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First published online September 5, 2008
Journal of Experimental Biology 211, 2943-2949 (2008)
Published by The Company of Biologists 2008
doi: 10.1242/jeb.018176
Hormonal regulation of glucose clearance in lactating northern elephant seals (Mirounga angustirostris)
Sonoma State University, Biology Department, 1801 E. Cotati Ave, Rohnert Park, CA 94928, USA
* Author for correspondence (e-mail: mfowler{at}biology.ucsc.edu)
Accepted 10 July 2008
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Summary |
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 TOP Summary INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Key words: glucose tolerance test, insulin, glucose metabolism, elephant seal, lactation, fasting
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INTRODUCTION |
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TOPSummaryINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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). A
major challenge of long-term fasting is providing fuel substrates for
glucose-dependent tissues while sparing vital body protein. Protein sparing is
facilitated by the contribution of non-amino acid precursors (e.g. glycerol
and lactate) to gluconeogenesis and the use of ketone bodies as an alternative
to glucose oxidation. Phocid seals provide an excellent system within which to
investigate fuel partitioning strategies during fasting as they undertake
predictable fasts concurrent with life history events that elevate substrate
demands (e.g. lactation, development).
Temporal separation of foraging and reproduction has led to simultaneous
extended fasting and lactation in several species of phocid seals, including
northern elephant seals (Mirounga angustirostris Linnaeus). Elephant
seals spend the majority of their lives at sea, returning to land only to
breed and molt (Le Boeuf et al.,
2000). During the molting fast, seals come ashore to grow new skin
and fur, a process which takes approximately 1 month
(Le Boeuf and Laws, 1994).
Females give birth and nurse their young for 
26 days, during which time
they transfer enough nutrients to facilitate the tripling of pup mass, while
depleting their own mass by up to 40%
(Crocker et al., 2001;
Kretzmann et al., 1993). Both
milk production and energy expenditure in elephant seals are strongly impacted
by body reserves (Crocker et al.,
2001).
Of all reproductive costs, lactation demands the most energy
(Gittleman and Thompson,
1988). Lactation is characterized by homeorhesis, or a shift in
nutrient partitioning for the priorities of a physiological state
(Bauman and Currie, 1980). The
constraints associated with simultaneous fasting and lactation may require a
significant change in the nutrient partitioning relative to either fasting or
lactation alone, enabling the mother to provide the necessary nutrients for
her offspring. An animal's capacity to sustain the production of large amounts
of milk is closely related to its ability to mobilize body reserves
(Bauman and Elliot, 1983). The
low carbohydrate, high fat composition of pinniped milk has been hypothesized
to be driven by the constraints of fasting
(Oftedal, 1993). Pinniped milk
contains only trace amounts of carbohydrate
(Oftedal, 1984), thus there
are no carbohydrate demands for milk synthesis and we would expect glucose
uptake by the mammary gland to be limited to that used for oxidation.
Little is known about hormonal regulation of glucose metabolism in phocids.
Despite efficient protein sparing, plasma glucose levels in lactating elephant
seals have been shown to increase across the fast
(Champagne et al., 2006), and
are high relative to fasting glucose levels in non-fasting adapted animals of
similar body mass (Umminger,
1975). This presents a paradox, as fasting normally results in a
decrease in plasma glucose (Cahill et al.,
1966; Klein et al.,
1990), even during lactation
(Chelikani et al., 2004;
Neville et al., 1993). The
role of increased plasma glucose in seals, simultaneous with the cessation of
nutrient input, remains undetermined. Levels of glucose production are typical
of that observed in post-absorptive terrestrial mammals and fail to exhibit
the suppression with fasting duration seen in non-fasting adapted species
(Champagne et al., 2006).
Kirby and Ortiz (Kirby and Ortiz,
1994) found a lack of insulin response to injected glucose in
weaned pups and suggested that elephant seal weanlings do not use the typical
mammalian insulin–glucagon counter-regulation of glucose metabolism.
Champagne et al. (Champagne et al.,
2006), however, found significant relationships between
proportional glucose cycle activity and plasma insulin:glucagon ratios (I:G)
in adult females, consistent with their typical regulatory roles. Basal
glucose, as well as the changes in insulin and glucagon across the fast,
differ between adult females (Champagne et
al., 2006) and weaned pups
(Champagne et al., 2005;
Ortiz et al., 2003;
Costa and Ortiz, 1982),
suggesting that glucose regulation may vary with development and physiological
state.
In this study, glucose tolerance tests (GTT) were used to assess the
efficiency of glucose disposal, to investigate the insulin response to
elevated glucose levels and gain insight into how elephant seals regulate the
utilization of nutrient reserves. In most other mammals, insulin secretion
increases in response to elevated glucose, enabling tissues to uptake the
circulating glucose and reduce glucose levels in the blood. Most species
exhibit concurrent dramatic reductions in plasma levels of glucagon in
response to an exogenous glucose load (Basu
et al., 1996; Butler and
Rizza, 1991). The magnitude of the insulin response to glucose is
indicative of the pancreatic β cells response to glucose, and the
disappearance of glucose over time relative to a given release of insulin is
indicative of the sensitivity of peripheral tissues to the hormone. Few
previous studies have investigated insulin responses to GTT in pinnipeds
(Hochachka et al., 1979;
Kirby and Ortiz, 1994;
Robin et al., 1981), and none
in simultaneously fasting and lactating individuals. We tested the hypothesis
that pancreatic cells in lactating elephant seals are insensitive to elevated
plasma glucose levels.
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MATERIALS AND METHODS |
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TOPSummaryINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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3 weeks of fasting
(Le Boeuf and Laws, 1994).
Sample collection and processing
Females were initially immobilized with Telazol (tiletamine/zolazepam HCl,
Fort Dodge Labs, Ft Dodge, IA, USA) at a dosage of 1 mg
kg–1, administrated intramuscularly. Continued immobilization
was maintained with 100 mg bolus intravenous injections of ketamine. A
blood sample was taken prior to the administration of glucose to ascertain
basal glucose and hormone levels. The glucose tolerance test (hereafter
referred to as a GTT) was administered intravenously. Females were given a
bolus injection of 150 g glucose as a 50% glucose solution. Injections were
administered via the epidural vein and the duration of the injection
averaged 8 min. Samples were collected into chilled, heparinized blood
collection tubes (BD Vacutainer®, Fisher Scientific, Franklin Lakes, NJ,
USA) every 10 min for the first 30 min post-injection and every 15 min until
180 min post-injection. Additional serum samples for hormone analysis were
collected into chilled blood collection tubes every 10 min for the first 30
min and every 30 min until 180 min. Samples were immediately placed on ice and
transported back to laboratory within 2–3 h. Samples were centrifuged at
4°C, and frozen at –80°C until further analysis.
Body composition measurements were made using the truncated cones method
(Crocker et al., 2001;
Gales and Burton, 1987). This
method allows the proportion of adipose and lean tissue masses to be
calculated and has been validated in elephant seals using isotopic methods
(Webb et al., 1998). Dorsal,
lateral and ventral blubber depth measurements were made using a portable
ultrasound scanner (Ithaca Scanprobe, Ithaca, NY, USA) at each of six
locations along the seal. Lengths and girths were taken at these six points,
as well as total curved length. These measurements allowed the seal to be
modeled as a series of truncated cones. Mass was measured using a tripod,
canvas sling and scale (±2 kg) (MSI, Seattle, WA, USA).
Sample analysis
Plasma glucose was measured in duplicate using an YSI 2300 glucose
autoanalyzer (YSI, Yellow Springs, OH, USA). Serum glucagon and insulin levels
were measured by radioimmunoassay (all kits from Linco, St Louis, MO, USA).
Glucagon (# GL-32K) and insulin (# SRI-13K) kits have been previously
validated for use in elephant seals
(Champagne et al., 2005;
Ortiz et al., 2003). The
average intra-assay coefficients of variation for insulin and glucagon were
10.2% and 12.3%, respectively.
Statistical analysis
Differences between matched early and late lactation samples were examined
using a paired t-test. Differences between molt and late lactation
samples were examined using a Student's t-test. We used a linear
mixed model with individual as a random effect subject to examine the effects
of body composition on the insulin response. Hormonal responses were assessed
using a repeated measures analysis of variance (RM ANOVA), with a multivariate
approach to detect differences within a time series. Significant RM ANOVAs
were analyzed by looking for significant differences from basal hormone
values. All data are expressed ± standard error of the mean (s.e.m.).
Results were considered significant at P<0.05.
A glucose tolerance index (K) was calculated assuming that the 20
min post-glucose-injection sample represented complete dilution of the
injected glucose within the total body pool
(Champagne et al., 2006).
K was then calculated using least-squares linear regression as the
negative slope of the natural log of glucose concentrations from 20 min to 180
min post-injection (Alder et al.,
1997; Bergman et al.,
1981; Chen and Nyomba,
2004).
Average glucose present was calculated using the area under the curve (AUC)
for glucose divided by the total duration of the sampling period. The area
under the curve was calculated using the trapezoid rule from 20–180 min
post-injection and after subtraction of basal levels
(Chen and Nyomba, 2004;
Grottoli et al., 1997;
Hatfield et al., 1999). Area
under the curve (AUC) for insulin and glucagon were likewise calculated using
the trapezoid rule, after subtracting basal values
(Chen and Nyomba, 2004) from
10 min post-injection until the final sample. Average secretion per minute of
each hormone was calculated by dividing the AUC by the duration of the
sampling period, in minutes.
There are numerous methods available to assess insulin sensitivity
(Avignon et al., 1999;
Bergman et al., 1987;
Bonora et al., 2000;
Ciampelli et al., 2005;
Katz et al., 2000). These
insulin sensitivity indices are based on basal insulin and glucose levels and
have been developed in human subjects who display either normal or abnormally
high basal insulin levels. The insulin:glucose ratio may not maintain the same
relationship in individuals who lack endogenous insulin secretion
(Avignon et al., 1999;
Katz et al., 2000). Elephant
seals display low basal insulin, therefore, the indices were inappropriate in
this case and we developed an Is index unique to this
study. Insulin sensitivity indices (Is) were calculated by
dividing the area under the insulin curve (AUCI) by the area under
the glucose curve (AUCG).
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RESULTS |
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TOPSummaryINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Basal glucose and hormone levels
Glucose levels (125.2±3.1 mg dl–1) did not vary
between classes (P>0.05). I:G ratio decreased significantly across
lactation (paired t=–3.76, P=0.01;
Table 1). Insulin, glucagon or
I:G ratio were not related to plasma glucose in any group
(P>0.05). Basal insulin levels decreased significantly across the
fast (paired t=–3.0, P=0.02;
Table 1). Late in the molt
insulin values were significantly different from those of the late lactation
females (84.2±5.5 pg ml–1; t=–3.6,
P=0.005) but not early lactation insulin values
(t=–0.08, P=0.93;
Table 1). Basal glucagon levels
did not change significantly across the fast (P=0.34;
Table 1).
Responses to glucose tolerance test
Glucose levels post glucose injection are shown in
Fig. 1A. Glucose levels 20 min
post-injection increased by 144.0±5.8% in early lactation,
158.2±5.3% in late lactation and 130.8±10.4% in the molt. These
differences were probably due to body mass differences among subjects. Despite
the differences in percentage increase among groups, there were no
relationships between percentage increase and rate of glucose clearance
(P>0.05). By 180 min post-injection, plasma glucose levels
remained high in all classes (61.1±7.0% above basal in early lactation,
90.0±8.1% above basal in late lactation and 58.9±10.4% above
basal late in the molt). Glucose tolerance indices (K) were not
different among classes (P>0.05;
Table 2).
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Peak insulin response occurred at 10 min post-injection (Fig. 1B). The 10 min response values and mean insulin secreted are shown for all groups in Table 2. Early lactation females showed a significant insulin response (viewed as the percentage increase 10 min post-injection; RM ANOVA F7,63=5.49, P=0.001). The 10 min sample showed a 129.0±24.4% increase above basal in early lactation (paired t=4.88, P=0.001). There was no insulin response to exogenous glucose in late lactation (P>0.05). Insulin levels deviated only –4.8±21.6% from basal 10 min post-injection and never deviated more than 55.4±47.8%. The molted female insulin response to the GTT was significant (F7,49=8.04, P=0.001), with a 61.6±11.6% increase above basal at 10 min post-injection (paired t=7.64, P=0.0001). The response of the molted females was intermediate to responses observed during early (t=2.49, P=0.03) and late lactation (t=–2.71, P=0.03; Table 2). Mean insulin secreted per minute did not predict K in early or late lactation or after the molt. There were no relationships between mean insulin secreted per minute and mean glucose present per minute in early or late lactation, or post-molt, respectively. The percentage increase in insulin at 10 min post-injection was significantly affected by adipose tissue proportions (F1,4=13.0, P=0.02; Fig. 2).
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Mean calculated Is for all groups is shown in Table 2. Is declined significantly from early to late lactation (paired t=2.47, P=0.005). The early lactation Is was not significantly different from the post-molt Is (t=0.83, P=0.42). Late lactation Is was significantly lower than the post-molt Is (t=–2.67, P=0.02).
Is was not related to body composition in early or late lactation, or in molted females. There were no relationships between body composition and average glucose present per minute in any sample group, nor were there relationships between body composition and K in any sample group.
The mean level of glucagon secreted per minute (pg ml–1) in early lactation was –0.14±1.06 pg ml–1 and in late lactation was –2.44±1.42 pg ml–1. There was no significant difference in levels between early and late lactation (paired t=–1.13, P>0.05). There was a significant decrease in glucagon following exogenous glucose in both early (RM ANOVA, F7,63=6.65, P<0.001) and late (F6,36=3.2, P=0.013) lactation.
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DISCUSSION |
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TOPSummaryINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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). Lipid
catabolism powers 90% of maternal metabolism
(Crocker et al., 2001).
Although it is not possible to separate the effects of lactation and body
reserve depletion in the current study (i.e. lactating females deplete
reserves to greater levels than molting females over similar fasting
durations), our findings suggest that efficient mechanisms of maximizing the
energy obtained from adipose reserves while simultaneously protecting protein
stores may be the selective force behind variations in hormone action relative
to that observed in non-fasting-adapted mammals.
Suppression of insulin response to glucose tolerance test
Elephant seals showed marked differences in insulin secretion in response
to exogenous glucose among different fasting states. Early lactation females
displayed the largest insulin response, whereas late lactation females showed
no insulin response to exogenous glucose. Molted females showed an
intermediate insulin response to the two lactation groups. This variation in
insulin response was directly related to variation in adipose tissue
proportions, suggesting functional suppression of insulin response as adipose
tissue stores are depleted during fasting. Rates of lipolysis are consistent
across lactation despite dramatic reductions in lipid stores
(Houser et al., 2007). The
need to maintain high net rates of lipolysis may be one of the driving forces
behind insulin suppression late in lactation, as fatty acid demands for milk
synthesis increase relative to body reserves. This is the first quantification
of insulin response to glucose administration in a naturally fasting and
lactating animal. Only two other groups that utilize fasting as a natural
stage in their life history have shown similar responses. In fasting elephant
seal pups (Kirby, 1992) and
fasting polar bears (Cattet,
2000), fasting duration and/or body composition have been shown to
have a significant relationship to insulin suppression.
Bauman and Elliott (Bauman and Elliott,
1983) reported that a marked decrease in pancreatic release of
insulin in response to glucose is a normal homeorhetic change in lactating
ruminants. Despite this generalization, insulin responses during lactation in
ruminants varied widely (Sano et al.,
1991; Sartin et al.,
1985). Elephant seals are part of a very small subset of mammalian
carnivores that fast and lactate. Although discussions about the similarities
and differences between ruminants and elephant seals are instructive, any such
comparisons should be made with caution. There is a dearth of literature on
lactation and glucose metabolism in free-ranging carnivores and more research
is required to better understand how insulin responses vary in this group of
animals.
Sustained insulin resistance
Elephant seals demonstrate some degree of insulin resistance, regardless of
fasting state, as indicated by the low K values and high levels of
glucose remaining 3 h post-GTT. Normal glucose tolerance indices in humans was
shown to drop from 2.1% min–1 to 0.63% min–1
after 8 days of fasting (Cahill et al.,
1966). Glucose tolerance indices as high as 3.94%
min–1 have been reported in non-fasting baboons
(Ensinck et al., 1997) and
3.66%min–1 in rats (Chen
and Nyomba, 2004). Glucose clearance is significantly impaired and
similar in all classes of fasting female elephant seals (0.19%
min–1 to 0.27% min–1), despite variation in
insulin response. Impaired clearance combined with the lack of relationship
between glucose clearance and insulin secretion suggests insulin resistance in
fasting elephant seals. In addition, insulin sensitivity declined slightly
late in lactation relative to the other samples.
Decreased sensitivity to insulin has been shown in response to a variety of
conditions. Diabetes is notable among these conditions, but insulin resistance
is demonstrated in pregnancy (Bauman and
Bell, 1997; Ryan,
2003), as well as during prolonged fasting in humans
(Cahill et al., 1966).
Although a review by Bauman and Bell
(Bauman and Bell, 1997)
suggests that lactating ruminants experience reduced tissue sensitivity to
insulin, the data on insulin resistance during lactation in other species
appear equivocal (Burnol et al.,
1986; Debras et al.,
1989; Hoffman et al.,
2003; Sano et al.,
1991; Tigas et al.,
2002). Performing an insulin tolerance test would give a clearer
picture of the level of insulin resistance in adult lactating elephant seals.
Kirby and Ortiz (Kirby and Ortiz,
1994) found that glucose levels were suppressed after the
injection of exogenous insulin in weaned elephant seals, suggesting some level
of tissue response to insulin.
Mechanisms for altering insulin secretion and sensitivity
Elevated nonesterified free fatty acids (NEFA) could directly impact the
ability of the islets of Langerhans to express insulin. Free fatty acids
stimulate insulin secretion, but chronically high levels of NEFA result in a
decrease of insulin content in pancreas cells by decreasing the expression of
insulin (Bollheimer et al.,
1998; Ritz-Laser et al.,
1999). High NEFA levels may also be implicated in the reduction of
insulin sensitivity. Although short-term elevations of NEFA are known to
stimulate insulin secretion (Bollheimer et
al., 1998), a considerable amount of research has shown that
chronically elevated NEFA are the initiating cause of an impairment in insulin
signal transduction (Boden and Laakso,
2004; Yu et al.,
2002). Previous research has shown that fasting elephant seals
have elevated NEFA (1.0–3.2 mmol l–1)
(Castellini et al., 1987;
Houser et al., 2007;
McDonald and Crocker, 2006) in
comparison to other non-fasting adapted species (e.g. 0.14 mmol
l–1 in humans) (Fery et
al., 1990).
Glucagon response
Insulin inhibits pancreatic release of glucagon
(Aronoff et al., 2004).
Non-fasting, non-obese, non-diabetic individuals in other mammalian species
display depression of glucagon levels following a GTT, even when lactating
(Aronoff et al., 2004;
Fery et al., 1990;
Sartin et al., 1985).
Individuals with reduced insulin secretion (e.g. diabetics or obese
individuals) do not suppress glucagon
(Greenbaum et al., 2002;
Staehr et al., 2001;
Velliquette et al., 2002)
exacerbating the hyperglycemia following a glucose tolerance test, due to
continued hepatic glucose production. Elephant seals in the present study
exhibited an equivalent depression of glucagon in response to a glucose load
during both stages of lactation despite a lack of insulin secretion late in
lactation. This disconnection between the insulin and glucagon responses
suggests alterations in the typical counter-regulatory responses of the
pancreatic hormones. Late lactation seals exhibited low glucose clearance
despite a biphasic insulin response coupled with glucagon depression. Although
the response was statistically significant, the magnitude of the glucagon
depression is smaller than that found in other studies that have documented
glucagon depressions following a GTT. Adult females do not appear to regulate
glucose metabolism with the normal mammalian insulin–glucagon push-pull
model, in agreement with measurements made on weaned elephant seal pups
(Kirby and Ortiz, 1994).
Basal glucose and hormone levels
Plasma glucose levels did not change across lactation. The present findings
of insulin decrease across lactation and fasting duration are in agreement
with previous measurements in fasting and lactating elephant seals
(Champagne et al., 2006;
McDonald, 2003). Many species
exhibit a decrease in insulin levels as they transition to lactation
(Burnol et al., 1983;
Hatfield et al., 1999;
Komatsu et al., 2005), while
insulin then increases throughout lactation
(Chelikani et al., 2003;
Debras et al., 1989;
Hoffman et al., 2003). In
humans, the anti-lipolytic properties of insulin remain evident even at
concentrations so low that glucose transport is not stimulated
(Kahn and Flier, 2000).
Despite a similar fasting duration to late lactation, molted females' insulin
levels were similar to early lactation values. This pattern may arise from the
need to mobilize lipids late in lactation and insulin suppression across the
fast may facilitate lactation.
Glucagon levels in fasting and lactating elephant seals remain stable
(Champagne et al., 2006;
McDonald, 2003), in contrast
to weanling elephant seals, which exhibit an increase in glucagon across the
fasting period (Champagne et al.,
2005; Ortiz et al.,
2003). Basal glucagon levels are lower in fasting elephant seals
than in other species during fasting (Fery
et al., 1990) and lactation
(Burnol et al., 1983;
Tigas et al., 2002). While
glucagon has been shown to increase with fasting duration in humans
(Boyle et al., 1989;
Fery et al., 1990), humans
that are fasting and lactating simultaneously have stable glucagon levels
(Tigas et al., 2002). Glucagon
is stable across lactation in cattle, rats and sheep
(Burnol et al., 1983;
Sartin et al., 1985;
Vernon and Pond, 1997).
Glucagon stimulates both gluconeogenesis and lipolysis
(Perea et al., 1995). Low
levels of glucagon are puzzling in light of high levels of lipolysis and
gluconeogenesis but probably contribute to protein sparing.
Studies of carnivore glucose metabolism in the context of lactation are
rare. We would expect that the lower carbohydrate diet of carnivores would
have important impacts on glucose metabolism; however, some studies do suggest
that the high protein diet of carnivores may be associated with impaired
ability for glucose clearance. Penguins
(Chieri et al., 1972), barn
owls (Myers and Klasing,
1999), rainbow trout (Palmer
and Ryman, 1972), white sturgeon
(Hung, 1991) and American
alligators (Coulson and Hernandez,
1983) exhibited reduced glucose clearance when compared to
omnivores. We are aware of no similar studies in wild mammalian
carnivores.
Conclusions
The combination of fasting with lactation creates a conflict in metabolic
processes with respect to the fate of nutrient stores. Simultaneously fasting
and lactating northern elephant seals exhibit suppression of insulin response
to exogenous glucose that varies across differing metabolic states. Elephant
seals also demonstrate some degree of insulin resistance, regardless of
fasting state. Additionally, the typical mammalian counter-regulatory
push-pull insulin–glucagon model appears to be modified in fasting and
lactating elephant seals. Carbohydrate, lipid and protein stores must be
tightly regulated during times of nutritional decrement concomitant with high
fat milk synthesis. These conflicts have apparently led to novel features of
carbohydrate regulation in some fasting adapted animals, including maintenance
of fasting blood glucose, avoidance of ketoacidosis, protein sparing despite
high rates of glucose production, impaired glucose clearance and insulin
resistance.
LIST OF ABBREVIATIONS
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Acknowledgments |
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