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

1240 interplay of various nutrients, GI hormones, pancreatic hormones,
and autonomic neurotransmitters. Glucose, amino acids (arginine,
etc.), fatty acids, and ketone bodies promote the secretion of insulin.
Glucose is the primary insulin secretagogue, and insulin secretion
is tightly coupled to the extracellular glucose concentration. Insulin
secretion is much greater when the same amount of glucose is delivered
orally compared to intravenously (incretin effect). Islets are
richly innervated by both adrenergic and cholinergic nerves.
Stimulation of α 2
adrenergic receptors inhibits insulin secretion,
whereas β 2
adrenergic receptor agonists and vagal nerve stimulation
enhance release. In general, any condition that activates the sympathetic
branch of the autonomic nervous system (such as hypoxia,
hypoglycemia, exercise, hypothermia, surgery, or severe burns) suppresses
the secretion of insulin by stimulation of α 2
adrenergic receptors.
Predictably, α 2
adrenergic receptor antagonists increase basal
concentrations of insulin in plasma, and β 2
adrenergic receptor
antagonists decrease them. Glucagon and somatostatin inhibit insulin
secretion.
The pancreatic β cell is a highly specialized cell that has considerable
structural and functional similarities to a sensory neuron:
Both cell types quickly sense and respond to external stimuli. The
molecular events controlling glucose-stimulated insulin secretion
begin with the transport of glucose into the β cell via a facilitative
glucose transporter (Figure 43–3). In rodents, this is the GLUT2,
which has a distinctive, low affinity for glucose and is also the primary
glucose transporter in hepatocytes. Human β cells express primarily
GLUT1 but little GLUT2. Upon entry into the β cell, glucose is
quickly phosphorylated by glucokinase (GK; hexokinase IV); this
phosphorylation is the rate-limiting step in glucose metabolism in
the β cell. GK’s distinctive affinity for glucose leads to a marked
increase in glucose metabolism over the range of 5-10 mM glucose,
where glucose-stimulated insulin secretion is most pronounced. The
glucose-6-phosphate produced by GK activity enters the glycolytic
pathway, producing changes in NADPH and the ratio of ADP/ATP.
Elevated ATP inhibits an ATP-sensitive K + channel (K ATP
channel),
leading to cell membrane depolarization. This K ATP
channel is a heteromeric
protein that consists of an inward rectifying K + channel
(Kir6.2) and a closely associated protein known as the sulfonylurea
receptor (SUR), which was identified originally because of its interaction
with this class of drugs. Mutations in the K ATP
channel are
responsible for some types of neonatal diabetes or hypoglycemia.
Membrane depolarization then leads to opening of a voltagedependent
Ca 2+ channel and increased intracellular Ca 2+ , resulting in
exocytotic release of insulin from storage vesicles. These intracellular
events are modulated by a number of processes, such as changes
in cAMP production, amino acid metabolism, and the level of transcription
factors. GPCRs for glucagon, GIP, and GLP-1 couple to
G s
to stimulate adenylyl cyclase and insulin secretion; receptors for
somatostatin and α 2
adrenergic agonists couple to G i
to reduce cellular
cAMP production and secretion.
SECTION V
HORMONES AND HORMONE ANTAGONISTS
Glucose
GLUT
glucokinase
Kir6.2
SUR1
K +
ATP-sensitive
K +
K + channel
Diazoxide
Sulfonylurea/meglitinide
K +
Depolarization
Ca 2+
Incretins
(acting via
GPCR-G s -AC)
G-6-P
ATP
Ca 2+ cAMP
Metabolism
Stored
insulin
Pancreatic β cell
+
Exocytosis
Plasma
insulin
Figure 43–3. Regulation of insulin secretion from a pancreatic β cell. The pancreatic β cell in a resting state (fasting blood glucose)
is hyperpolarized. Glucose, entering via GLUT transporters (primarily GLUT1 in humans, GLUT2 in rodents), is metabolized and
elevates cellular ATP, which inhibits. K + entry through the K ATP
channel; the decreased K + conductance results in depolarization, leading
to Ca 2+ - dependent exocytosis of stored insulin. The K ATP
channel, actually a hetero-octamer composed of SUR1 and Kir 6.2 subunits,
is the site of action of several classes of drugs: ATP binds to and inhibits Kir 6.2; sulfonylureas and meglitinides bind to and
inhibit SUR1; all 3 agents thereby promote insulin secretion. Diazoxide and ADP-Mg 2+ (low ATP) bind to and activate SUR1, thereby
inhibiting insulin secretion. Incretins enhance insulin secretion.