502
chapter
22
Metabolic Homeostasis
ATP and activation by inorganic phosphate, 5'-AMP,
and ADP (Chapter 13), and
3. Skeletal muscle phosphorylase b is allosterically
activated by 5'-AMP. Conversion of phosphorylase b
to phosphorylase a is affected by epinephrine, through
increased levels of cAMP, in a sequence of reactions
similar to that indicated in Figure 22-13. Following
depolarization of the muscle cell membrane, calcium
is released into the sarcoplasm from the sarcoplasmic
reticulum, resulting in the calcium-dependent
activation of phosphorylase kinase and conversion of
phosphorylase to the “a” form.
Lactate
Glycerol
Alanine ]
( .
Serine
1
= > Pyruvate
G lycine
J
I
A sp artate=
Valine
Isoleucine
Threonine
M ethionine
G lutam ate
Proline
Histidine
.
Glycerol 3-phosphate
_L
__
Glucose
Rate-lim iting steps
O xaloacetate — Phosphoenolpyruvate
F D P — Fructose 6-phosphate
G lucose 6-phosphate — Glucose
F I G U R E 2 2 - 1 5
Entry of precursors into the pathway of gluconeogenesis.
Gluconeogenesis
As hepatic glycogen stores become depleted, gluconeoge-
nesis becomes increasingly important. Although the kid-
ney is a source of glucose during protracted starvation,
during brief fasting at least 90% of total gluconeogenesis
occurs in the liver.
The three sources for this glucose synthesis are the fol-
lowing.
1.
Glycerol:
The hydrolysis of triacylglycerol to fatty
acids by adipocytes releases glycerol, which is
released into the plasma and converted to glucose in
the liver. It makes only a minor contribution to the
total glucose formed, but it helps to conserve protein.
2.
Lactate:
In sedentary humans 10-30% of plasma
glucose is recycled from lactate that originates from
glycolysis in blood cells. During exercise, anaerobic
glycolysis in muscle increases leading to enhanced
gluconeogenesis.
3.
Amino acids:
Amino acids are derived from
proteolysis in muscle. All except leucine and lysine
are potentially gluconeogenic in mammals; however,
alanine is the primary amino acid released from
muscle. This alanine is derived from muscle protein
and from the metabolism of many other amino acids.
Figure 22-15 shows the points of entry of precursors
into hepatic gluconeogenesis. Lactate and alanine enter
the gluconeogenic pathway at the pyruvate carboxylase
reaction. Glycerol is phosphorylated and then oxidized to
dihydroxyacetone phosphate. A number of amino acids
are converted to intermediates of the TCA cycle. Conver-
sion of gluconeogenic substrates to glucose is not a direct
reversal of glycolysis, since the pathway differs at three
rate-limiting steps (Chapter 15).
Regulation o f Gluconeogenesis
Tissues involved in glucose conservation are liver,
skeletal muscle, and adipose. Signals that attune the body
to the status of gluconeogenesis include glucagon (an acute
modulator), glucocorticoid (a chronic modulator), and ab-
sence of insulin. The general effects of these hormones are
shown in Figure 22-16.
Glucagon is directed toward glycogen degradation, glu-
coneogenesis, triacylglycerol hydrolysis, and fatty acid
oxidation. In the liver, it stimulates glycogen degradation
(Figure 22-13) and gluconeogenesis, possibly by inacti-
vation of pyruvate kinase. Glucagon also modulates the
levels of fructose-2,6-bisphosphate (Chapter 15). Insulin
opposes these effects by stimulating glycogen synthe-
sis, glycolysis, and fatty acid synthesis. The stimulation
of glycolysis by insulin is not meant to increase energy
production, since glycolysis is amphibolic and provides
metabolites for biosynthesis, e.g., acetyl-CoA for fatty
F I G U R E 2 2 - 1 6
Effects of glucagon, glucocorticoids, and insulin on the pathways of
carbohydrate and lipid metabolism. G-6-P, Glucose-6-phosphate;
PEP, phosphoenolpyruvate; OA, oxaloacetate; FA, fatty acid;
TG, triacylglycerol.
