DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

The pancreatic α cell, which has considerable similarity to
the β cell, secretes glucagon, primarily in response to hypoglycemia.
Glucagon biosynthesis begins with preproglucagon,
which is processed in a cell-specific fashion to several biologically
active peptides such as glucagon, GLP-1, and glucagon-like
peptide-2 (GLP-2) (Figure 43-9). The molecular mechanisms that
control glucagon secretion are unclear but may involve paracrine
regulation by the β cell and neural input. In general, glucagon and
insulin secretion are regulated in a reciprocal fashion; that is, the
agents or processes that stimulate insulin secretion inhibit
glucagon secretion. Notable exceptions are arginine and somatostatin:
arginine stimulates and somatostatin inhibits the secretion
of both hormones.
Insulin Action. The insulin receptor is expressed on
virtually all mammalian cell types, explaining the
broad array of biological responses to insulin. The tissues
that are considered critical for regulation of blood
glucose are liver, skeletal muscle, and fat (Figure
43–1). However, recent evidence suggests that specific
regions of the brain and the pancreatic islet are also
important targets for insulin. Systemically, the actions
of insulin are anabolic, and insulin signaling is critical
for promoting the uptake, use, and storage of the
major nutrients: glucose, lipids, and amino acids.
Importantly, while insulin action stimulates glycogenesis,
lipogenesis, and protein synthesis, it also
inhibits the catabolism of these compounds. On a cellular
level, insulin stimulates transport of substrates
and ions into cells, promotes translocation of proteins
between cellular compartments, regulates the action
of specific enzymes, and controls gene transcription
and mRNA translation. Some effects of insulin occur
within seconds or minutes, such as activation of glucose
and ion transport systems and phosphorylation
or dephosphorylation of specific enzymes. Other
effects, such as those promoting protein synthesis and
regulating gene transcription, manifest over minutes
to hours. The effects of insulin on cell proliferation
and differentiation occur over days. Metabolic effects
such as inhibition of lipolysis or hepatic glucose production
occur rapidly, within minutes of increasing
concentrations of plasma insulin; detectable increases
in glucose clearance from the blood may take nearly
an hour. The variability in the kinetics of insulin action
probably relate to variable access to insulin receptors
in different tissues, distinct intracellular signaling
pathways, and the inherent kinetics of the various
processes controlled by insulin.
The Insulin Receptor. Insulin action is transmitted
through a receptor tyrosine kinase that bears functional
similarity to the insulin-like growth factor 1
(IGF-1) receptor (Taniguchi et al., 2006). The insulin
receptor is composed of linked (α/β subunit dimers
that are products of a single gene; dimers linked by
disulfide bonds form a transmembrane heterotetramer
glycoprotein composed of two extracellular α-subunits
and two membrane-spanning β-subunits (Figure
43–4). The number of receptors varies from as few as
40 per cell on the relatively insulin-insensitive erythrocytes,
to 300,000 per cell on adipocytes and hepatocytes,
cell types that are highly responsive to
insulin.
The α-subunits inhibit the inherent tyrosine kinase activity
of the β-subunits. Insulin binding to the α-subunits releases this inhibition
and allows transphosphorylation of one β-subunit by the other,
and autophosphorylation at specific sites from the juxtamembrane
region to the intracellular tail of the receptor. There are two splice
variants of the α-subunits, which lead to insulin receptors with differential
expression and ligand binding. In addition, insulin receptor
dimers can form complexes with IGF-1 receptor α/β dimers, creating
another distinct receptor isoform. Activation of the insulin receptor
initiates signaling by phosphorylating a set of intracellular
proteins such as the insulin receptor substrates (IRS) and Src-homology-2-containing
protein (Shc). These insulin receptor substrates
interact with effectors that amplify and extend the signaling cascade.
As an example, binding of Shc to IRS1 leads to activation of the
GTPase Ras and initiation of the protein kinase cascade involving
MAPK and ERK that are involved in insulin-mediated gene transcription
and cell growth .
Insulin action, at least for glucose transport, is critically
dependent on the activation of phosphatidylinositol-3-kinase (PI3K).
PI3K is activated by interaction with IRS proteins and generates
phosphatidylinositol 3,4,5-trisphosphate (PIP3), which regulates the
localization and activity of several downstream kinases, including
Akt, atypical isoforms of protein kinase C (PKC ζ and λ/τ), and
mammalian target of rapamycin (mTOR) (Huang and Czech, 2007).
The isoform Akt2 appears to control the downstream steps that are
important for glucose uptake in skeletal muscle and adipose tissue,
and to regulate glucose production in the liver. Substrates of Akt2
coordinate the translocation of the glucose transporter 4 (GLUT4) to
the plasma membrane through processes involving actin remodeling
and other membrane trafficking systems (Zaid et al., 2008).
Despite the centrality of PI3K/Akt2 in mediating insulin signaling in
key target tissues, it seems likely that there are additional effects
mediated by the insulin receptor that do not directly involve these
enzymes. Actions of small G-proteins, such as Rac and TC10, have
been implicated in the actin remodeling necessary for GLUT4
translocation.
GLUT4 is expressed in insulin-responsive tissues such as
skeletal muscle and adipose tissue that constitute important sites of
glucose disposal after meal ingestion. GLUT4 is one of a family of
13 glucose transporters in humans that share 12 membrane-spanning
domains. GLUT4 is noteworthy among these transporters as the
most dependent on discrete stimuli by insulin or other effectors; in
the basal state, most GLUT4 resides in the intracellular space; following
activation of insulin receptors, GLUT4 is shifted rapidly and
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CHAPTER 43
ENDOCRINE PANCREAS AND PHARMACOTHERAPY OF DIABETES MELLITUS AND HYPOGLYCEMIA