(PI-3-kinase). SH2 domains are conserved sequences of
about 100 amino acids but the role of PI-3-kinase is not
understood.
Insulin-mediated IRS-1 phosphorylation also leads to
activation of ras
proteins. The ras proteins are proto-
oncogene products that mediate signaling pathways from
cell membrane receptors, the regulation of cellular prolif-
eration, differentiation, or apoptosis. They are posttransla-
tionally modified by famesylation at a conserved cysteine
residue in the C-terminal CAAX motif; the tripeptide AAX
is removed by proteolysis and the newly exposed C ter-
minus is methylated. The ras protein is functionally active
when GTP is bound and inactive when GDP is bound. The
ras-GTP/GDP cycle is regulated by GTPase-activating
proteins and guanine nucleotide exchange factor proteins.
The pathway of IRS-1 to activation of ras protein involves a
number of proteins such as growth factor receptor binding
protein-2 (GRB-2). Activated ras protein stimulates a cas-
cade of serine/threonine kinases affecting transcriptional
activation of specific genes. These pathways also involve
proteins with SH2 domains. In summary, responses due to
insulin binding to its receptor involve a cascade of phos-
phorylation and dephosphorylation steps that lead to gene
regulation.
One of the major effects of insulin is to promote glucose
transport from the blood into muscle and adipose tissue
cells. This is accomplished by recruiting and localizing
GLUT4 receptor molecules in the plasma membrane. In
the absence of insulin GLUT4 remains in the intracellu-
lar vesicles. Insulin-mediated GLUT4 trafficking to the
cell membrane is constitutive, multicompartmental, and
involves the participation of several proteins. Impairment
in any of the steps of GLUT4 transport can cause insulin
resistance and diabetes mellitus.
The importance of the biological actions of insulin on
target cells is underscored by defects in any of the five steps
involved in receptor function. These steps are analogous
to the scheme described for LDL receptor gene defects
(Chapter 20). Mutations can lead to:
1. Impaired receptor biosynthesis,
2. Impaired transport of receptors to the cell surface,
3. Decreased affinity of insulin binding,
4. Impaired tyrosine kinase activity, and
5. Accelerated receptor degradation.
Examples of disorders caused by mutations in the in-
sulin receptor gene are
leprechaunism
and
type A insulin
resistance. A
severe form of leprechaunism is due to mu-
tations in both alleles of the insulin receptor gene. These
patients exhibit insulin resistance, intrauterine growth
retardation, and many other metabolic abnormalities.
Patients with type A insulin resistance exhibit insulin
section 22.3
Endocrine Pancreas and Pancreatic Hormones
resistance, acanthosis nigricans, and hyperandrogenism.
The latter two have been ascribed to toxic effects of in-
sulin on the skin and ovaries. Insulin resistance is also
associated with
hyperandrogenism
and
polycystic ovary
disease syndrome
(diabetes mellitus
is discussed later in
this chapter).
Insulin is catabolized (inactivated) primarily in the liver
and kidney (and placenta in pregnancy). Liver degrades
about 50% of insulin during its first passage through
this organ. An insulin-specific protease and glutathione-
insulin transdehydrogenase are involved. The latter re-
duces the disulfide bonds with separation of A and B
chains, which are subjected to rapid proteolysis.
Glucagon
Glucagon is a single-chain polypeptide of 29 amino acids
that has a structural homology with secretin, vasoactive in-
testinal polypeptide (VIP), and gastric inhibitory polypep-
tide (GIP). The glucagon structure is also contained within
the sequence of glicentin (“gut glucagon”). The synthesis
of glucagon in the pancreatic
a
cells probably involves a
higher molecular weight precursor. Glucagon secretion is
inhibited by glucose and stimulated by arginine and ala-
nine. Depressed plasma glucagon levels result in depressed
hepatic glucose output at times when glucose is available
by intestinal absorption. Amino acid-stimulated glucagon
secretion counteracts the effects of the coincidental se-
cretion of insulin, which otherwise would provoke hy-
poglycemia. Secretion of glucagon from the
a
cells and
somatostatin from the
S
cells is regulated by the other pan-
creatic hormones. Figure 22-9 illustrates the coordination
of islet hormone secretion. This coordination may occur
by the product of one cell type regulating secretion by the
others and by direct intercommunication between cells
495
F I G U R E 2 2 - 9
Paracrine regulation of islet cell hormonal secretion. © , Stimulation;
0 , inhibition. [Drawn after R. H. Unger, R. E. Dobbs, and L. Orci, Insulin,
glucagon, and somatostatin secretion in the regulation of metabolism.
A r r n u . R e v . P h y s i o l .
40, 307 (1978). © 1978 by Annual Reviews Inc.]
