Materials and Methods · In neonatal calves, nutrient intake shifts from continuous glucose supply via the ... However, recent findings in neonatal pigs and rats may indicate systemic

H. M. Hammon, J. Steinhoff-Wagner, J. Flor, U. Schönhusen and C. C. MetgesRole of colostrum and colostrum components on glucose metabolism in neonatal calves

2012 published online October 16, 2012 originally published online October 16,J ANIM SCI

http://www.journalofanimalscience.org/content/early/2012/10/16/jas.2012-5758.1the World Wide Web at:

The online version of this article, along with updated information and services, is located on

www.asas.org

by Jennifer Trout on January 29, 2013www.journalofanimalscience.orgDownloaded from

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1

Running head: Glucose metabolism in neonatal calves

Role of colostrum and colostrum components on glucose metabolism in

neonatal calves1,2

H. M. Hammon*3, J. Steinhoff-Wagner*, J. Flor*, U. Schönhusen*, and C. C. Metges*

*Nutritional Physiology “Oskar Kellner”, Leibniz Institute for Farm Animal Biology (FBN),

Dummerstorf, Germany

1 Based on a presentation at the Lactation Biology Symposium titled “The long-term impact of

epigenetics and maternal influence on the neonate through milk-borne factors and nutrient

status” at the Joint Annual Meeting, July 15-19, 2012, Phoenix, Arizona, with publication

sponsored by the Journal of Animal Science and the American Society of Animal Science.

2 This project was supported by Schweizer Nationalfond (Grant no. 32-59311.99) and Deutsche

Forschungsgemeinschaft (DFG; Grant no. HA 4372/5-1).

3 Corresponding author: [email protected]

Published Online First on October 16, 2012 as doi:10.2527/jas.2012-5758 by Jennifer Trout on January 29, 2013www.journalofanimalscience.orgDownloaded from


2

ABSTRACT: In neonatal calves, nutrient intake shifts from continuous glucose supply via the

placenta to discontinuous colostrum and milk intake with lactose and fat as main energy sources.

Calves are often born hypoglycemic and have to establish endogenous glucose production (eGP)

and gluconeogenesis, because lactose intake by colostrum and milk does not meet glucose

demands. Besides establishing a passive immunity, colostrum intake stimulates maturation and

function of the neonatal gastrointestinal tract (GIT). Nutrients and non-nutritive factors, such as

hormones and growth factors, which are present in high amounts in colostrum of first milking

after parturition, affect intestinal growth and function and enhance the absorptive capacity of the

GIT. Likely as a consequence of that, colostrum feeding improves the glucose status in neonatal

calves by increasing glucose absorption that results in elevated postprandial plasma glucose

concentrations. Hepatic glycogen concentrations rise much greater when colostrum instead of a

milk-based colostrum replacer (formula with same nutrient composition as colostrum but almost

no biologically active substances, such as hormones and growth factors) is fed. In contrast, first-

pass glucose uptake in the splanchnic tissue tended to be greater in calves fed formula. The

greater plasma glucose rise and improved energy status in neonatal calves after colostrum intake

lead to greater insulin secretion and accelerated stimulation of anabolic processes indicated by

enhanced maturation of the postnatal somatotropic axis in neonatal calves. Hormones involved in

stimulation of eGP, such as glucagon and cortisol, depend on neonatal diet, but their effects on

eGP stimulation seem to be impaired. Although colostrum feeding affects systemic insulin, IGF-

I, and leptin concentrations, evidence for systemic action of colostral insulin, IGF-I, and leptin in

neonatal calves is weak. Studies so far indicated no absorption of insulin, IGF-I, and leptin from

colostrum in neonatal calves, unlike in rodents where systemic effects of colostral leptin are

demonstrated. Therefore, glucose availability in neonatal calves is promoted by perinatal



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maturation of eGP and colostrum intake. There may be long-lasting effects of an improved

colostrum supply and glucose status on postnatal growth and development, and colostrum supply

may contribute to neonatal programming of performance (milk, growth) in later life, but data

proving this concept are missing.

Key words: Colostrum feeding, endogenous glucose production, glucose absorption, neonatal

calf

INTRODUCTION

Glucose is essential in mammals as energy fuel for brain, erythrocytes, and medulla of

the kidney (Zierler, 1999) and is the primary energy source during fetal development (Fowden,

1997; Bell et al., 2005a,b). After birth, glucose supply changes from prenatal ‘parenteral’ via

placenta to lactose supply by colostrum and milk feeding (Aynsley-Green, 1988; Girard et al.,

1992). Because lactose uptake does not meet glucose demand in the neonate, glycogenolysis and

especially gluconeogenesis (GNG) are important metabolic pathways to establish postnatal

euglycemia (Girard, 1990). However, fetal GNG is low and maturation processes around birth

are necessary to achieve sufficient endogenous glucose production (eGP) (Girard, 1990; Girard

et al., 1992; Fowden, 1997), as also seen in calves (Steinhoff-Wagner et al., 2011b). Calves,

especially when born preterm, often develop marked hypoglycemia after birth that may impair

postnatal growth and development (Girard et al., 1992; Hammon and Blum, 1998b; Bittrich et

al., 2002; Steinhoff-Wagner et al., 2011b).

Colostrum, the first milk neonates receive after birth, is rich in nutrients and non-nutrient

biologically active factors. Colostrum feeding has an impact on postnatal development and

possibly glucose homeostasis in several species (Kelly, 1994; Koldovský, 1989; 1994; Burrin et



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al., 1995; Savino et al., 2011). In cattle, colostrum contains plenty of bioactive components and

their effects on neonatal development are intensively investigated (Blum and Hammon, 2000;

Blum, 2006; Blum and Baumrucker, 2008). The main focus of this review is to summarize data

of colostrum feeding or feeding of colostral growth factors and hormones on glucose metabolism

in neonatal calves. Evidence is growing that colostrum feeding has a significant impact on the

glucose status of the neonatal calf and colostral bioactive substances, such as hormones and

growth factors, may contribute to neonatal glucose homeostasis, as discussed for humans (Savino

et al., 2011).

COLOSTRUM EFFECTS ON NEONATAL INTESTINAL DEVELOPMENT

In cattle, colostrum provides newborns with great amounts of nutrients, vitamins, and

non-nutrient biologically active substances, such as immunoglobulins, hormones, growth factors,

cytokines, and other peptides with biological action (Campana and Baumrucker, 1995; Blum and

Hammon, 2000; Blum, 2006; Gauthier et al., 2006; Blum and Baumrucker, 2008). Besides the

great importance of colostral immunoglobulins for passive immunity of the neonate (Godden,

2008), colostrum has a broad impact on postnatal intestinal development. In mammals, non-

nutritional or bioactive factors, such as insulin, IGF-I and -I, or leptin, are present in high

concentrations in first colostrum and affect postnatal intestinal development (Bird et al., 1996;

Burrin et al., 1996; Odle et al., 1996; Sangild, 2001; Blum, 2006; Blum and Baumrucker, 2008).

Most non-nutritional components of colostrum are accumulated in the mammary gland during

the prepartum period. Colostrogenesis ends abruptly at parturition (Barrington et al., 2001;

Godden, 2008). Therefore, concentrations (and often also mass) of many of its components are

greatest in the first secretion after calving (i.e., first colostrum milking), then decline steadily

over the next milkings to much lower concentrations after about 1 wk in mature milk (Blum and



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Hammon, 2000; Blum and Baumrucker, 2008; Montoni et al., 2009).

For neonatal calves, the interaction between colostral non-nutritional factors and the

neonatal gastrointestinal tract (GIT) was recently demonstrated, as reviewed by Blum (2006).

Studies indicate that individual growth factors or hormones affect neonatal GIT development of

several species, probably by acting through specific receptor binding sites in the gut mucosa

(Arsenault and Menard, 1987; Berseth, 1987; Burrin et al., 1996; Alexander and Carey, 1999;

Blum and Hammon, 2000; Blum, 2006). In neonatal calves, the epithelium along the GIT

indicates gene expression of IGF and insulin receptors (Ontsouka et al., 2004a,d). Gene

expression of the insulin but not IGF receptors differ among different mucosal fractions of the

small intestine (Ontsouka et al., 2004c). Gene expression and maximal binding capacities of IGF

and insulin receptors in the intestinal mucosa of neonatal calves are variably affected by feeding

and age, and are partly related to villus growth and mucosal cell proliferation (Baumrucker et al.,

1994b; Hammon and Blum, 2002; Georgiev et al., 2003; Georgieva et al., 2003; Ontsouka et al.,

2004a,d). However, for other colostral factors, such as lactoferrin and vitamin A, when fed as

single growth-promoting substances to neonatal calves, stimulatory effects on mucosal cell

proliferation and protein synthesis in the small intestine could not be shown (Rufibach et al.,

2006). It seems quite obvious, that these growth-promoting effects of colostrum are not induced

by single factors, but rather by interaction of the great number of growth-promoting substances

in colostrum (Koldovský, 1989; Roffler et al., 2003; Blum 2006). Most of these colostral

biologically-active factors do not seem to be absorbed in significant amounts to induce systemic

effects in the neonatal calves (Blum, 2006) because several studies failed to show significant

absorption of growth factors or hormones and questioned physiological relevance in calves and

piglets (Grütter and Blum, 1991; Vacher et al., 1995; Donovan et al., 1997; Roffler et al., 2003;



6

Sparks et al., 2003). However, recent findings in neonatal pigs and rats may indicate systemic

effects of colostral factors for postnatal development that may require intestinal absorption in the

neonate (Sánchez et al., 2005; Bartol and Bagnell, 2012).

Colostrum feeding stimulates intestinal cell growth, protein synthesis, and digestive and

absorptive function in neonatal mammals (Kelly, 1994; Burrin et al., 1995; Odle et al., 1996; Xu

et al., 2000; Sangild, 2001; Blum, 2006; Guilloteau et al., 2009). In neonatal calves, the amount

of ingested colostrum corresponds with villus size of the small intestine (Bühler et al., 1998;

Blättler et al., 2001). Nutrient content, as well as non-nutrient components, of bovine colostrum

affect villus size and/or mucosal cell proliferation (Bühler et al., 1998; Blättler et al., 2001;

Roffler et al., 2003; Sauter et al., 2004). Therefore, the intestinal absorptive capacity increases in

neonatal calves after colostrum intake, indicated by elevated xylose absorption in colostrum-fed

calves as compared with calves fed either milk replacer or a milk-based formula with the same

nutrient content as colostrum but almost no biologically-active factors (Table 1; Hammon and

Blum, 1997a; Rauprich et al., 2000; Sauter et al., 2004; Steinhoff-Wagner et al., 2011a).

Stimulatory effects of bovine colostrum are also seen in human epithelial cells or in weaned

piglets, indicating the potential of bovine colostrum milk as species-independent growth

promoting substrate (Purup et al., 2007; Boudry et al., 2008).

GLUCOSE METABOLISM IN THE NEONATAL CALF

Glucose is the main source for fetal energy supply in farm animals, including calves

(Fowden, 1997; Père, 2003; Bell et al., 2005a,b). Although plasma concentrations of fetal

fructose are high, contribution of fructose to fetal oxidative metabolism is small when compared

with glucose, as indicated in several species including cattle (Battaglia and Meschia, 1978;

Meznarich et al., 1987; Kurz and Willett, 1992; McGowan et al., 1995; Père, 1995). In addition,



7

free amino acids contribute significantly to fetal energy utilization, whereas fatty acids and

ketone bodies are less important (Fowden, 1997; Père, 2003; Bell et al., 2005a,b). Fetal glucose

depends almost exclusively on placental glucose supply (Fowden et al., 2009). A linear

relationship between maternal and fetal plasma glucose concentration, with lower concentrations

in the fetus was demonstrated in ruminants and pigs (Silver et al., 1973; Père, 1995).

Endogenous glucose production, especially GNG, is negligible in the fetus, unless

glucose supply by the placenta is impaired (Hay, 2006). Maternal fasting or under-nutrition for

several days induces hypoglycemia in the fetal sheep (Bell and Ehrhardt, 2002). Under these

conditions, glucose transfer to the placenta and placental glucose consumption are reduced and

GNG is enhanced in the sheep fetus (Leury et al., 1990; Bell and Ehrhardt, 2002). However, a

moderate reduction in maternal energy intake does not cause an increase of gluconeogenic

enzyme activities in the bovine fetus (Prior and Scott, 1977). This might be due to the

homeorhetic regulation of the glucose status, that is, a high priority of the fetal demand relative

to the maternal demand for glucose, allowing for maintenance of relatively high and stable

plasma glucose concentrations through activation of glucose sparing mechanisms (Bell and

Bauman, 1997).

Close to term, maturational changes in the fetus result in increased gluconeogenic

activity, and hepatic glycogen storage. These metabolic changes are caused by the increased fetal

action of glucocorticoids, catecholamines, and thyroid hormones during late gestation (Fowden,

1997; Fowden et al., 1998, 2001; Forhead et al., 2009; Fowden and Forhead, 2011). Because

continuous glucose supply by the placenta ceases after birth, the neonate must meet the glucose

demand by lactose (i.e., glucose plus galactose) intake and by eGP. Lactose intake on its own is

not sufficient to meet glucose demands in the neonate (Mellor and Cockburn, 1986; Girard,



8

1990; Girard et al., 1992). Hepatic glycogen stored during late gestation serves as first energy

source and glycogen breakdown usually assures euglycemia in the neonate immediately after

birth (Swiatek et al., 1970; Liggins, 1994; Steinhoff-Wagner et al., 2011b). When no milk intake

occurs during the first 24 h of life, plasma glucose concentrations persist on a low, but constant

level with plasma concentrations greater than 3.5 mmol/L in neonatal calves (Hadorn et al.,

1997; Steinhoff-Wagner et al., 2011b). Therefore, the function of the eGP in full-term born

calves is to avoid a severe decrease of plasma glucose concentrations. This is in contrast to

preterm born calves, where a severe hypoglycemia occurs and eGP is insufficient (Bittrich et al.,

2002; Schmidt et al., 2004; Steinhoff-Wagner et al., 2011b), an observation also found in

preterm infants (Van Kempen et al., 2003).

Although calves receive glucose from lactose digestion with colostrum and milk feeding,

eGP increases with age, indicating maturation of the gluconeogenic pathway after birth due to

feeding and(or) ontogenic development and that the availability of glucose from milk is not

sufficient to fully cover glucose requirements (Steinhoff-Wagner et al., 2011b;). This is different

from the situation in heavy veal calves, in which excessive hyperglycemia is often seen

(Hostettler-Allen et al., 1994; Hugi et al., 1998). During the first days of life, eGP in calves

provides 25 to 30 µmol glucose/(kg × min), where up to 60% derives from GNG (Scheuer et al.,

2006; Steinhoff-Wagner et al., 2011a,b).

In neonates, lactate, amino acids (especially alanine), and glycerol are used as substrates

for GNG within 8 h after birth (Girard et al., 1992). Newborn ruminants (i.e., pre-ruminants

because of the absence of a functional rumen) are able to use lactate, besides gluconeogenic

amino acids, but glycerol only to a limited extent for GNG (Donkin and Hammon, 2005).

Gluconeogenesis from propionate is measurable in hepatocytes of 14-d-old calves (Donkin and



9

Armentano, 1994; Donkin, 1999). With the development of a functional rumen, the production

of volatile fatty acids increases and propionate becomes the preferred gluconeogenic substrate in

cattle (Donkin and Hammon, 2005). Renal GNG contributes 10 to 15% of total GNG and is

unrelated to age, because 10-d-old calves show rates of GNG similar to non-lactating cows

(Krebs and Yoshida, 1963).

Pyruvate carboxylase (PC), phosphoenolpyruvate carboxykinase (PEPCK), and glucose-

6-phosphatase (G6Pase) are rate-limiting enzymes of GNG (Rognstad, 1979; Kraus-Friedmann,

1984; Girard et al., 1992; Pilkis and Granner, 1992; Donkin, 1999; Jitrapakdee and Wallace,

1999; Van Schaftingen and Gerin, 2002). The decline of hepatic glycogen storage immediately

after birth goes along with increasing G6Pase activities (Böhme et al., 1983). Higher activities of

G6Pase favor conversion of glucose-6-phosphate to glucose and ensure the release of glucose

into the circulation (Van Schaftingen and Gerin, 2002). Activities of G6Pase are low in the fetus

during late gestation, increase at birth, peak at a few days after birth, and remain relatively

constant up to adulthood. This holds for piglets, lambs, infants, rats, and in part for calves

(Dawkins, 1961; Grün, 1981; Ballard and Oliver, 1965; Steinhoff-Wagner et al., 2011b).

Pyruvate carboxylase and PEPCK activities in fetal rats increase from low values at a few days

before birth to high levels after the first week of life (Kalhan and Parimi, 2000). In piglets, which

are born more mature than rats, activities of both PC and PEPCK increase around birth (Tildon et

al., 1971; Grün, 1981), whereas in fetal bovine liver, PC and PEPCK activities are measurable

and substrates such as lactate, alanine, and aspartate are used by fetal bovine hepatocytes (Prior

and Scott, 1977). Close to birth, only PEPCK shows a distinct increase (Prior and Scott, 1977;

Steinhoff-Wagner et al., 2011b). The rise of PEPCK activities from preterm to full-term and in 4-

d-old calves is accompanied by an increase of GNG and eGP, but also by increasing hepatic



10

glycogen storage with age (Steinhoff-Wagner et al., 2011b).

DEPENDENCE OF GLUCOSE METABOLISM ON COLOSTRUM SUPPLY

Newborn calves have low plasma glucose concentrations immediately after birth, but

plasma glucose concentrations increase after the first meal and depend on amount and time-point

of colostrum feeding (Hadorn et al., 1997; Hammon and Blum, 1998b; Kühne et al., 2000;

Rauprich et al., 2000; Hammon et al., 2003; Steinhoff-Wagner et al., 2011a). Furthermore,

colostrum intake has long-term effects on plasma glucose concentrations in neonatal calves

(Hadorn et al., 1997; Hammon and Blum 1998b; Rauprich et al., 2000). Colostrum intake

promotes glucose absorption, similar to xylose absorption, in neonatal calves indicating that the

elevated intestinal surface due to colostrum feeding facilitates enhanced glucose absorption

(Hammon and Blum, 1997a; Rauprich et al., 2000; Sauter et al., 2004; Steinhoff-Wagner et al.,

2011a). In addition, colostrum feeding improves lactose digestion in neonatal calves.

Postprandial lactase activities tended to be greater in colostrum- than formula-fed calves fed for

4 d (J. Steinhoff-Wagner and H. M. Hammon, unpublished data), although lactose intake was the

same (Table 1). This was not the case when lactase activities were measured in neonatal calves

under fasted condition (Sauter et al., 2004). Lactase is a disaccharide synthesized in the brush

border membrane of mucosal epithelial cells in the small intestine, has greatest activities in

jejunum and at birth, is affected by feeding, and decreases with increasing age (Zhang et al.,

1997; Sangild et al., 2002; Ontsouka et al., 2004b). Lactase activity is comparably high at birth

in preterm and full-term born calves (Bittrich et al., 2004), but postprandial lactase activities are

lower in preterm than full-term calves (J. Steinhoff-Wagner and H. M. Hammon, unpublished

data). Interestingly, colostrum feeding does not stimulate gene expression and protein

concentrations of sodium-dependent glucose transporter (SGLT)-1 or facilitated glucose



11

transport by glucose transporter-2 (U. Schönhusen, J. Steinhoff-Wagner, and H. M. Hammon,

unpublished data). First-pass glucose uptake in the splanchnic tissue on d 2 of life was greater in

formula- than colostrum-fed calves, indicating greater glucose utilization in the GIT of calves not

fed with colostrum (Steinhoff-Wagner et al., 2011a). Possibly, nutrient absorption is generally

impaired in formula-fed calves, leading to elevated glucose utilization in the splanchnic tissue,

whereas colostrum-fed calves are able to use greater amounts of digested fat and protein as

energy fuel in the splanchnic tissue. This hypothesis is supported by the finding that oral fat

absorption was also greater in colostrum- than in formula- or milk replacer-fed calves, providing

more fat as energy fuel in the splanchnic tissue instead of glucose (Hammon and Blum, 1998b;

Kühne et al., 2000; Rauprich et al., 2000).

Because lactose intake by colostrum does not meet postnatal glucose demands, hepatic

glycogenolysis and especially GNG increase rapidly in newborns (Girard, 1990; Girard et al.,

1992; Steinhoff-Wagner et al., 2011b). However, based on recent studies in neonatal calves

either in the fasted or in the fed state, a direct effect of bioactive substances on eGP or GNG

stimulation in neonatal calves can be excluded (Scheuer et al., 2006; Steinhoff-Wagner et al.,

2011a; Hammon et al., 2012). Therefore, a stimulating influence of colostrum intake on eGP, as

found in piglets, may not be the result of a direct effect of growth-promoting substances of

ingested colostrum, but may depend indirectly on postnatal maturation (Lepine et al., 1991;

Hammon et al., 2012). Although eGP and GNG do not depend on postnatal milk diet, differences

in gene expression of gluconeogenic enzymes could be observed, primarily in the postprandial

state, but not in the fasted state (Hammon et al., 2003; Steinhoff-Wagner et al., 2011a). Gene

expression and activity of PC were greater in formula- than in colostrum-fed calves (Steinhoff-

Wagner et al., 2011a).



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Although eGP did not differ between colostrum- and formula-fed calves, postprandial

glycogen concentration in liver was markedly greater in colostrum- than formula-fed calves

(Steinhoff-Wagner et al., 2011a). Thus, the elevated plasma glucose concentrations and the

greater hepatic glycogen content indicate an improved glucose status by colostrum feeding. This

improved glucose status is a result of enhanced glucose absorption and probably lower glucose

utilization in the splanchnic tissue, when colostrum was fed instead of formula. Improved

glucose status in colostrum-fed calves is likely an important prerequisite for the accelerated

maturation of the somatotropic axis, as indicated by several studies in neonatal calves that were

recently summarized (Hammon and Blum, 1997b; Cordano et al., 2000; Sauter et al., 2003;

Hammon et al., 2012).

DEPENDENCE OF ENDOCRINE GLUCOSE REGULATION ON COLOSTRUM

SUPPLY

Plasma insulin concentrations were low at birth and increased after first intake of

colostrum, milk replacer, milk-based formula, or glucose, indicating that nutrient intake,

especially glucose intake, stimulates insulin secretion (Hadorn et al., 1997; Hammon and Blum,

1998b; Rauprich et al., 2000; Nussbaum et al., 2002). There is no evidence that colostral insulin

is absorbed in significant amounts from the GIT in neonatal calves to achieve systemic effects

(Grütter and Blum, 1991). Therefore, insulin measured in blood plasma of neonatal calves

originates from pancreatic secretion. Amount, time point ,and frequency of colostrum intake

influence plasma insulin concentrations and have partly prolonged effects on plasma insulin

(Hadorn et al., 1997; Hammon and Blum, 1998b; Rauprich et al., 2000; Nussbaum et al., 2002).

A greater insulin response after colostrum feeding than milk replacer or formula feeding in

neonatal calves was hypothesized to result from greater nutrient intake and from improved



13

nutrient absorption in colostrum-fed calves because elevated insulin concentrations were

associated with elevated plasma concentrations of glucose and amino acids (Hammon and Blum,

1998b; Hammon and Blum, 1999; Kühne et al., 2000; Rauprich et al., 2000; Steinhoff-Wagner et

al., 2011a). In addition, insulin secretion may be stimulated by gastrointestinal hormones, which

also increased after colostrum intake (Guilloteau et al., 1997; Hadorn et al., 1997). Studies using

the euglycemic-hyperinsulinemic clamp technique revealed no effects of colostrum or formula

feeding on insulin-dependent glucose utilization in neonatal calves (Scheuer et al., 2006), an

effect seen in neonatal rats after oral leptin supplement (Sánchez et al., 2008).

Besides insulin, the IGF system affects glucose metabolism, especially when IGF-I or -II

are not bound to IGFBP (Douglas et al., 1991; Jones and Clemmons, 1995; Hammon and Blum,

1998a; Wang et al., 2012). In addition, the IGF system in neonatal calves is affected by

colostrum feeding (Blum and Baumrucker, 2008; Hammon et al., 2012). As mentioned

previously, colostrum contains high amounts of IGF-I and -II, but colostral IGF or long-R3-IGF-I

are not absorbed in significant amounts in neonatal calves and piglets (Vacher et al., 1995;

Donovan et al., 1997; Hammon and Blum, 1997b; Roffler et al., 2003). In addition, no effects on

plasma glucose concentrations were observed after feeding rhIGF-I or long-R3-IGF-I together

with milk replacer (Baumrucker et al., 1994a; Hammon and Blum, 1998a). However, as stated

previously, IGF-I and -II may contribute to the growth promoting effects of colostrum on the

GIT and, therefore, stimulate nutrient digestion and absorption (Baumrucker et al., 1994b; Burrin

et al., 1996; Alexander and Carey, 1999; Blum, 2006). The elevated glucose and insulin status in

colostrum-fed calves support endogenous IGF-I production (Brameld et al., 1999; Butler et al.,

2003), as indicated by enhanced hepatic IGF-I production in neonatal calves fed colostrum

instead of formula (Cordano et al., 2000). Therefore, the improved glucose status in colostrum-



14

fed calves leads to functional maturation of the somatotropic axis indicated by a decreased GH to

IGF-I ratio in blood plasma when colostrum is fed instead of milk replacer or formula

(Gluckman et al., 1999; Sauter et al., 2003). However, colostral IGF-I has no direct effect on

glucose utilization or insulin-dependent glucose metabolism in calves, as discussed for diabetic

mice (Hwang et al., 2011).

Plasma glucagon concentrations increased after first colostrum feeding in calves. The

postprandial glucagon rise in blood plasma after first meal was greater in colostrum-fed than

formula-fed or milk replacer-fed calves (Hammon and Blum, 1998b; Kühne et al., 2000;

Rauprich et al., 2000). Glucagon is an antagonist of insulin, is necessary for glucose homeostasis

and counteracts decreasing plasma glucose concentrations after insulin release, especially after a

high protein intake, but is not enriched in colostrum milking (Kraus-Friedmann, 1984; Blum and

Baumrucker, 2008). Both insulin and glucagon plasma concentrations increased after first

colostrum feeding, probably due to the high protein intake with colostrum (Hammon and Blum,

1998b; Kühne et al., 2000; Rauprich et al., 2000). During the 1st wk of life, plasma glucagon

concentrations were often greater in calves fed formula or milk replacer instead of colostrum,

which was probably a response of insufficient glucose uptake with formula or milk replacer

feeding when compared with colostrum feeding (Kühne et al., 2000; Rauprich et al., 2000;

Steinhoff-Wagner et al., 2011a). Interestingly, elevated plasma glucagon concentrations were

associated with greater PC activities in colostrum- than in formula-fed calves, although elevated

plasma glucagon concentrations did not result in stimulation of eGP and GNG in neonatal calves

(Steinhoff-Wagner et al., 2011a).

Plasma cortisol concentrations, which were high at birth and decreased after first feed

intake and during the 1st wk of life in neonatal calves, were greater in formula- and milk



15

replacer- than in colostrum-fed calves (Hammon and Blum, 1998b; Rauprich et al., 2000;

Steinhoff-Wagner et al., 2011a). As seen for glucagon, elevated plasma cortisol concentrations

did not stimulate eGP or GNG (Steinhoff-Wagner et al., 2011a), although recent findings showed

a greater number of glucocorticoid binding sites in liver of colostrum-fed calves when compared

with formula-fed calves (Rohrbeck et al., 2012). Dexamethasone, a potent glucocorticoid analog,

treatment in addition did not stimulate eGP or GNG in neonatal calves (Scheuer et al., 2006).

Furthermore, PC and PEPCK activities were depressed after dexamethasone treatment (Hammon

et al., 2003, 2005), although glucocorticoids are known for their stimulatory effects on PC and

PEPCK, including cattle (McDowell, 1983; Brockman and Laarveld, 1986; Pilkis and Granner,

1992; Jitrapakdee and Wallace, 1999). However, plasma glucose concentrations were elevated

after dexamethasone treatment due to peripheral insulin resistance (Hammon et al., 2003;

Scheuer et al., 2006), pointing out that not enhanced glucose production, but reduced peripheral

glucose utilization is responsible for elevated plasma glucose concentrations after glucocorticoid

treatment.

Besides glucagon and cortisol, catecholamines are involved in eGP and stimulate hepatic

glycogenolysis and GNG through α1- and β2-adrenergic receptors (Rizza et al., 1980; Kraus-

Friedmann, 1984), also shown in ruminants (McDowell, 1983; Brockman and Laarveld, 1986)

and neonatal calves (Carron et al., 2005b; Hammon et al., 2012). In addition, catecholamines

play an important role in postnatal glucose homeostasis (Sperling et al., 1984) and plasma

concentrations of catecholamines are elevated around birth (Richet et al., 1985; Fowden et al.,

1998). Whether plasma catecholamine concentrations are affected by nutrition in neonatal

calves, is presently not known. As indicated recently in calves, α1-adrenergic receptors are

related to eGP during perinatal maturation (Hammon et al., 2012), but different diet did not



16

affect eGP (Steinhoff-Wagner et al., 2011a) and binding studies on α1- and β2-adrenergic

receptors indicated only a trend for a greater number of hepatic α1-, but no differences in β2-

adrenergic receptors in neonatal calves with colostrum instead of formula feeding (Carron et al.,

2005a; Rohrbeck et al., 2012). Interestingly, colostrum feeding stimulated gene expression of β3-

adrenergic binding sites in liver of neonatal calves (Carron et al., 2005a), but binding studies on

β3-adrenergic receptors in liver were not performed and the physiological relevance of these

finding has to be confirmed.

Leptin, in addition, is a glucose-regulating hormone that is, besides in adipose tissue,

produced in the mammary gland, is enriched in colostrum and first milk after parturition in

several species including cattle, and affects postnatal development and maturation (Casabiell et

al., 1997; Chilliard et al., 2001; McFadin et al., 2002; Blum and Baumrucker, 2008; Sánchez et

al., 2005; Attig et al., 2011; Morton and Schwartz, 2011). Leptin from colostrum is absorbed in

neonatal rats and infants (and probably other species) and has systemic effects on food intake,

thermogenic capacity, intestinal development, and insulin-dependent glucose metabolism

(Casabiell et al., 1997; McFadin et al., 2002; Sánchez et al., 2005; 2008; Attig et al., 2011).

However, leptin is already produced in fetal fat depots and is obviously related to fetal fat mass

in several species (Schubring et al., 1999; McMillen et al., 2004). In calves, plasma leptin

concentrations were greater in calves born at term than born preterm, did not increase

immediately after colostrum intake, but increased slowly during the subsequent days after

colostrum feeding in dairy calves, and increased dramatically in beef calves that were suckling

their mothers. Plasma leptin concentrations decreased during the first days of life in calves, when

formula was fed instead of colostrum (Blum et al., 2005; J. Steinhoff-Wagner, H. Sauerwein, and

H. M. Hammon, unpublished observations). Therefore, plasma leptin concentrations in neonatal



17

calves seem to be more related to fat accretion and(or) fat mass than to leptin intake via

colostrum. However, studies on colostral leptin absorption in neonatal calves are lacking.

Colostral leptin may contribute to postnatal intestinal maturation in calves and may affect

postnatal energy and glucose metabolism, as seen for other species (McMillen et al., 2004;

Sánchez et al., 2008; Attig et al., 2011; Morton and Schwartz, 2011).

SUMMARY AND CONCLUSIONS

Postnatal glucose metabolism in calves is dictated by perinatal maturation of eGP and by

colostrum feeding (Hammon et al., 2012). Colostrum feeding does not affect eGP and GNG, but

improves glucose absorption; thus, more glucose is stored in liver and more glucose is available

for peripheral tissues during the postprandial state. Systemic effects of colostral hormones and

growth factors on glucose metabolism are not described at present in neonatal calves, but

colostral hormones and growth factors support maturation of the GIT and may stimulate lactose

digestion and glucose absorption (Blum, 2006; Blum and Baumrucker, 2008; Hammon et al.,

2012). Systemic effects of colostral hormones and growth factors, such as leptin and IGF-I on

glucose metabolism, as recently described in rodents, cannot be confirmed in neonatal calves

(Baumrucker et al., 1994a; Hammon and Blum, 1998a; Sánchez et al., 2008; Attig et al., 2011;

Hwang et al., 2012). There might be species differences with regard to systemic effects of

hormones and growth factors originated from colostrum or milk. Thus, intestinal transport of

IGF-I was described in rats (Philipps et al., 2002).

Present literature with regard to milk feeding of calves does focus on imprinting effects

of milk intake on subsequent growth and lactation performance (Bach, 2012; Soberon et al.,

2012). Because colostrum feeding improves the metabolic status of neonatal calves and

stimulates postnatal growth and development, including an elevated glucose status, this might



18

have effects on performance in later life and contribute to advanced growth and lactation.

However, more long-term studies will be needed to clarify the concept of imprinting effects of

milk feeding in calves on long-term performance, and colostrum supply to neonatal calves

should be part of this concept.

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Table 1. Composition of colostrum milkings from d 1, 2, and 3 after parturition and respective milk-based formulas fed to neonatal calves. Table

is adapted from Steinhoff-Wagner et al. (2011a).

Composition Day 1 Day 2 Day 3, 4

Colostrum1 Formula2 Colostrum1 Formula2 Colostrum1 Formula2

(Milking 1) (Day 1) (Milking 3) (Day 2) (Milking 5) (Day 3)

Dry matter (DM), g/kg 239 240 179 179 151 153

Gross energy, MJ/(kg DM) 22.1 22.5 23.6 23.8 23.3 23.5

Crude protein, g/(kg DM) 523 514 396 409 297 338

Crude fat, g/(kg DM) 195 173 269 246 293 246

Ash, g/(kg DM) 44.8 87.1 50.8 72.2 53.5 68.6

NfE3, g/(kg DM) 237 226 284 272 357 347

Lactose, g/(kg DM) 201 d 201 260 d 260 341 4 338

IGF-1, µg/L 373 15 192 7.5 86 15

Insulin, µg/L 34 12 2.0 2.4 3.6 2.7

1 Colostrum fed on d 1 to d 4 of life was derived from pooled milkings 1, 3, and 5, respectively. Milk was only collected from cows in the second

or following lactations.



36

2 Formula (per kg DM fed on d 1, to d 4 of life, respectively) are composed of sodium-caseinate (80, 239, and 250 g, respectively), lactalbumin

(540, 175, and 50 g, respectively), vegetable fat (136, 202, and 200 g, respectively, coconut oil, made up to crude fat content with palm oil),

sweet whey powder (170, 294, and 410 g, respectively) and a mineral-vitamin premix (40.1 g). The premix is included in all formulae in the

following final concentrations (per kg DM) calcium (2.25 mol; 90 g), phosphorus (2.26 mol; 70 g), sodium (2.17 mol; 50 g), iron (0.358 mol;

20 mg), manganese (9.1 mmol, 0.5 mg), zinc (7.65 mmol; 0.5 mg), copper (2.36 mmol; 0.15 mg), iodine (78.8 µmol, 0.01 mg), selenium (0.127

mmol; 0.01 mg), retinol (60.2 µmol), α-tocopherol (63.45 mmol), and β-carotene (1.86 mmol).

3 Nitrogen-free extract (NfE) is calculated as 100 - % (Moisture + Crude protein + Lipid + Ash).

4 Lactose values include an addition of lactose powder to colostrum milkings (77.0, 39.1, and 41.6 g, per kg DM for colostrum milkings 1, 3, and

5, respectively).



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