Starvation
A lack of food has profound effects on the
normal flow of nutrients in the body. The immediate result of food
deprivation is decreased intake of glucose. Glucose is vital to the
animal for survival because certain cells, such as erythrocytes, cells
of the renal medulla, and cells of the central nervous system, have an
absolute requirement for glucose, amounting to approximately 180 g/d (Fig. 74–2).
Despite reduced sugar intake, the circulating blood glucose
concentration varies little. This is because humans adapt to decreased
glucose intake during starvation by two mechanisms that serve to
maintain the plasma glucose concentration. First, fatty acids mobilized
from triglyceride stores in adipose tissue are used as an alternative
fuel to glucose in those tissues that can oxidize fats. This use of
alternative fuel for energy production lowers the requirements for
glucose, thereby decreasing the demand for more glucose at a time when
input via feeding is not available. Second, several adaptations in
intracellular glucose metabolism occur that result in an inhibition of
glucose-utilizing pathways and a stimulation of glucose-producing
pathways (Fig. 74–3).
Initially, to maintain the plasma glucose concentration, glycogen is
broken down. The loss of glycogen is rapid and significant. Within
48 hours of starvation, rats show a 99.5 percent loss of liver
glycogen and a 70.3 percent loss of carcass glycogen. However, the
amount of glucose released by glycogenolysis is insufficient to sustain
the energy needs of the whole body for more than a short period of time.
The liver, and to a certain extent, the kidneys have the ability to
synthesize glucose from different carbon sources via the process of
gluconeogenesis (Fig. 74–4).
Glucose is synthesized primarily from glycerol, lactate, pyruvate, and
certain amino acids, particularly alanine. Lactate and pyruvate are
released by peripheral tissues, particularly skeletal muscle. Lactate
provides 60 to 70 percent of the glucose carbon used for
gluconeogenesis. Glycerol is derived from adipose tissue after the
breakdown of triglycerides. Amino acids are derived from the breakdown
of proteins in both liver and peripheral tissues.
More than 35 years ago, an
interorgan cycle (Cori cycle) accounting for the flow of glucose carbon
during starvation was proposed. Glucose taken up by peripheral organs
is converted to lactate, which enters the blood and is returned to
liver. The lactate is taken up by the liver and is synthesized to
glucose (Fig. 74–5).
The amount of lactate that
can be produced and cleansed by the liver may be extremely high. The
normal liver can clear up to 400 g of lactate per day. Lactate
production by skeletal muscle must increase to provide the necessary
gluconeogenic precursors for the maintenance of sustained rates of
gluconeogenesis in starvation or diabetes. Lactate arises from the
reduction of tissue pyruvate.
Lactate production occurs
whenever the rate of pyruvate production from glycolysis exceeds glucose
oxidation by the mitochondria. Therefore, for increased lactate
production to be important physiologically, mitochondrial glucose
oxidation must decrease under conditions known to result in increased
gluconeogenesis. In
humans, whole-body glucose oxidation is inhibited 90 percent in
starvation, 70 percent in type 1 diabetes mellitus, and 40 percent in
non– insulin-dependent (type 2) diabetes mellitus. Each of these
conditions is associated with enhanced rates of gluconeogenesis (Ch. 25).
At the enzymatic level, the pyruvate
dehydrogenase (PDH) complex catalyzes the first irreversible reaction in
the mitochondrial oxidation of glucose. Pyruvate is oxidized by the PDH
complex in the presence of the oxidized form of nicotinamide adenine
dinucleotide (NAD+ ) and coenzyme A (CoA) to form acetyl-CoA, the reduced form of NAD (NADH), and CO2 . As such, the PDH complex is the primary regulator of glucose oxidation in mammalian cells. 4, 5, 6
Regulation by this complex is important to glucose homeostasis because
the oxidation of pyruvate results in the net loss of body glucose
carbon sources since glucose cannot be synthesized from acetyl-CoA and
the PDH reaction is physiologically irreversible. Thus, the activity of
the PDH complex determines whether pyruvate is oxidized to CO2
and water or is converted to lactate via lactate dehydrogenase. The
decreased activity of the PDH complex is caused by several mechanisms,
the most prominent of which is reversible phosphorylation (Fig. 74–6).. Increased phosphorylation results in a decreased flux of glucose through the PDH complex (Fig. 74–7)
Release of amino acids
from skeletal muscle is intimately related to glucose homeostasis
because amino acids represent an important precursor for
gluconeogenesis. Most amino acids are released from muscle in proportion
to their concentration in muscle proteins. 7
However, the exceptions are alanine and glutamine, which are released
in excess of their concentration in muscle proteins. These observations
implied that de novo synthesis of alanine and glutamine occur in
skeletal muscle. Because alanine is utilized by the liver and kidney as a
major substrate for gluconeogenesis, Felig et al 8
proposed a glucose-alanine cycle as a means of transferring amino
nitrogen from muscle to liver and kidney. According to this hypothesis,
glucose taken up by muscle is metabolized to pyruvate. Pyruvate, instead
of being oxidized via the PDH complex, serves as a nitrogen acceptor,
with alanine being formed through transamination from glutamate. The
alanine released from muscle recirculates to the liver, where it is
taken up and reconverted to glucose.
Although the proposed glucose-alanine cycle
allows for the transfer of nitrogen groups derived from amino acid
catabolism to liver, it does not account for a net flow of carbon from
protein to carbohydrate. Both alanine and glutamine are also synthesized
from other amino acids. In the postabsorptive state, about 40 percent
of the circulating plasma alanine is derived from endogenous proteins,
whereas 60 percent is derived from de novo synthesis in humans. 9 In addition, at least 20 percent of the nitrogen required for the de novo alanine synthesis comes from leucine. 10
Leucine (isoleucine and valine) nitrogen is incorporated into alanine
through a series of reversible transamination reactions involving the
nitrogen transfer from leucine to glutamate via the branched-chain
aminotransferase and the subsequent transamination of glutamate with
pyruvate forming alanine. The rate of alanine synthesis is determined by
(1) the rate of leucine appearance and (2) the rate of pyruvate
availability.
If requirements for glucose carbon continued
unabated, protein breakdown would result in a severe depletion of vital
proteins. However, ketone body concentrations rise in long-term
starvation or diabetes mellitus. Ketone bodies are derived from the
incomplete oxidation of fatty acids in the liver. The brain adapts to
using alternative fuels such as ketone bodies as a primary energy
source, rather than glucose. Thus, by utilizing alternative fuels, the
demand for glucose is further reduced (Table 74–2).
An important consequence of this adaptation is that the breakdown of
muscle is no longer required to maintain the flow of alanine to the
liver for gluconeogenesis (Fig. 74–8).
The net result is that muscle proteins are spared further degradation.
The adaptive ability of the organism to use alternative fuels instead of
glucose is of fundamental importance to the survival of the animal
because otherwise, protein function would eventually be compromised.
TABLE 74–2. Fuels in Circulation in Man
These adaptive processes
are under hormonal control, which serves to regulate the flow of glucose
carbon to ensure adequate levels of glucose in the blood. These
hormones can be broadly categorized into two groups: anabolic hormones
and catabolic hormones. At any given time, the net effect of the
hormones, whether to break down or to store fuels, depends on the ratio
of concentrations of each of the hormones to each other, as well as on
their absolute concentration. The principal anabolic hormone is insulin.
Insulin is of major importance in fuel storage, promoting the
deposition of glycogen, triglycerides, and proteins. At basal levels,
insulin has an important anticatabolic role in restraining
glycogenolysis, gluconeogenesis, and lipolysis. Growth hormone is also
anabolic, but only with respect to protein metabolism, in
which growth hormone stimulates amino acid transport and protein
synthesis. Some studies have suggested that parts of the anabolic
effects of growth hormone are mediated by a faster-term insulin-like
growth factor-1. 11
The major catabolic hormones are glucagon, cortisol, and
catecholamines. Individually, none of these hormones totally opposes the
action of insulin; instead, they act together to counterbalance insulin
action. Glucagon has its major effects on the liver, promoting
gluconeogenesis, amino acid uptake, ureogenesis, and protein catabolism.
Cortisol enhances extrahepatic protein catabolism, thereby increasing
the release of amino acids, and promotes hepatic utilization of the
mobilized amino acids for gluconeogenesis. Catecholamines stimulate
lipolysis and glycogenolysis in both hepatic and extrahepatic tissues.
Copyright © 2000, 1995, 1990, 1985, 1979 by Churchill Livingstone
 nerve (including brain), (2) pure glycolyzers producing lactate (red blood cells and white blood cells), and (3) the remainder of the body (heart, kidney, and muscle) that can use fatty acids and ketones. The brain can also use ketone bodies after injury and starvation. (Modified from Cahill<!--refref refref="r074010194" refnum="194"--><sup>194</sup>)'))
)
, glycerol, and lactate join the pathway of gluconeogenesis. The reactions common to gluconeogenesis and glycolysis are those indicated by the straight arrows; the downward arrows show the direction of gluconeogenesis, the upward arrows the direction of glycolysis. The curved arrows represent the reactions (pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose 1,6-diphosphatase, glucose 6-phosphatase) circumventing the energy barriers obstructing the direct reversal of glycolysis. (Modified from Biebuyck<!--refref refref="r074010195" refnum="195"--><sup>195</sup>)'))
)
 in mammalian cells; DCA activates pyruvate dehydrogenase, thereby increasing the flux of C<sub>3</sub> compounds into the tricarboxylic acid cycle and decreasing the release of lactate, pyruvate, and alanine into the circulation. (Modified from Blackshear et al<!--refref refref="r074010196" refnum="196"--><sup>196</sup>)'))
 complex activity in starvation and diabetes. FA, fatty acid; KAP, kinase activator protein.'))
![Click thumbnail to see full size image](javascript:parent.ShowImage('../figures/5074F08.gif', 'FIGURE 74–8 Use of metabolic fuels during fasting. The energy fuel substrate flux shown in terms of calories per day has been calculated from experimental data. Protein loss would be equal to approximately 16.6 g of nitrogen. Aa, amino acid; ADP, adenosine diphosphate; ATP adenosine triphosphate; FFA, free fatty acid; Glc, glucose; KB, ketone body; RQ, respiratory quotient; Tg, triglyceride. (Modified from Blackburn and Phinney<!--refref refref="r074010197" refnum="197"--><sup>197</sup>)'))