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chapter31
Endocrine Metabolism II: Hypothalamus and Pituitary
TABLE 31-5
Insulin and Insulin-like Growth Factors
Insulin
IGF-I
IGF-I I
MW
5,734
7,649
7,471
Site of production
/3-cell, pancreatic islet
Many sites
Many sites
Major source of circulating
form
/3-cell, pancreatic islet
Liver
Liver
Regulation of secretion
Glucose, amino acids,
catecholamines
GH, insulin, nutritional status
GH
GH-dependence
-
0
-
++++
+
Production rate
2
mg/day
1 0
mg/day
13 mg/day
Plasma levels (adults)
< 5 ng/ml
2 0 0
ng/ml
700 ng/ml
Characteristics in circulation
Pulsatile
Nonpulsatile
Nonpulsatile
Variable
Steady, nonvariable
Steady, nonvariable
Binding proteins in serum
None
3 (types 1,3,4)
6
(types
1
-
6
)
Half-life
1 0
min
12-15h
15h
Target tissues
Liver, muscles, adipose, skin,
Muscles, connective tissue,
Muscles, connective tissue,
connective tissue, bone
cartilage, bone
cartilage, bone
Receptor type
Plasma membrane
Plasma membrane
IGF-I receptor; plasma
heterote tramer (« 2/32 )
heterotetramer (Ot2/32)
membrane IGF-II/Man-
6
-P
Ins > IGF-I
1 0 0
IGF-I > II
, 0
» Ins
, 0 0 0
receptor (monomeric)
ig f -i i »
i
5 0 0
Regulation of receptor density
Ins inhib
IGF-I inhib
IGF-I inhib (IGF-IR);
GH inhib
Starvation inhib
Starvation inhib (IGF-IR);
Insulin, IGF-I stim (IGF-IIR)
differences of IGFs with insulin and among themselves
are summarized in Table 31-5.
Six serum proteins produced mainly in the liver that
bind IGFs in the circulation have been identified; these
are designated IGF-binding proteins (IGFBPs) 1
through
6
. IGFBP-1 appears to retard target tissue uptake of IGF-I,
while IGFBP-3 appears to enhance it. The latter accounts
for most of the IGF found in blood. About 80-90% of
the IGF-I in circulation is bound to IGFBP-3, along with
an
8 8
-kDa acid-labile subunit (ALS); this complex con-
fers protection on the IGF and prolongs its half-life to
12-15 hours. About 5% of the IGF is unbound, and the
remaining 5-15% is bound to IGFBP-1, 2, or 4 as smaller
complexes.
Unlike insulin and other peptide hormones that are re-
leased from storage granules, IGFs are released as they are
produced. Most tissues produce IGFs in small amounts
that are sufficient for local (paracrine/autocrine) effects
and do not contribute significantly to the circulating pool
of IGFs. The highest concentration of IGF-I and II is found
in circulation and is primarily derived from the liver. GH
and insulin are positive regulators of IGF-I synthesis in
the nonfasting state. During mild starvation when GH
levels increase, there is a decline in hepatic production
of IGF-I due, in part, to the decline in insulin. Refeed-
ing, which causes insulin to rise and GH to fall, pro-
motes IGF-I production only if the diet is adequate in
caloric and protein content. Note that circulating IGF-
I does not mediate the growth-promoting effect of GH
but is an important feedback regulator of GH. The indis-
pensability of IGF-I for linear growth and the fact that it
mediates this effect of GH are firmly established. IGF-I,
locally produced in endochondral bone in response to GH,
promotes skeletal growth by stimulating clonal chondro-
cyte expansion of the distal proliferative zone of the epi-
physeal plate.
Under physiological conditions, IGF-I is a relatively
minor regulator of fuel homeostasis. It does not mediate
the effects of GH on intermediary metabolism; in fact,
many of the effects of IGF-I resemble those of insulin, not
GH. IGF-I promotes production and actions of erythropoi-
etin and is responsible for the increased packed volume of
blood that results from elevated GH levels.
Disturbances in GH and IGF
Only rarely has a condition of IGF deficiency or excess
been described that is not accompanied by a disturbance in
