quantitation of the ambient glucose level appears to be
glucokinase, which is ultimately responsible for glucose-
regulated insulin secretion.
The oxidation of glucose-
-phosphate via glycolysis,
the TCA cycle, and the electron transport system coupled
to oxidative phosphorylation leads to increased ATP levels
(or ATP/ADP ratio) in the
cell. The elevated ATP levels
cause a closure of the ATP-sensitive K+ channel, leading
to inhibition of K+ efflux and depolarization of the /1-cell
membrane potential. The ATP-sensitive K+ channel con-
sists of two different types of protein subunits, namely,
the sulfonylurea receptor (SUR) and a potassium channel
(Kir6.2). SUR is the regulatory subunit and belongs to the
family of ATP-binding cassette proteins. Kir6.2 subunits
participate in the actual conduction of K+. It has been sug-
gested that the overall functional K+ channel is an octame-
ric complex composed of equal numbers of SUR and
Kir6.2 subunits. The depolarization of /1-cell membrane
that occurs with the closure of the ATP-sensitive K+
channel activates the voltage-sensitive Ca2+ channel caus-
ing Ca2+ influx, which ultimately leads to release of
insulin from stored insulin granules. The exocytosis of
insulin involves both phosphorylation and exocytosis-
related ATPases. Along with insulin and C-peptide, a
37-amino-acid peptide known as amylin is also secreted
during exocytosis. Amylin is obtained by proteolytic pro-
cessing of an 89-amino-acid precursor molecule. The pre-
cise physiological role of amylin remains to be understood.
Mechanisms that alter the level of cytosolic Ca2+ in
cells, other than glucose metabolism, also affect in-
sulin release. For example, a regulatory protein associated
with the ATP-sensitive K+-channel, when occupied with
sulfonylurea, inhibits K+ efflux causing insulin secretion.
Sulfonylureas are drugs used in the management of type 2
diabetes mellitus (discussed later). Diazoxide has an op-
posite effect to that of sulfonylureas. It either prevents the
closing or prolongs the open time of the ATP-sensitive
K+ channel resulting in the inhibition of insulin secretion
and thus hyperglycemia. Somatostatin inhibits Ca2+ influx
and causes diminished insulin secretion. Acetylcholine
causes elevation of cytosolic Ca2+ followed by insulin
secretion caused by activation of GQ-protein, phospho-
lipase C-inositol trisphosphate-Ca2+, and protein kinase
C (Chapter 30). Norepinephrine and epinephrine depress
insulin secretion by binding at the a-adrenergic receptor
sites and by inhibiting adenylate cyclase mediated by the
activation of the inhibitory G-protein (G;). This leads to the
inhibition of cAMP production and results in decreased ac-
tivity of protein kinase A. Decreased protein kinase A lev-
els determine exocytosis-related phosphorylation required
for insulin secretion. Release of epinephrine during stress
signals the need for catabolic rather than anabolic activity.
section 22.3
Endocrine Pancreas and Pancreatic Hormones
Depression of insulin secretion during exercise or trauma
also is associated with epinephrine (catecholamine) secre-
tion. A gastrointestinal hormone known as glucagon-like
peptide (GLP-1) promotes insulin secretion via G-protein
activation of the adenylate cyclase-cAMP-protein kinase
A system. Gastrointestinal hormones that regulate insulin
secretion may act in a feed-forward manner to signal gas-
trointestinal activity and metabolic fuel intake. Pancre-
atic glucagon, simply known as glucagon, stimulates se-
cretion of insulin while somatostatin depresses it. Thus,
various regulatory inputs to the
cells are integrated to
maintain secretion of optimal quantities of insulin and to
maintain glucose homeostasis. The coordinated activity
of three pancreatic hormones (insulin, glucagon, and so-
matostatin) is essential for fuel homeostasis. Furthermore,
the action of insulin is opposed by glucagon and by other
counterregulatory hormones, namely, epinephrine, corti-
sol, and growth hormone. All of these hormones correct
hypoglycemia by maintaining adequate levels of glucose
in tissues such as brain, which is primarily dependent on
glucose as a fuel source.
Some amino acids also function as secretagogues of in-
sulin secretion. An example is leucine, which stimulates
the release of insulin by allosteric activation of glutamate
dehydrogenase. Glutamate dehydrogenase, a mitochon-
drial enzyme, converts glutamate to a-ketoglutarate by
oxidative deamination (Chapter 17). Glutamate dehydro-
genase is positively modulated by ADP and negatively
modulated by GTP. The a-ketoglutarate is subsequently
oxidized to provide ATP which blocks the ATP-sensitive
K+ channel, eventually causing insulin release.
The overall glucokinase-glucose sensor mechanism as
the primary regulator of glucose-controlled insulin se-
cretion of
cells has been substantiated by identifying
mutations that affect human glucokinase. Both gain-in-
function and loss-of-function mutants of glucokinase are
known. The activating glucokinase mutation (Val455Met)
with increased affinity for glucose results in hyperinsulin-
ism with fasting hypoglycemia. Other mutations have been
identified that impair glucokinase activity. These defects
result in hyperglycemia and diabetes mellitus, known as
maturity-onset diabetes of the young
(MODY), which also
occurs as a result of mutations in genes that encode hép-
atocyte nuclear factors la, 4a,
and insulin promoter
factor 1. Hyperinsulinémie hypoglycemia can be caused
by mutations in the SUR/Kir6.2 components of the K+
channel. Abnormalities can also result from defects in glu-
tamate dehydrogenase function. Conversion of glutamate
to a-ketoglutarate by glutamate dehydrogenase provides
substrates for ATP production and the enzyme is inhib-
ited by GTP at an allosteric site. The importance of the
sensitivity of glutamate dehydrogenase to inhibition by
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