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chapter
22
Metabolic Homeostasis
GTP is illustrated in patients with hyperinsulinism with
episodes of hypoglycemia. All of these patients carry mu-
tations affecting the allosteric domain of glutamate de-
hydrogenase and result in insensitivity to GTP inhibi-
tion. This caused increased a-ketoglutarate production
followed by ATP formation and consequent insulin se-
cretion. In addition to hyperinsulinemia, these patients
also have high levels of plasma ammonia (
hyperammone-
mia
]i that result from hepatic glutamate dehydrogenase
activity. In liver mitochondria glutamate is converted to
N-acetylglutamate, which is the required positive al-
losteric
effector of carbamoyl-phosphate
synthetase.
Carbamoyl-phosphate synthetase catalyzes the first step
in the conversion of ammonia to urea (see Chapter 17 for
ammonia metabolism). Increased activity of glutamate de-
hydrogenase causes depletion of glutamate required for
the synthesis of N-acetylglutamate. The decreased level
of N-acetylglutamate impairs ureagenesis in the liver and
is accompanied by hyperammonemia.
Biological Actions o f Insulin
Insulin affects virtually every tissue. Insulin is an an-
abolic signal and promotes fuel storage in the form of
glycogen and triacylglycerols while inhibiting the break-
down of these two fuel stores. Insulin also promotes pro-
tein synthesis while inhibiting its breakdown. Regulation
of expression of several genes, either positive or negative,
is mediated by insulin. The genes involved in the expres-
sion of enzymes that participate in fuel storage (e.g., hep-
atic glucokinase) are induced; those that encode catabolic
enzymes (e.g., hepatic phosphoenolpyruvate carboxyki-
nase) are inhibited. The principal effect of insulin on blood
glucose is its uptake into muscle and adipose tissue via
the recruitment and translocation of glucose transporter
4 (GLUT4).
The mechanism of action of insulin is complex and can
be divided into three parts. The first part is the binding of
insulin to its receptor on the cell membrane; the second
consists of postreceptor events; and the third consists of
biological responses.
Insulin Receptor
The insulin receptor is derived from a single polypep-
tide chain that is the product of a gene located on the
short arm of chromosome 19. The proreceptor undergoes
extensive posttranslational processing consisting of glyco-
sylation and proteolysis. The proteolytic cleavage yields
a
(M.W. 135,000) and /3 (M.W. 95,000) subunits that are
assembled into a heterotetrameric
(a2fi2)
complex. The
subunits are held together by both disulfide linkages and
noncovalent interactions. The heterotetrameric receptor is
incorporated into the cell membrane with the a-subunits
projecting into the extracellular space and the /
1
-subunit
with its transmembrane subunit projecting into cytoso-
lic space (Figure 22-8). The a-subunits contain the in-
sulin binding domain, but it is not clear whether insulin
binds to both a-subunits. Insulin binding to one site in-
duces negative cooperativity for the second insulin bind-
ing site. The intracellular portion of the /3-subunit has a
tyrosine-specific protein kinase (tyrosine kinase) activ-
ity. Tyrosine kinase activity initiated by insulin binding
to a-subunits results in autophosphorylation on at least
six tyrosine residues in /1-subunits. Other protein sub-
strates also are targets of a series of phosphorylations cat-
alyzed by the activated /1-subunit tyrosine kinase. One of
the key proteins that is phosphorylated is insulin recep-
tor substrate-1 (IRS-1), which has many potential tyro-
sine phosphorylation sites as well as serine and threonine
residues. Phosphorylated IRS-1 interacts and initiates a
cascade of reactions involving other proteins. Phospho-
tyrosine motifs of IRS-1
have binding sites for SH2 do-
mains
(src homology domain
2
) contained in signal trans-
ducing proteins such as phosphatidylinositol-3-kinase
Insulin binding
domain
F I G U R E 2 2 -8
Model of the insulin receptor. The receptor contains two a- and two
/1-subunits, held together by disulfide linkages. The a-subunits are entirely
extracellular and contain the insulin binding site. The /3-subunits have
transmembrane and intracellular domains. Both autophosphorylation and
tyrosine kinase activity reside in the /3-subunit and are markedly enhanced
upon insulin binding.
