarian development around weaning, in parallel with a decrease in insulin and IGF-I circulating concentrations during late lactation ŽQuesnel et al., 1998; Quesnel et al., unpublished data.. We hypothesized that insufficient insulin andror IGF-I might be responsible for lower ovarian activity in part by decreasing LH secretion and in part via direct effects on follicular populations. Shifts in feed intake are accompanied by the changes in circulating levels of insulin in pigs ŽBooth et al., 1996; Koketsu et al., 1996; Zak et al., 1997.. Insulin receptors have been detected in the hypothalamo-pituitary complex in rats ŽWerther et al., 1987; Lesniak et al., 1988. and insulin may alter LH profiles in gilts. For instance, infusion of glucose increased circulating insulin concentrations simultaneous with LH secretion in feed-restricted gilts ŽBooth, 1990.. Depending on studies, insulin treatment had positive or no effect on circulating LH in cyclic gilts ŽCox et al., 1987.. Withdrawing insulin therapy in diabetic gilts had no clear effect on basal LH secretion within 6 days, but pituitary LH stores were depleted and oestrous cycles were interrupted ŽCox et al., 1994; Angell et al., 1996.. Insulin receptors have been described in the ovary of sows ŽRein and Schomberg, 1982. and women ŽPoretsky et al., 1985.. Exogenous insulin increased ovulation rate ŽCox et al., 1987. and reduced follicular atresia in gilts ŽMatamoros et al., 1990, 1991., and this was associated or not with increased gonadotrophin secretion. Inversely, withdrawal of insulin from diabetic gilts during the luteal phase decreased ovulation rate and increased the rate of follicular atresia ŽCox et al., 1994.. The objective of this study was to test the hypothesis that undernutrition-derived decrease in insulin concentrations before weaning may alter reproductive function. Thus, we determined whether exogenous insulin administration in late lactation can improve post-weaning reproductive performance of feed-restricted primiparous sows.
2. Materials and methods 2.1. Preliminary experiment Four lactating pure Large White gilts were used. Within 2 days after farrowing, litter size was standardized to 9–11 piglets by crossfostering. During lactation, sows received
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in two equal meals Ž0815 h and 1315 h. 4 kg dayy1 of a diet containing 13.1 MJ DE kgy1 , 17.1% crude protein and 0.9% lysine. At day 19 postpartum, jugular vein catheterization was performed under general anaesthesia. At days 22 and 23 postpartum, sows received a subcutaneous injection of intermediate-acting human insulin ŽInsulatard w , Novo Nordisk, Denmark.. Four doses were tested Ž0, 0.1, 0.25 and 0.5 IU kg live weighty1 . and each dose was tested in two females. The injection was performed at 1600 h, i.e. about 3 h after the afternoon meal. Blood samples were collected in heparinized tubes before the injection at 1545 and 1600 h and after the injection at 1630, 1700, 1730, 1800, 2000, 2200, 0400 and 0800 h. 2.2. Animals and treatments Pure Large White gilts were inseminated at 315 " 2 and 309 " 5 days of age for the first Ž n s 12. and the second replicate Ž n s 12., respectively Žmean " S.D... They were kept in individual pens during the last week of gestation and during lactation, under constant daylength Ž12 h light dayy1 .. Within 2 days after farrowing, litter size was standardized to 9–11 piglets by crossfostering. Piglets had free access to water but received no supplemental food during lactation. They were weaned at 0900 h at 23.5 " 1 days post-partum. After weaning, the sows were checked twice daily for oestrus in the presence of a mature boar. They were slaughtered 10 days after weaning. During gestation, all females received 2.7 kg dayy1 of a diet containing 12.6 MJ DE y1 kg , 13.2% crude protein and 0.6% lysine. During lactation, they received a diet containing 13.1 MJ DE kgy1 , 17.1% crude protein and 0.9% lysine twice daily Ž0815 h and 1315 h.. After weaning, they all received 3 kg dayy1 of the gestation diet, in two equal meals. During farrowing, the females were assigned to one of the three following experimental groups. Control sows ŽCTRL. were fed on a plane of nutrition close to ad libitum and received 6 kg food dayy1 on average over lactation. Restricted saline- ŽRS. and insulin-treated ŽRI. sows received only 4 kg food dayy1 . RI sows received subcutaneous injections of intermediate-acting human insulin ŽInsulatard w , Novo Nordisk. once daily during the 5 days preceding weaning. A dose of 0.4 IU kg live weighty1 was chosen according to the results of a preliminary experiment. The injection was performed at 1700 h, about 4 h after the afternoon meal. Control and RS sows received saline injections as a sham treatment. 2.3. Sample collection Blood samples were collected using a vacuutainer 2 days before weaning ŽDay W y 2. at 2000 h and 2 days after weaning ŽDay W q 2. at 0800 h. Samples were collected in heparinized tubes, immediately placed on ice and centrifuged to remove plasma. Plasma samples were stored at y208C until assayed. Ovaries were collected immediately after slaughter and examined macroscopically. The number of corpora lutea was recorded. Some corpora lutea were unusually large ŽG 15 mm in diameter. and were designed as «hypertrophied».
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2.4. Analyses 2.4.1. Measurements Animals were weighed and backfat depth was measured at three sites Žshoulder, last rib and loin, at 65 mm from the midline. on the day after farrowing, on the first day of injections and at weaning. Piglets were weighed at birth, on the first day of injection and at weaning. 2.4.2. Hormone and metabolite assays Insulin, insulin-like growth factor-I ŽIGF-I., follicle-stimulating hormone ŽFSH. and oestradiol-17b concentrations were determined in plasma samples by validated radioimmunoassays ŽPrunier et al., 1993; Louveau and Bonneau, 1996; Camous et al., 1985; Thibier and Saumande, 1975.. Concentrations of glucose and non-esterified fatty acids ŽNEFA. were measured by automated enzymatic methods with a Cobas Mira ŽHoffman Laroche, Basel, Switzerland. apparatus. Plasma concentrations of insulin, IGF-I, NEFA and glucose were determined at Day W y 2, and those of FSH and oestradiol-17b at Day W q 2. 2.5. Statistical analyses All data Žsow and litter parameters, blood concentrations. were analysed by analysis of variance using the GLM procedure of SAS ŽSAS, 1990.. All models of analyses included the effects of the treatment group, replicate and the interaction between these two factors. No interaction between the group and the replicate was found. When the effect of the group was significant Ž P - 0.05., comparison between the groups were performed using Bonferroni’s test. For daily weight gain of the litters, litter live weight before insulin treatment was introduced as a covariate in the model and comparisons between groups used the Dunnett’s one-tailed t-test, testing if treatment was significantly smaller than that of the control.
3. Results 3.1. Preliminary experiment The preliminary dose–response trial was performed to select the appropriate dose of insulin and was focused on plasma concentrations of insulin and glucose. In both control sows Ždose 0., plasma insulin concentrations decreased 2 h after injection, indicating that the postprandial peak of insulin was not completely achieved at 1600 h ŽFig. 1.. Thereafter, insulin remained at low levels for 16 h. Similar results were obtained with the dose 0.1 Ždata not shown.. In sows which received the doses of 0.25 or 0.5 IU kgy1 , plasma insulin concentrations increased after the injection and remained at
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Fig. 1. Mean plasma insulin and glucose concentrations relative to an injection of 0, 0.25 or 0.5 IU insulin kg live weighty1 in primiparous lactating sows. Time 0 represents the time of injection.
a higher level compared with control sows for 10 h ŽFig. 1.. In these sows, glucose concentrations decreased after the injection of insulin and remained at low levels for 10 h ŽFig. 1.. Therefore, we chose to use an intermediate dose of 0.4 IU kgy1 , in order to be sure to double plasma concentrations of insulin during at least 8–10 h, without inducing a strong hypoglycemia. Moreover, we decided to perform the injections at 1700 h instead of 1600 h, when the postprandial peak of insulin was completely achieved. 3.2. Sow and litter performance On the day after farrowing, there was no significant difference in live weight and backfat depth between sows ŽTable 1.. During lactation, the decrease in live weight and backfat depth was significantly greater in restricted RS and RI sows than in CTRL sows ŽTable 1..
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Table 1 Live weight and backfat measurements Žmeans"S.E.M.. in primiparous sows Treatment group
Effect of group
CTRL Number of sows
RS
RI
8
8
8
LiÕe weight (kg) At farrowing Before treatment At weaning Loss during lactation Loss during treatment
221"5 215"4 210"4a y10"3a y4.5"2
219"4 200"3 194"2 b y25"2 b y6.7"1
228"3 201"3 195"2 b y32"3b y5.1"1
NS )) ))) ))) NS
Backfat depth (mm) At farrowing At weaning Loss during lactation
17.5"1.8 15.2"2.0 y2.2"0.6 a
19.6"1.2 14.4"0.9 y5.3"0.6 b
18.6"0.9 13.9"0.9 y4.7"0.4 b
NS NS ))
CTRL s control group; RSs restricted saline-treated group; RI s restricted insulin-treated group. NS: P ) 0.1, )): P - 0.01, ))): P - 0.001.
Litter size at weaning was similar for the three groups of sows ŽTable 2.. Litter live weights did not differ between the three groups after crossfostering, at the beginning of the treatment and at weaning. Daily weight gain of litters was similar in the three groups of sows before insulin treatment but was lower in RI group during treatment Ž P - 0.05..
Table 2 Litter performance Žmeans"S.E.M.. Treatment group CTRL Number of sows
8
Effect of group RS
RI
8
8
Total number of piglets Born 10.2"1.5 Weaned 9.5"0.3
10.6"1.2 9.1"0.3
10.7"0.7 9.4"0.3
NS NS
Litter liÕe weight (kg) At birth Before treatment At weaning
15.1"0.9 51.9"2.1 60.9"2.7
15.2"0.5 57.5"1.9 65.1"2.1
NS NS NS
2040"102 1800"156 a
2240"63 1530"114b
NS )
14.5"0.7 53.1"2.3 62.6"2.7
Daily litter weight gain (g d y 1) Before treatment 2120"102 During treatment 1900"118 a
CTRL s control group; RSs restricted saline-treated group; RI s restricted insulin-treated group. NS: P ) 0.1, ): P - 0.05.
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Table 3 The reproductive performance of primiparous sows Žmeans"S.E.M.. Treatment group CTRL Number of sows 8 Number of sows in oestrus 8 W-O-I Žday. 5.7"0.2 Mean ovarian weight Žmg. 10.2"1.3 Number of CL 19.2"1.2 Number of hyper CL 3.0"1.1
RS
RI
Effect of group
8 7 5.9"0.3 8.5"1.1 20.7"1.4 1.6"0.8
8 7 5.6"0.3 10.4"1.3 22.1"1.4 5.1"1.6
NS NS NS NS NS
Number of sows in oestruss number of sows in oestrus within 10 days after weaning. W-O-Is weaning-tooestrus interval. Number of CL s number of corpora lutea per sow. Number of hyper CL s number of hypertrophied corpora lutea per sow. CTRL s control group; RSs restricted saline-treated group; RI s restricted insulin-treated group. NS: P ) 0.1.
3.3. ReproductiÕe performance Only two sows did not revert into oestrus within 10 days after weaning and did not ovulate. For the other sows, there was no treatment effect on the weaning-to-oestrus interval and no effect on the number of healthy or hypertrophied corpora lutea and on mean ovarian weight recorded 10 days after piglet removal ŽTable 3..
Fig. 2. Mean plasma concentrations of insulin, insulin-like growth factor-I ŽIGF-I., non-esterified fatty acids ŽNEFA. and glucose in CTRL, RS and RI sows 2 days before weaning. CTRL s control group; RSs restricted saline-treated group; RI s restricted insulin-treated group.
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Fig. 3. Mean plasma concentrations of FSH and oestradiol-17b in CTRL, RS and RI sows 2 days after weaning. CTRL s control group; RSs restricted saline-treated group; RI s restricted insulin-treated group.
3.4. Hormones On Day W y 2, insulin concentration was significantly higher in RI sows compared with CTRL and RS sows, and glucose concentration was significantly lower ŽFig. 2.. Concentrations of NEFA and IGF y I did not differ significantly between groups of females ŽFig. 2.. On Day W q 2, concentrations of FSH and oestradiol-17b did not differ between groups Ž P ) 0.1, Fig. 3..
4. Discussion Insulin treatment resulted in a significant increase in plasma insulin concentrations, as it was anticipated. This elevation of insulin was accompanied by a decrease in glucose concentrations, without any effect on IGF-I and NEFA levels before weaning. Daily litter weight gain during the period of injection was lower in insulin-treated compared with non-treated sows. This may be related to the lower level of glucose in insulin-treated sows, since the availability of glucose is regarded as a primary limit to milk production ŽBoyd et al., 1995.. Moreover, high plasma insulin concentration may favour the partitioning of nutrients into maternal body stores rather than into milk. In this study, exogenous insulin administration to feed-restricted primiparous sows during late lactation had no influence on ovarian activity, contrarily to what we had
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expected. Similarly, it had no influence on plasma FSH and oestradiol-17b concentrations 2 days after weaning. Since Pettigrew and Tokach Ž1993. have described a high positive correlation between insulin concentration in early lactation ŽDay 7. and number of LH peaks in late lactation ŽDay 21., the effects of insulin administration during early lactation remain to be investigated. Two hypotheses may explain this failure of insulin treatment to alter ovulation rate or weaning-to-oestrus interval in the current experiment. First, reproductive performance of saline-restricted sows was relatively good and similar to those observed in well-fed sows. Thus, reproductive performance of feed-restricted sows was unlikely to be improved by insulin treatment. Lack of influence of feed restriction on reproductive performance and reproductive hormone concentrations of saline-treated sows may be related to the absence of significant differences in plasma glucose, NEFA, insulin and IGF-I despite higher losses in live weight and fat depth in feed-restricted compared with well-fed sows Žy25 vs. y10 kg live weight and y5 vs. y2 mm fat depth.. The food restriction imposed during lactation was probably not sufficient to induce a catabolic state severe enough to provoke reproductive failure. It can be assumed that the effect of insulin on reproductive performance in lactating sows might depend on the nutritional state, as previously suggested for weaned sows ŽRamirez et al., 1993. and that it can not improve the performances in non- or slightly-catabolic sows. Second, the increase in plasma insulin might not have altered LH secretion in the present study, as reported in primiparous sows after insulin administration at weaning ŽRojkittikhun et al., 1993. and after glucose infusion in late lactation ŽTokach et al., 1992. or after weaning ŽPlaine et al., 1995.. Similarly, infusion of glucose into underfed rams did not affect GnRH pulsatility, although blood glucose and insulin concentrations were highly increased ŽBoukhliq et al., 1996.. To our knowledge, this is the first study to investigate the effect of insulin treatment during lactation. Previous data concerning insulin administration showed a clear positive effect on ovulation rate and follicular atresia in cyclic or prepuberal gilts ŽCox et al., 1987; ŽMatamoros et al., 1990, 1991. and inconsistent results in weaned sows. Insulin administration at or after weaning had no effect on reproductive performance in primiparous, multiparous, or mixed-parity sows ŽKirkwood and Thacker, 1991; Rojkittikhun et al., 1993; Cox et al., 1994. or had a positive influence on farrowing rate or subsequent litter size in primiparous sows ŽRamirez et al., 1997.. Cox et al. Ž1995. have also reported that the administration of insulin in post-weaning primiparous sows was more efficient in increasing litter size when the level of feeding was higher. In conclusion, insulin administration during late lactation to feed-restricted primiparous sows does not improve the interval between weaning and oestrus or subsequent ovulation rate, but is likely to decrease milk production.
Acknowledgements The authors wish to acknowledge the swine barn staff of Saint-Gilles, Y. Lebreton for performing surgical procedures, and A. Pasquier and A.M. Mounier for expert technical assistance. They are also grateful to J.Y. Dourmad for a critical evaluation of the manuscript.
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References Angell, C.A., Tubbs, R.C., Moore, A.B., Barb, C.R., Cox, N.M., 1996. Depressed luteinizing hormone response to oestradiol in vivo and gonadotropin-releasing hormone in vitro in experimentally diabetic swine. Dom. Anim. Endocrinol. 13, 453–463. Booth, P.J., 1990. Metabolic influences on hypothalamic–pituitary–ovarian function in the pig. J. Reprod. Fertil. Suppl. 40, 89–100. Booth, P.J., Cosgrove, J.R., Foxcroft, G.R., 1996. Endocrine and metabolic responses to re-alimentation in feed-restricted prepubertal gilts: associations among gonadotropins, metabolic hormones, glucose, and utero-ovarian development. J. Anim. Sci. 74, 840–848. Boukhliq, R., Miller, D.W., Martin, G.B., 1996. Relationship between nutritional stimulation of gonadotrophin secretion and the peripheral and cerebrospinal fluid ŽCSF. concentrations of glucose and insulin in rams. Anim. Reprod. Sci. 41, 201–214. Boyd, R.D., Kensinger, R.S., Harrell, R.J., Bauman, D.E., 1995. Nutrient uptake and endocrine regulation of milk synthesis by mammary tissue of lactating sows. J. Anim. Sci. 73, 36–56, Suppl. 2. Camous, S., Prunier, A., Pelletier, J., 1985. Plasma prolactin, LH, FSH and estrogen excretion patterns in gilts during sexual development. J. Anim. Sci. 60, 1308–1317. Cox, N.M., Stuart, M.J., Althen, T.G., Bennett, W.A., Miller, H.W., 1987. Enhancement of ovulation rate in gilts by increasing dietary energy and administering insulin during follicular growth. J. Anim. Sci. 64, 507–516. Cox, N.M., Meurer, K.A., Carlton, C.A., Tubbs, R.C., Mannis, D.P., 1994. Effect of diabetes mellitus during the luteal phase of the oestrous cycle on pre-ovulatory follicular function, ovulation and gonadotrophins in gilts. J. Reprod. Fertil. 101, 77–86. Cox, N.M., Quirk, M.N., Moore, A.B., Ramirez, J.L., 1995. Influences of parity and level of feed intake on reproductive responses to insulin administered to sows after weaning. J. Anim. Sci. 73, 433, Suppl 1. Kirkwood, R.N., Thacker, P.A., 1991. The influence of pre-mating feeding level and exogenous insulin on the reproductive performance of sows. Can. J. Anim. Sci. 71, 249–251. Koketsu, Y., Dial, G.D., Pettigrew, J.E., Marsh, W.E., King, V.L., 1996. Influence of imposed feed intake patterns during lactation on reproductive performance and on circulating levels of glucose, insulin, and luteinizing hormone in primiparous sows. J. Anim. Sci. 74, 1036–1046. Lesniak, M.A., Hill, J.M., Kiess, W., Rojeski, M., Pert, C.B., Roth, J., 1988. Receptors for insulin-like growth factors I and II: autoradiographic localization in rat brain and comparison to receptors for insulin. Endocrinology 123, 2089–2099. Louveau, I., Bonneau, M., 1996. Effect of a growth hormone infusion on plasma insulin-like growth factor-I in Meishan and Large White pigs. Reprod. Nutr. Dev. 36, 301–310. Matamoros, I.A., Cox, N.M., Moore, A.B., 1990. Exogenous insulin and additional energy affect follicular distribution, follicular steroid concentrations, and granulosa cell human chorionic gonadotropin binding in swine. Biol. Reprod. 43, 1–7. Matamoros, I.A., Cox, N.M., Moore, A.B., 1991. Effects of exogenous insulin and body condition on metabolic hormones and gonadotropin-induced follicular development in prepubertal gilts. J. Anim. Sci. 69, 2081–2091. Pettigrew, J.E., Tokach, M.D., 1993. Metabolic influences on sow reproduction. Pigs News Inf. 14, 69–72. Plaine, K.J., Tilton, J.E., Weigl, R.M., 1995. Influence of insulin andror glucose infusion on luteinizing hormone and oestradiol secretion in the weaned primiparous sow. J. Reprod. Fertil. 15, 113. Poretsky, L., Grigorescu, F., Seibel, M., Moses, A.C., Flier, J.S., 1985. Distribution and characterization of insulin and insulin-like growth factor-I receptors in normal human ovary. J. Clin. Endocrinol. Metab. 61, 728–734. Prunier, A., Martin, C., Mounier, A.M., Bonneau, M., 1993. Metabolic and endocrine changes associated with undernutrition in the peripubertal gilt. J. Anim. Sci. 71, 1887–1894. Quesnel, H., Pasquier, A., Mounier, A.M., Prunier, A., 1998. Influence of feed restriction during lactation on reproductive hormone and ovarian development in primiparous sows. J. Anim. Sci. 76, 856–863. Ramirez, J.L., Cox, N.M., Moore, A.B., Holtxamp, A.J., Tubbs, R.C., 1993. Administration of insulin to first litter sows on a commercial farm: effects on conception rate and litter size in relation to body condition. In: Proc. of the 4th Int. Conference on Pig Reproduction, Columbia, MO, May 23–26, Abstr. p. 96.
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Ramirez, J.L., Cox, N.M., Moore, A.B., 1997. Influence of exogenous insulin before breeding on conception rate and litter size of sows. J. Anim. Sci. 75, 1893–1898. Reese, D.E., Peo, E.R., Lewis, A.J., 1984. Relationship of lactation energy intake and occurrence of post-weaning oestrus to body and backfat composition in sows. J. Anim. Sci. 58, 1236–1244. Rein, M.S., Schomberg, D.W., 1982. Characterization of insulin receptors on porcine granulosa cells. Biol. Reprod. 26, 113, Suppl. 1. Rojkittikhun, T., Einarsson, S., Zilinskas, H., Edqvist, L.E., Uvnas-Moberg, K., Lundeheim, N., 1993. Effects ¨ of insulin administration at weaning on hormonal patterns and reproductive performance in primiparous sows. J. Vet. Med. A 40, 161–168. SAS, 1990. User’s guide: Statistical Analysis System Institute, Cary, NC. Thibier, M., Saumande, J., 1975. Oestradiol-17b , progesterone and 17a-hydroxyprogesterone concentrations in jugular venous plasma in cows prior and during oestrus. J. Steroid Biochem. 6, 1433–1437. Tokach, M.D., Pettigrew, J.E., Dial, G.D., Wheaton, J.E., Crooker, B.A., Koketsu, Y., 1992. Influence of glucose infusions on luteinizing hormone secretion in the energy-restricted primiparous lactating sow. J. Anim. Sci. 70, 2202–2206. Werther, G.A., Hogg, A., Oldfield, B.J., McKinley, M.J., Fogdor, R., Allen, A.M., Mendelson, F.A.O., 1987. Localization and characterization of insulin receptors in rat brain and pituitary gland using in vitro autoradiography and computerized densitometry. Endocrinology 121, 1562–1569. Zak, L.J., Cosgrove, J.R., Aherne, F.X., Foxcroft, G.R., 1997. Pattern of feed intake and associated metabolic and endocrine changes differentially affect post-weaning fertility in primiparous lactating sows. J. Anim. Sci. 75, 208–216.
Effect of insulin administration before weaning on reproductive performance in feed-restricted primiparous sows H. Quesnel ) , A. Prunier Station de Recherches Porcines, Institut National de la Recherche Agronomique, 35590 Saint-Gilles, France Accepted 10 January 1998
Abstract The objective of this study was to determine whether exogenous insulin administration in late lactation can improve reproductive performance of feed-restricted primiparous sows. A total of 24 pure Large White gilts were assigned at farrowing to one of the three following experimental groups. Control sows ŽCTRL. were fed on a plane of nutrition close to ad libitum and received 6 kg food dayy1. Restricted saline-treated ŽRS. and insulin-treated ŽRI. sows received only 4 kg food dayy1. Sows from RI group received 0.4 IU insulin per kg of live weight once daily during the 5-day pre-weaning period, whereas CTRL and RS sows received saline injections as a sham treatment. Litters Ž8–10 piglets. were weaned at 23.5 " 1 days post-partum. Blood samples were collected 2 days before ŽDay W y 2. and after weaning ŽDay W q 2.. Restricted sows RS and RI lost significantly more weight than CTRL sows Ž25 kg and 32 kg, respectively, vs. 10 kg. and more fat Ž5.3 mm and 4.7 mm, respectively, vs. 2.2 mm.. During insulin treatment, daily litter weight gain was lower in RI than in RS and CTRL groups Ž P - 0.05.. On Day W y 2, insulin concentration was higher, while that of glucose was lower in RI than in RS and CTRL sows Ž P - 0.05.. Concentrations of NEFA and IGF-I were similar in the three groups of sows. On Day W q 2, concentrations of FSH and oestradiol-17b did not differ significantly between females of the different groups. Weaning-to-oestrus interval and ovulation rate were similar in CTRL, RS and RI females Ž5.7, 5.9 and 5.6 days; 19.2, 20.7 and 22.1 corpora lutea, respectively.. We concluded that insulin administration during late lactation to feed-restricted primiparous sows did not
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Corresponding author. Tel.: q33 299 28 72 49; fax: q33 299 28 50 80; e-mail: [email protected]. 0378-4320r98r$19.00 q 1998 Elsevier Science B.V. All rights reserved. PII S 0 3 7 8 - 4 3 2 0 Ž 9 8 . 0 0 0 6 1 - X
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improve weaning-to-oestrus interval and post-weaning ovulation rate, but was likely to decrease milk production. q 1998 Elsevier Science B.V. Keywords: Pig, reproductive performance; Lactation; Metabolic state; Reproductive performance; Insulin
1. Introduction Energy balance during lactation influences the interval from weaning to oestrus in sows ŽReese et al., 1984; Koketsu et al., 1996; Zak et al., 1997. and ovulation rate in cyclic and weaned sows ŽCox et al., 1987; Zak et al., 1997.. In a previous experiment with primiparous sows, we observed that restricting feed intake during lactation induced a decrease in LH pulsatility and ovarian development around weaning, in parallel with a decrease in insulin and IGF-I circulating concentrations during late lactation ŽQuesnel et al., 1998; Quesnel et al., unpublished data.. We hypothesized that insufficient insulin andror IGF-I might be responsible for lower ovarian activity in part by decreasing LH secretion and in part via direct effects on follicular populations. Shifts in feed intake are accompanied by the changes in circulating levels of insulin in pigs ŽBooth et al., 1996; Koketsu et al., 1996; Zak et al., 1997.. Insulin receptors have been detected in the hypothalamo-pituitary complex in rats ŽWerther et al., 1987; Lesniak et al., 1988. and insulin may alter LH profiles in gilts. For instance, infusion of glucose increased circulating insulin concentrations simultaneous with LH secretion in feed-restricted gilts ŽBooth, 1990.. Depending on studies, insulin treatment had positive or no effect on circulating LH in cyclic gilts ŽCox et al., 1987.. Withdrawing insulin therapy in diabetic gilts had no clear effect on basal LH secretion within 6 days, but pituitary LH stores were depleted and oestrous cycles were interrupted ŽCox et al., 1994; Angell et al., 1996.. Insulin receptors have been described in the ovary of sows ŽRein and Schomberg, 1982. and women ŽPoretsky et al., 1985.. Exogenous insulin increased ovulation rate ŽCox et al., 1987. and reduced follicular atresia in gilts ŽMatamoros et al., 1990, 1991., and this was associated or not with increased gonadotrophin secretion. Inversely, withdrawal of insulin from diabetic gilts during the luteal phase decreased ovulation rate and increased the rate of follicular atresia ŽCox et al., 1994.. The objective of this study was to test the hypothesis that undernutrition-derived decrease in insulin concentrations before weaning may alter reproductive function. Thus, we determined whether exogenous insulin administration in late lactation can improve post-weaning reproductive performance of feed-restricted primiparous sows.
2. Materials and methods 2.1. Preliminary experiment Four lactating pure Large White gilts were used. Within 2 days after farrowing, litter size was standardized to 9–11 piglets by crossfostering. During lactation, sows received
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in two equal meals Ž0815 h and 1315 h. 4 kg dayy1 of a diet containing 13.1 MJ DE kgy1 , 17.1% crude protein and 0.9% lysine. At day 19 postpartum, jugular vein catheterization was performed under general anaesthesia. At days 22 and 23 postpartum, sows received a subcutaneous injection of intermediate-acting human insulin ŽInsulatard w , Novo Nordisk, Denmark.. Four doses were tested Ž0, 0.1, 0.25 and 0.5 IU kg live weighty1 . and each dose was tested in two females. The injection was performed at 1600 h, i.e. about 3 h after the afternoon meal. Blood samples were collected in heparinized tubes before the injection at 1545 and 1600 h and after the injection at 1630, 1700, 1730, 1800, 2000, 2200, 0400 and 0800 h. 2.2. Animals and treatments Pure Large White gilts were inseminated at 315 " 2 and 309 " 5 days of age for the first Ž n s 12. and the second replicate Ž n s 12., respectively Žmean " S.D... They were kept in individual pens during the last week of gestation and during lactation, under constant daylength Ž12 h light dayy1 .. Within 2 days after farrowing, litter size was standardized to 9–11 piglets by crossfostering. Piglets had free access to water but received no supplemental food during lactation. They were weaned at 0900 h at 23.5 " 1 days post-partum. After weaning, the sows were checked twice daily for oestrus in the presence of a mature boar. They were slaughtered 10 days after weaning. During gestation, all females received 2.7 kg dayy1 of a diet containing 12.6 MJ DE y1 kg , 13.2% crude protein and 0.6% lysine. During lactation, they received a diet containing 13.1 MJ DE kgy1 , 17.1% crude protein and 0.9% lysine twice daily Ž0815 h and 1315 h.. After weaning, they all received 3 kg dayy1 of the gestation diet, in two equal meals. During farrowing, the females were assigned to one of the three following experimental groups. Control sows ŽCTRL. were fed on a plane of nutrition close to ad libitum and received 6 kg food dayy1 on average over lactation. Restricted saline- ŽRS. and insulin-treated ŽRI. sows received only 4 kg food dayy1 . RI sows received subcutaneous injections of intermediate-acting human insulin ŽInsulatard w , Novo Nordisk. once daily during the 5 days preceding weaning. A dose of 0.4 IU kg live weighty1 was chosen according to the results of a preliminary experiment. The injection was performed at 1700 h, about 4 h after the afternoon meal. Control and RS sows received saline injections as a sham treatment. 2.3. Sample collection Blood samples were collected using a vacuutainer 2 days before weaning ŽDay W y 2. at 2000 h and 2 days after weaning ŽDay W q 2. at 0800 h. Samples were collected in heparinized tubes, immediately placed on ice and centrifuged to remove plasma. Plasma samples were stored at y208C until assayed. Ovaries were collected immediately after slaughter and examined macroscopically. The number of corpora lutea was recorded. Some corpora lutea were unusually large ŽG 15 mm in diameter. and were designed as «hypertrophied».
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2.4. Analyses 2.4.1. Measurements Animals were weighed and backfat depth was measured at three sites Žshoulder, last rib and loin, at 65 mm from the midline. on the day after farrowing, on the first day of injections and at weaning. Piglets were weighed at birth, on the first day of injection and at weaning. 2.4.2. Hormone and metabolite assays Insulin, insulin-like growth factor-I ŽIGF-I., follicle-stimulating hormone ŽFSH. and oestradiol-17b concentrations were determined in plasma samples by validated radioimmunoassays ŽPrunier et al., 1993; Louveau and Bonneau, 1996; Camous et al., 1985; Thibier and Saumande, 1975.. Concentrations of glucose and non-esterified fatty acids ŽNEFA. were measured by automated enzymatic methods with a Cobas Mira ŽHoffman Laroche, Basel, Switzerland. apparatus. Plasma concentrations of insulin, IGF-I, NEFA and glucose were determined at Day W y 2, and those of FSH and oestradiol-17b at Day W q 2. 2.5. Statistical analyses All data Žsow and litter parameters, blood concentrations. were analysed by analysis of variance using the GLM procedure of SAS ŽSAS, 1990.. All models of analyses included the effects of the treatment group, replicate and the interaction between these two factors. No interaction between the group and the replicate was found. When the effect of the group was significant Ž P - 0.05., comparison between the groups were performed using Bonferroni’s test. For daily weight gain of the litters, litter live weight before insulin treatment was introduced as a covariate in the model and comparisons between groups used the Dunnett’s one-tailed t-test, testing if treatment was significantly smaller than that of the control.
3. Results 3.1. Preliminary experiment The preliminary dose–response trial was performed to select the appropriate dose of insulin and was focused on plasma concentrations of insulin and glucose. In both control sows Ždose 0., plasma insulin concentrations decreased 2 h after injection, indicating that the postprandial peak of insulin was not completely achieved at 1600 h ŽFig. 1.. Thereafter, insulin remained at low levels for 16 h. Similar results were obtained with the dose 0.1 Ždata not shown.. In sows which received the doses of 0.25 or 0.5 IU kgy1 , plasma insulin concentrations increased after the injection and remained at
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Fig. 1. Mean plasma insulin and glucose concentrations relative to an injection of 0, 0.25 or 0.5 IU insulin kg live weighty1 in primiparous lactating sows. Time 0 represents the time of injection.
a higher level compared with control sows for 10 h ŽFig. 1.. In these sows, glucose concentrations decreased after the injection of insulin and remained at low levels for 10 h ŽFig. 1.. Therefore, we chose to use an intermediate dose of 0.4 IU kgy1 , in order to be sure to double plasma concentrations of insulin during at least 8–10 h, without inducing a strong hypoglycemia. Moreover, we decided to perform the injections at 1700 h instead of 1600 h, when the postprandial peak of insulin was completely achieved. 3.2. Sow and litter performance On the day after farrowing, there was no significant difference in live weight and backfat depth between sows ŽTable 1.. During lactation, the decrease in live weight and backfat depth was significantly greater in restricted RS and RI sows than in CTRL sows ŽTable 1..
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Table 1 Live weight and backfat measurements Žmeans"S.E.M.. in primiparous sows Treatment group
Effect of group
CTRL Number of sows
RS
RI
8
8
8
LiÕe weight (kg) At farrowing Before treatment At weaning Loss during lactation Loss during treatment
221"5 215"4 210"4a y10"3a y4.5"2
219"4 200"3 194"2 b y25"2 b y6.7"1
228"3 201"3 195"2 b y32"3b y5.1"1
NS )) ))) ))) NS
Backfat depth (mm) At farrowing At weaning Loss during lactation
17.5"1.8 15.2"2.0 y2.2"0.6 a
19.6"1.2 14.4"0.9 y5.3"0.6 b
18.6"0.9 13.9"0.9 y4.7"0.4 b
NS NS ))
CTRL s control group; RSs restricted saline-treated group; RI s restricted insulin-treated group. NS: P ) 0.1, )): P - 0.01, ))): P - 0.001.
Litter size at weaning was similar for the three groups of sows ŽTable 2.. Litter live weights did not differ between the three groups after crossfostering, at the beginning of the treatment and at weaning. Daily weight gain of litters was similar in the three groups of sows before insulin treatment but was lower in RI group during treatment Ž P - 0.05..
Table 2 Litter performance Žmeans"S.E.M.. Treatment group CTRL Number of sows
8
Effect of group RS
RI
8
8
Total number of piglets Born 10.2"1.5 Weaned 9.5"0.3
10.6"1.2 9.1"0.3
10.7"0.7 9.4"0.3
NS NS
Litter liÕe weight (kg) At birth Before treatment At weaning
15.1"0.9 51.9"2.1 60.9"2.7
15.2"0.5 57.5"1.9 65.1"2.1
NS NS NS
2040"102 1800"156 a
2240"63 1530"114b
NS )
14.5"0.7 53.1"2.3 62.6"2.7
Daily litter weight gain (g d y 1) Before treatment 2120"102 During treatment 1900"118 a
CTRL s control group; RSs restricted saline-treated group; RI s restricted insulin-treated group. NS: P ) 0.1, ): P - 0.05.
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Table 3 The reproductive performance of primiparous sows Žmeans"S.E.M.. Treatment group CTRL Number of sows 8 Number of sows in oestrus 8 W-O-I Žday. 5.7"0.2 Mean ovarian weight Žmg. 10.2"1.3 Number of CL 19.2"1.2 Number of hyper CL 3.0"1.1
RS
RI
Effect of group
8 7 5.9"0.3 8.5"1.1 20.7"1.4 1.6"0.8
8 7 5.6"0.3 10.4"1.3 22.1"1.4 5.1"1.6
NS NS NS NS NS
Number of sows in oestruss number of sows in oestrus within 10 days after weaning. W-O-Is weaning-tooestrus interval. Number of CL s number of corpora lutea per sow. Number of hyper CL s number of hypertrophied corpora lutea per sow. CTRL s control group; RSs restricted saline-treated group; RI s restricted insulin-treated group. NS: P ) 0.1.
3.3. ReproductiÕe performance Only two sows did not revert into oestrus within 10 days after weaning and did not ovulate. For the other sows, there was no treatment effect on the weaning-to-oestrus interval and no effect on the number of healthy or hypertrophied corpora lutea and on mean ovarian weight recorded 10 days after piglet removal ŽTable 3..
Fig. 2. Mean plasma concentrations of insulin, insulin-like growth factor-I ŽIGF-I., non-esterified fatty acids ŽNEFA. and glucose in CTRL, RS and RI sows 2 days before weaning. CTRL s control group; RSs restricted saline-treated group; RI s restricted insulin-treated group.
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Fig. 3. Mean plasma concentrations of FSH and oestradiol-17b in CTRL, RS and RI sows 2 days after weaning. CTRL s control group; RSs restricted saline-treated group; RI s restricted insulin-treated group.
3.4. Hormones On Day W y 2, insulin concentration was significantly higher in RI sows compared with CTRL and RS sows, and glucose concentration was significantly lower ŽFig. 2.. Concentrations of NEFA and IGF y I did not differ significantly between groups of females ŽFig. 2.. On Day W q 2, concentrations of FSH and oestradiol-17b did not differ between groups Ž P ) 0.1, Fig. 3..
4. Discussion Insulin treatment resulted in a significant increase in plasma insulin concentrations, as it was anticipated. This elevation of insulin was accompanied by a decrease in glucose concentrations, without any effect on IGF-I and NEFA levels before weaning. Daily litter weight gain during the period of injection was lower in insulin-treated compared with non-treated sows. This may be related to the lower level of glucose in insulin-treated sows, since the availability of glucose is regarded as a primary limit to milk production ŽBoyd et al., 1995.. Moreover, high plasma insulin concentration may favour the partitioning of nutrients into maternal body stores rather than into milk. In this study, exogenous insulin administration to feed-restricted primiparous sows during late lactation had no influence on ovarian activity, contrarily to what we had
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expected. Similarly, it had no influence on plasma FSH and oestradiol-17b concentrations 2 days after weaning. Since Pettigrew and Tokach Ž1993. have described a high positive correlation between insulin concentration in early lactation ŽDay 7. and number of LH peaks in late lactation ŽDay 21., the effects of insulin administration during early lactation remain to be investigated. Two hypotheses may explain this failure of insulin treatment to alter ovulation rate or weaning-to-oestrus interval in the current experiment. First, reproductive performance of saline-restricted sows was relatively good and similar to those observed in well-fed sows. Thus, reproductive performance of feed-restricted sows was unlikely to be improved by insulin treatment. Lack of influence of feed restriction on reproductive performance and reproductive hormone concentrations of saline-treated sows may be related to the absence of significant differences in plasma glucose, NEFA, insulin and IGF-I despite higher losses in live weight and fat depth in feed-restricted compared with well-fed sows Žy25 vs. y10 kg live weight and y5 vs. y2 mm fat depth.. The food restriction imposed during lactation was probably not sufficient to induce a catabolic state severe enough to provoke reproductive failure. It can be assumed that the effect of insulin on reproductive performance in lactating sows might depend on the nutritional state, as previously suggested for weaned sows ŽRamirez et al., 1993. and that it can not improve the performances in non- or slightly-catabolic sows. Second, the increase in plasma insulin might not have altered LH secretion in the present study, as reported in primiparous sows after insulin administration at weaning ŽRojkittikhun et al., 1993. and after glucose infusion in late lactation ŽTokach et al., 1992. or after weaning ŽPlaine et al., 1995.. Similarly, infusion of glucose into underfed rams did not affect GnRH pulsatility, although blood glucose and insulin concentrations were highly increased ŽBoukhliq et al., 1996.. To our knowledge, this is the first study to investigate the effect of insulin treatment during lactation. Previous data concerning insulin administration showed a clear positive effect on ovulation rate and follicular atresia in cyclic or prepuberal gilts ŽCox et al., 1987; ŽMatamoros et al., 1990, 1991. and inconsistent results in weaned sows. Insulin administration at or after weaning had no effect on reproductive performance in primiparous, multiparous, or mixed-parity sows ŽKirkwood and Thacker, 1991; Rojkittikhun et al., 1993; Cox et al., 1994. or had a positive influence on farrowing rate or subsequent litter size in primiparous sows ŽRamirez et al., 1997.. Cox et al. Ž1995. have also reported that the administration of insulin in post-weaning primiparous sows was more efficient in increasing litter size when the level of feeding was higher. In conclusion, insulin administration during late lactation to feed-restricted primiparous sows does not improve the interval between weaning and oestrus or subsequent ovulation rate, but is likely to decrease milk production.
Acknowledgements The authors wish to acknowledge the swine barn staff of Saint-Gilles, Y. Lebreton for performing surgical procedures, and A. Pasquier and A.M. Mounier for expert technical assistance. They are also grateful to J.Y. Dourmad for a critical evaluation of the manuscript.
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