Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

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Chapter | 4 Lipids and Ketones
gluconeogenesis. In a lactating cow, plasma glucose concentration
represents the balance point between hepatic
glucose production and peripheral glucose utilization, with
the mammary gland being the chief user. If peripheral glucose
utilization should leap ahead of hepatic glucose production,
hypoglycemia will result. In theory, hypoglycemia
under these circumstances should lead to a decrease in
plasma insulin and an increase in plasma glucagon levels.
Lower plasma insulin and higher plasma glucagon should
increase the activity of hormone-sensitive lipase in adipose
tissue, which will lead to increased plasma levels of LCFA.
Consequently, more LCFA will reach the liver and exceed
its capacity to oxidize them completely or to reesterify
them, and increased ketogenesis will result.
What evidence supports this theory First, the vast
majority of cows with clinical spontaneous ketosis are
indeed hypoglycemic ( Baird et al ., 1968 ; Gröhn et al ., 1983 ;
Schwalm and Schultz, 1976 ). Second, cows with spontaneous
ketosis usually are hypoinsulinemic ( Hove, 1974 ;
Schwalm and Schultz, 1976 ). Third, compared to the prelactation
period, postparturient dairy cows have been found to
have elevated levels of plasma immunoreactive glucagon
(De Boer et al ., 1985 ; Manns, 1972 ), which is even greater
in cows with ketosis ( Sakai et al ., 1993 ). Fourth, ketotic
cows have elevated levels of plasma LCFA ( Baird et al .,
1968 ; Ballard et al ., 1968 ; Schwalm and Schultz, 1976 ).
Some investigation of molecular mechanisms of ketogenesis
in the liver ketotic cows has been performed ( Baird
et al ., 1968 ; Ballard et al ., 1968 ). In particular, there has
been interest in hepatic mitochondrial oxaloacetate levels.
In the discussion of ketogenesis presented earlier, it was
noted that when increased levels of plasma LCFA occur,
the liver can reesterify them or can oxidize them to acetyl-
CoA. The acetyl-CoA can be oxidized to carbon dioxide
provided there is sufficient oxaloacetate to permit entry
into the citric acid cycle as citrate. For the citric acid cycle
to operate, there must also be a sufficient amount of ADP
available for phosphorylation as well, or accumulation of
NADH will slow the cycle. If acetyl-CoA accumulates, the
excess will be diverted into ketogenesis.
Two studies have attempted to investigate oxaloacetate
concentrations in the livers of ketotic cows ( Baird et al .,
1968 ; Ballard et al ., 1968 ). Different methodologies were
used to estimate oxaloacetate concentrations; one study
(Ballard et al ., 1968 ) concluded that there was no change in
oxaloacetate concentration during ketosis, and the other concluded
that oxaloacetate concentrations were lower in ketotic
than in healthy cows ( Baird et al ., 1968 ). Actually, both studies
measured total hepatic oxaloacetate rather than mitochondrial
oxaloacetate, which may be critical in ketogenic control.
However, there has been no evidence to indicate that the
ruminant liver should be any different from the nonruminant
liver with regard to the concept that if the liver is presented
with sufficient LCFA, ketogenesis will result. There has been
insufficient research on the control of lipolysis in adipose in
ruminants. In particular, there has been insufficient research
in differences in plasma levels of lipogenic and lipolytic hormones
and sensitivity of adipose to these hormones in cow
populations that are susceptible and nonsusceptible to ketosis.
No matter how low mitochondrial oxaloacetate levels
might be in the liver, ketogenesis will not occur at a significant
rate without a sufficient precursor in the form of LCFA,
and conversely, ketogenesis could occur with normal oxaloacetate
levels if the liver were presented with a sufficiently
high concentration of LCFA.
It has been noticed, however, that dairy cattle can
become ketonemic without the presence of significant
hypoglycemia ( Ballard et al ., 1968 ; Gröhn et al ., 1983 ).
This is often the case with subclinical ketosis in which ketonemia
exists without other signs of ketosis. It has been postulated
that there is a lipolytic signal of unknown identity
for lipolysis to meet mammary demand for LCFA, which
is independent of plasma glucose concentration ( Kronfeld,
1982 ; Kronfeld et al ., 1983 ). The increased plasma LCFA
lead directly to increased hepatic ketogenesis.
When it was first observed that glucocorticoids
appeared to be an effective treatment for spontaneous ketosis,
it was hypothesized that the disease was due to adrenal
cortical insufficiency ( Shaw, 1956 ). This theory has
fallen into disfavor because it has been shown that ketotic
cows have higher plasma levels of glucocorticoids than
healthy cows ( Robertson et al ., 1957 ). Glucocorticoids are
efficacious and probably have their effect by stimulating
proteolysis and inhibiting glucose use in muscle, thereby
providing gluconeogenic precursors and glucose ( Bassett
et al ., 1966 ; Braun et al ., 1970 ; Reilly and Black, 1973 ;
Robertson, 1966 ; Ryan and Carver, 1963 ).
The efficacy of glucose or glucose precursors as ketosis
treatments favors the hypoglycemic theory. Parenteral
glucose provides nearly immediate relief although relapses
are common ( Kronfeld, 1980 ). Gluconeogenic precursors,
such as propylene glycol, glycerol, and sodium propionate,
have been shown to be efficacious ( Emery et al ., 1964 ;
Kauppinen and Gröhn, 1984 ; Schultz, 1952 ; Simesen,
1956 ). Treatment of cows with bovine somatotropin in
one lactation appears to decrease the likelihood of ketosis
in the next lactation ( Lean et al ., 1994 ). Cows treated with
somatotropin appear to have less body fat and more skeletal
muscle, so after calving, there is less fat to mobilize to
LCFA and more protein to mobilize as a glucose precursor.
Therefore, hypoglycemia and subsequent fatty acidemia
and ketonemia are less likely to occur.
2 . Ovine Pregnancy Toxemia
This syndrome occurs in pregnant ewes that are carrying
more than one fetus and that have been subjected to caloric
deprivation or stress. Because of intense genetic selection
for twinning, the syndrome is, to a large extent, a manmade
disease. Susceptibility increases as ewes approach