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Changing the composition of milk proteins and AA affects the nutritional and physical properties of dairy products. Intravenous infusions of glucagon decreases milk protein production and concentration by promoting the use of gluconeogenic blood AA for hepatic glucose synthesis. Little is known about how the diversion of AA to gluconeogenesis affects the composition of milk proteins and AA. The objective was to quantify changes in composition of milk protein and AA in response to i.v. glucagon infusions. Three separate experiments were used: 1) 8 Holstein cows were fed ad libitum and infused with glucagon at 10 mg/d for 14 d, 2) 7 Holstein cows were feed restricted and infused with glucagon at 10 mg/d for 14 d, and 3) 4 Brown Swiss cows were infused with glucagon at 5 and 10 mg/d for 2 d each. Milk and milk component yields and milk protein and amino acid composition of samples, collected with blood samples at the first and last day of the glucagon infusion period, were compared with those collected 1 d before and after the glucagon infusion period. Glucagon infusions decreased milk protein production and concentration in each experiment by at least 0.2 +/- 0.05 kg/d and 4 +/- 0.4 g/L, respectively. The decrease was accompanied by changes in milk protein composition, the most consistent being an increase in kappa-casein (1.68 +/- 0.27%). Overall, glucagon infusions resulted in higher proportions of kappa-casein and alpha(S2)-casein (1.34 +/- 0.51%) and smaller proportions of alpha(S1)-casein (-3.83 +/- 1.75%) and alpha-lactalbumin (-0.91 +/- 0.32%). Glucagon had little impact on milk AA composition except an increase in glycine (0.26 +/- 0.11%). The results suggest that milk protein synthesis is regulated by many factors including AA and glucose availability.

Severe fatty liver, a metabolic disease of dairy cows in early lactation, results in decreased health and reproductive performance, but can be alleviated by treatment with i.v. injections of glucagon. Mild fatty liver in cows effects on health and reproductive performance were determined by treatment with 14-day s.c. injections of glucagon at 7.5 or 15 mg/day. Multiparous Holstein cows (n=32) were grouped into Normal and Susceptible based on liver triacylglycerol concentrations (>1% liver tissue biopsy wet weight) at day 8 postpartum (day 0=day of parturition). Susceptible cows (n=24) were assigned randomly to three groups and s.c. injected with 0mg glucagon [60 ml 0.15M NaCl] [n=8] (same for Normal cows), 2.5 mg glucagon, or 5 mg glucagon every 8 h for 14 days, beginning day 8 postpartum. Mild fatty liver resulted in an increased number of days with elevated body temperature during the injection period, an increased incidence of mastitis after glucagon treatment, increased days to first estrus and insemination, increased days before conception occurred, and decreased conception rate. In cows with mild fatty liver, glucagon (15 mg/day) decreased the number of days with elevated body temperature and the incidence of mastitis after hormone treatment. From these results, we suggest that mild fatty liver is detrimental to health and reproduction of dairy cows and, furthermore, that exogenous glucagon decreases some of these detrimental effects.

Decreased concentrations of phospholipids, free cholesterol, and cholesteryl ester in plasma and liver are associated with fatty liver, a major metabolic disease of dairy cows in early lactation. The objective was to test whether daily subcutaneous injections of 7.5 and 15 mg of glucagon, which can decrease concentrations of liver triacylglycerol, affect concentrations of plasma lipoprotein components and liver lipids other than triacylglycerol. Multiparous Holstein cows (n = 32) were grouped on the basis of liver triacylglycerol concentrations at d 8 postpartum into "normal" (n = 8; triacylglycerol <1% liver wet wt) and "susceptible to fatty liver" (n = 24; triacylglycerol >1% liver wet wt) cows. Susceptible cows were assigned randomly to three groups and beginning at d 8 postpartum received 0 (same for Normal cows), 2.5, or 5 mg of glucagon by subcutaneous injections every 8 h for 14 d. In comparison to saline injections, subcutaneous injections of glucagon either increased or tended to increase concentrations of phospholipids and free cholesterol in liver, with greater increases of the latter during ambient temperatures below 35 degrees C. Glucagon injections decreased or tended to decrease concentrations of very low-density lipoprotein-triacylglycerol, high-density lipoprotein1-phospholipids, and high-density lipoprotein2-free cholesterol in plasma, with no changes of the latter two during ambient temperatures below 35 degrees C. The results indicate that subcutaneously administered glucagon has only minor effects on the lipid transport in plasma of dairy cows in early lactation with more beneficial effects occurring during ambient temperatures below 35 degrees C and, most importantly, no indications that glucagon has negative effects.

Continuous, intravenous infusions of glucagon improve carbohydrate status in lactating dairy cows without increasing concentrations of plasma NEFA. The objective was to test whether single subcutaneous injections and multiple subcutaneous injections of glucagon delivered at 8-h intervals over 14 d improve the carbohydrate status in lactating dairy cows without increasing concentrations of plasma BHBA and NEFA. In a single-injection experiment, four midlactation cows each were injected with 2.5 and 5 mg of glucagon 1 wk apart. In a multiple-injection experiment, nine cows, assigned randomly to three treatments, were injected subcutaneously with 0, 2.5, or 5 mg of glucagon every 8 h for 14 d, beginning at d 8 postpartum. Single subcutaneous injections of glucagon increased concentrations of plasma glucagon and single and multiple subcutaneous injections of glucagon increased concentrations of plasma glucose, with larger increases at the 5-mg dosage. Injections of 5 mg of glucagon increased concentrations of plasma insulin in both experiments, whereas the 2.5-mg dosage increased plasma insulin only in the multiple-injection experiment. The response of glucose and insulin to injections of 5 mg of glucagon persisted throughout the 14-d injection period. Concentrations of plasma NEFA decreased in the single-injection experiment, and concentrations of BHBA decreased after 5 mg of glucagon was injected in the multiple-injection experiment. These results document that both single and multiple injections of 5 mg of glucagon over 14 d consistently improve the carbohydrate status of dairy cows and decrease concentrations of plasma NEFA and BHBA.

Twenty cows were assigned at parturition to two groups to study metabolic effects of continuous intravenous infusions of glucagon. Groups were control cows and cows treated with glucagon at 10 mg/d for 14 d starting at d 21 postpartum. Daily blood samples and nine liver biopsies were taken from d 7 to 49 postpartum. Plasma glucagon increased six- to seven-fold during infusions of treated cows. Plasma insulin was increased heterogeneously by glucagon infusions. Plasma glucose increased 11.5 and 9.0 mg/dl during wk 1 and 2 of glucagon infusions. No other plasma metabolites tested (nonesterified fatty acids, beta-hydroxybutyrate, and urea N) were affected by glucagon infusions. Liver glycogen decreased by d 2 of glucagon infusion but was repleted to preinfusion values by d 7 and increased to 169% of the preinfusion baseline values at 3 d after cessation of glucagon. Milk production decreased transiently during glucagon infusions. Both milk production and milk protein percentage decreased during glucagon infusion, which could imply a decreased availability of amino acids for milk protein synthesis. Feed intakes did not increase during glucagon infusions, which was in contrast to the control group. Results indicated that glucagon infusions caused liver glycogenolysis initially and probably enhanced gluconeogenesis but glucagon did not appear to increase lipolysis from adipose tissue in these early lactating dairy cows.

The effects of glucagon infusions on expression of mRNA for enzymes that regulate gluconeogenesis were studied in lactating cows. Normal cows and cows with fatty liver that were susceptible to ketosis were assigned to either glucagon-treated or control groups. Glucagon at 0 or 10 mg/d was infused for 14 d beginning at d 21 postpartum. In normal cows, glucagon infusions increased concentrations of both plasma glucagon and glucose, which caused plasma insulin to increase. Consequently, hepatic phosphoenolpyruvate carboxykinase mRNA decreased during wk 1 of glucagon infusions. Glucagon infusions into cows with fatty liver also increased plasma glucagon and glucose, but concentrations of plasma insulin and hepatic phosphoenolpyruvate carboxykinase mRNA did not change. More phosphoenolpyruvate carboxykinase mRNA was present in the livers of cows with fatty liver than in livers of normal cows. In a follow-up experiment with midlactation cows, 3.5-h infusions of glucagon at 14 mg/d increased plasma glucose and insulin and decreased plasma nonesterified fatty acids and hepatic glycogen. Hepatic phosphoenolpyruvate carboxykinase mRNA was decreased 41%, pyruvate carboxylase mRNA was increased 50%, but fructose-1,6-bisphosphatase mRNA did not change. We conclude that the expression of the hepatic phosphoenolpyruvate carboxykinase gene in normal cows is inhibited by insulin to balance elevated carbohydrate status during glucagon infusions; however, inhibited expression of hepatic phosphoenolpyruvate carboxykinase mRNA probably is not involved in the pathogenesis of lactation ketosis.

Thirty-two cows, averaging 112 DIM, were assigned to four dietary treatments: 1) control, 2) Ca salts of fatty acids, 3) nicotinamide, and 4) Ca salts of fatty acids blended with nicotinamide during manufacture. Preliminary studies showed that nicotinamide survives blending with Ca salts of fatty acids during manufacture and that a blended mixture of nicotinamide and Ca salts of fatty acids gave results similar to those from nicotinamide plus Ca salts of fatty acids supplemented separately. Calcium salts of fatty acids increased milk fat percentage, decreased milk protein percentage, but had no effect on production of milk, FCM, fat, or protein. Nicotinamide increased production of milk and protein, decreased fat percentage, but had no effect on either production of FCM and protein or percentage of protein. Calcium salts of fatty acids increased NEFA in blood, and dietary nicotinamide increased concentrations of nicotinamide in blood, but glucose and BHBA in blood were unaffected by either dietary ingredient. Therefore, in these midlactation cows, the decreased milk protein percentage caused by supplemental dietary fat was prevented by nicotinamide. Supplementation with only nicotinamide increased total production of milk protein.

After a preliminary trial to establish dose responses to phlorizin, five Holstein cows at 6 wk postpartum were used to test the response of cows in negative energy balance to a sudden decrease in availability of glucose caused by phlorizin. Cows were fed equal amounts of feed twice daily to supply 100% of NRC recommendations for protein and 90% of NRC recommendations for NEL and were in negative energy balance throughout the experiment. Phlorizin at 0, 2, and 4 g/d was injected subcutaneously in equal amounts every 6 h for 48 h and caused excretion of 0, 225, and 337 g/d of glucose in urine. Milk production was not decreased, but percentage of milk fat increased linearly (3.34, 3.56, and 3.70%) with increasing phlorizin. Concentrations of glucose (64.2, 62.6, and 59.4 mg/dl) and insulin (518, 432, and 329 pg/ml) in blood plasma decreased linearly, whereas beta-hydroxybutyrate (6.11, 8.88, and 9.98 mg/dl) and NEFA (181, 220, and 271 mu eq/L) increased linearly. The changes were most dramatic during the final 12 h of the 48-h injection interval. Healthy, early lactation cows in negative energy balance seem to have the capacity to make metabolic adjustments to provide adequate substrates for maintenance and milk synthesis and to compensate for short-term increased needs for glucose.

Regulatory effects of carnitine, glucose, some glucogenic compounds (propionate, pyruvate, alanine, lactate, glycerol, and fructose), ketone bodies (acetate, acetoacetate, and beta-hydroxybutyrate), and insulin on oxidation of palmitate were studied in slices of liver obtained from high producing dairy cows during early lactation. A total of 77 biopsies of liver from 21 multiparous Holstein cows (36 +/- 16 d postpartum) was used. L-Carnitine increased oxidation of palmitate to CO2 by more than twofold and oxidation to acid-soluble products by about fourfold. Propionate decreased oxidation of palmitate in liver slices incubated without added carnitine, but the decrease was lessened by carnitine. Pyruvate, lactate, and alanine increased palmitate oxidation, especially in the presence of carnitine. Glycerol, glucose, and insulin tended to decrease palmitate oxidation in the absence of carnitine. Fructose tended to decrease oxidation to CO2 but did not affect oxidation to acid-soluble products. Acetate and acetoacetate decreased oxidation of palmitate, whereas beta-hydroxybutyrate decreased palmitate oxidation in the absence of carnitine but increased palmitate oxidation in its presence. In general, carnitine decreased the inhibitory effects of compounds that decreased palmitate oxidation but increased the stimulatory effects of compounds that increased palmitate oxidation.

Two groups of 10 Holstein cows were chosen by pairs from a 20-yr genetic selection project that used either breed average or breed high sires chosen only for Predicted Differences in milk production. Milk production (305-d mature equivalent) was 10,814 kg and 6912 kg for the high and average groups of cows. Days to first visual estrus and number of ovulations before first visual estrus were greater for the high versus the average group (66 vs. 43 d and 1.6 vs. .7 ovulations). No differences were significant between groups for the interval from parturition to uterine involution or for days to first ovulation. Energy balance was less for the high group during wk 1, 2, 10, and 11. Plasma glucose concentration was lowest during wk 2 for both groups, and nonesterified fatty acids and beta-hydroxybutyrate were greatest for both groups during wk 1 and 2. Liver glycogen content was lower at d 15 postpartum for the high group, and liver triglyceride content was greater on d 30 for the high group. The data for reproductive functions support the concept that high milk production is antagonistic to expression of estrous behavior but not to reactivation of ovarian function.

Acute effects of dietary 1,3-butanediol and tributyrin on concentrations of glucose, beta-hydroxybutyrate, and insulin in plasma were compared in lactating goats. In Experiment 1, glucose was decreased by intraruminal administration of 75 or 150 g of 1,3-butanediol or by 84 or 168 g of tributyrin. Tributyrin caused transient hyperglycemia immediately after administration. beta-Hydroxybutyrate was increased in a dose-dependent manner by tributyrin and increased independently of dose by 1,3-butanediol. Tributyrin, but not 1,3-butanediol. Tributyrin, but not 1,3-butanediol, caused large increases of insulin in plasma. In Experiment 2, 75 g of 1,3-butanediol or 84 g of tributyrin administered intraruminally decreased glucose, whereas 73 g of butyric acid (pH 5.6) increased glucose compared with water or 25.6 g of glycerol. All treatments produced transient hyperglycemia immediately after administration. Tributyrin, butyric acid, or 1,3-butanediol greatly increased beta-hydroxybutyrate compared with administration of water or glycerol. Concentrations of beta-hydroxybutyrate in both experiments increased more slowly for 1,3-butanediol than for tributyrin. Both 1,3-butanediol and tributyrin decreased glucose and increased beta-hydroxybutyrate. Because 1,3-butanediol does not stimulate increases of insulin in plasma, it may be more desirable than tributyrin for inducing metabolic changes characteristic of lactation ketosis.

Feed restriction and dietary 1,3-butanediol were used with lactating goats in an attempt to induce metabolic changes characteristic of bovine lactation ketosis and fatty liver. In Experiment 1, midlactation goats were fed 80, 102, or 114% of metabolizable energy requirements and 0, 50, or 100 g/d of 1,3-butanediol. Concentration of beta-hydroxybutyrate in blood plasma decreased with increasing metabolizable energy but was increased greatly at 2 h after goats were fed 50 or 100 g butanediol and remained elevated at 6 h postfeeding with 100 g of butanediol. Concentration of glucose in plasma was decreased at 2 and 6 h postfeeding in goats fed 100 g of butanediol. In Experiment 2, goats in early lactation were fed for ad libitum intake or were restricted to 70% of ad libitum intake with 1,3-butanediol included at 10% of diet DM. The treatment decreased milk production, increased concentrations of beta-hydroxybutyrate and nonesterified fatty acids, and decreased the concentration of insulin and the insulin to glucagon ratio in plasma. Concentrations of glucose, acetate, and glucagon in plasma were not affected. After 28 d of treatment, concentration of total lipid in liver was increased, but concentrations of glycogen and triglyceride were unaffected. Changes caused in goats by feed restriction plus dietary 1,3-butanediol were characteristic of subclinical lactation ketosis in cows, but the response was more moderate than seen previously in cows.

Ketosis was induced in four lactating dairy cows at an average of 36 d postpartum and 24 d after initiation of a protocol for inducing ketosis. Liver and adipose biopsies were taken at five stages; once prepartal, once early postpartal, once during an induction protocol, once during ketosis, and once during recovery after treatment of ketosis. At each stage, in vitro estimates were made of capacities of liver slices for gluconeogenesis, fatty acid oxidation, and ketogenesis and of capacities of adipose tissue slices for lipogenesis and lipolysis. There were no significant differences for any metabolic capacity between prepartal and early postpartal stages; however, a significant decrease in hepatic metabolic activity was associated with ketosis. Gluconeogenic rates from all substrates tested were decreased significantly during ketosis, and similar decreases were measured for oxidation of gluconeogenic substrates and fatty acids. Treatment of ketosis resulted in complete recovery from impairments of metabolism in liver. Results suggest that a prolonged energy deficit, plus a major influx of ketone precursors, is accompanied by eventual hepatic impairment, that clinical ketosis is associated with this impairment, and that the impairment is reversed by effective treatment of ketosis.

During the 5 wk immediately after parturition, five high producing cows that were overfed prepartum completed a protocol for inducement of ketosis. By 12 d postpartum, hepatic glycogen decreased by 75% and hepatic triglyceride, beta-hydroxybutyrate, and acetoacetate increased by 6, 4, and 2.5 times. The protocol, initiated at 2 wk postpartum, consisted of a 15 to 20% decrease from ad libitum feed intake plus dietary supplementation with 1,3-butanediol, a ketogenic substrate. Severity of the ketotic state increased gradually, and four cows developed clinical signs of ketosis at an average of 36 d postpartum. Glycogen was 90% depleted, and triglycerides, beta-hydroxybutyrate, and acetoacetate concentrations in liver were increased to 10, 10, and 15 times above average prepartum concentrations. In plasma, beta-hydroxybutyrate increased and glucose decreased. Plasma insulin exhibited an initial postpartal decrease (40%) but then was stable at that concentration through 36 d. After treatment for ketosis, glucose and insulin concentrations of plasma were greater than prepartal concentrations. Results indicate that a relatively simple protocol of prolonged energy deficit combined with an influx of ketone body precursors can induce experimental lactation ketosis in overfed cows. The protocol should be a valuable tool for ketosis research.

These studies have been designed to test whether 1,3-butanediol (BD) alleviates milk fat depression in lactating cows, to observe physiological changes in blood and rumen constituents when BD is fed to cows or growing cattle, and to test the effects of BD on growth rates and feed efficiency in growing cattle. In trials with lactating cows, milk fat percentage and total fat production were higher for cows fed BD than for controls. Feeding BD to either cows or growing cattle had no consistent effect on rumen pH or relative concentrations of rumen volatile fatty acids. 1,3-Butanediol feeding had little effect on blood glucose concentrations. Feeding more than 4% BD in diets sometimes caused increased concentrations of blood ketones. In trials where growing cattle were fed 4% BD, rates of gain and feed efficiency were at least as good as and often better than those of cattle fed the same diets without BD. Body composition was not significantly affected. 1,3-Butanediol can be utilized effectively as an energy source for cattle and causes no obvious problems with 4% in diets.

Eight Holstein cows were sampled to examine plasma concentrations of hormones and some energy related metabolites. Sampling was every hour for 12 h at about 2 wk prepartum, at 3 wk postpartum, during an energy restriction ketonemia, and after a recovery period. Cows were fed ad libitum except for four cows induced into ketonemia by restricting feed intake 50%. Pulse doses of glucagon were injected intravenously during each period. Feed restriction increased concentrations of growth hormone, acetoacetate, beta-hydroxybutyrate, and free fatty acids in blood plasma. Concentrations of insulin and glucose showed some tendencies to decrease. Distribution space and turnover rate of glucagon were not different between periods, and pool size was increased in the dry period. Metabolic clearance rate of glucagon was not significantly different between periods. Insulin and glucose concentrations were increased 1 to 2 min after injection of glucagon and remained increased for 25 min. Covariance analysis showed that glucagon injection caused glucose concentration to increase proportionally in all periods, suggesting that cows had equal gluconeogenic capacity in all periods. Basal concentration, pool size, and secretion rate of glucagon showed some tendency to be decreased during ketonemia.

Six Holstein cows were sampled hourly for 24 h for plasma concentrations of hormones and metabolites. Cows were sampled at about 2 wk prepartum, at 3 wk postpartum, during a ketonemia induced by feed restriction to 54% of ad libitum intake, and after a recovery period. They were fed long alfalfa hay postpartum. The onset of lactation caused concentrations of growth hormone, glucagon, acetoacetate, beta-hydroxybutyrate, and total amino acids of plasma to increase and those of glucose and insulin to decrease. Feed restriction exacerbated changes at 3 wk postpartum except for total amino acids and glucagon, which both decreased to prepartal concentrations. Resumption of ad libitum feeding caused most hormones and metabolites to return to prepartum concentrations. Diurnal variations in response to feeding twice daily were most evident for growth hormone, free fatty acids, and total amino acids. The 3-wk postpartum and ketonemic periods gave the greatest responses to feeding. Molar ratios of insulin to glucagon and insulin to growth hormone tended to decrease at 3 wk postpartum and decreased further in ketonemia, demonstrating hormonal adaptations to decreased energy intake during lactation. Lactation ketosis results from more than severe energy deficit.

Fatty liver is a major metabolic disease of dairy cows in early lactation that can be treated with 14-d continuous, intravenous infusions of 10 mg/d of glucagon. The objective was to test whether similar effects can be obtained with 14-d subcutaneous 7.5- or 15-mg daily dosages of glucagon beginning at d 8 postpartum. Multiparous Holstein cows (n = 32) were grouped on the basis of their liver triacylglycerol concentration at d 8 postpartum into "normal" (n = 8; triacylglycerol <1% liver wet wt) and "susceptible" (n = 24; triacylglycerol >1% liver wet wt) cows. Susceptible cows were assigned randomly to three groups and beginning at d 8 postpartum received 0, 2.5, or 5 mg of glucagon in 60 ml of saline by subcutaneous injections every 8 h for 14 d. Beginning at d 8 postpartum, normal cows received 60 ml of saline by subcutaneous injections every 8 h for 14 d. Both dosages of glucagon increased concentrations of plasma glucose and insulin and decreased concentrations of plasma nonesterfied fatty acids. Glucagon injections of 15 mg/d decreased concentrations of liver triacylglycerol in cows older than 3.5 yr, but not in younger multiparous cows. Our results document that subcutaneous injections of glucagon have the potential to decrease the degree of fatty liver in older dairy cows in early lactation. [ABSTRACT FROM AUTHOR]