
the periphery, followed by fusion of the granule mem-
brane with the plasma membrane and liberation of
the granule contents into the blood.
0009 More specific details of events concerning biosyn-
thesis and secretion are best known for insulin. In the
b cell, transcription of messenger ribonucleic acid
(mRNA) gives rise to production of preproinsulin,
an 11.5-kDa polypeptide. This is rapidly cleaved
within 1 min by proteolytic enzymes to proinsulin
(86 amino acid residues, 9 kDa) which is transported
by microvesicles to the Golgi apparatus. Proinsulin is
then packaged into secretory granules, where it is
converted by proteases to equimolar amounts of
insulin (51 residues, 6 kDa) and proinsulin C-peptide.
A number of second messengers are involved in
coupling stimulus recognition to the secretion of
insulin by exocytosis. These include cytoplasmic
calcium ion concentration ([Ca
2þ
]
i
), cyclic adenosine
monophosphate (cAMP), diacylglycerol (DAG), and
inositol 1,4,5-trisphosphate (IP
3
).
0010 In pancreatic a
2
cells, the initial product of the
proglucagon is a 160-residue polypeptide (18 kDa)
that contains the amino acid sequences of several
biologically active peptides in addition to glucagon.
Posttranslational processing of proglucagon yields
glucagon (29 residues, 3.5 kDa) as the main product,
plus a proglucagon fragment and, possibly, small
amounts of glicentin-related pancreatic peptide
(GRPP). In pancreatic a
1
cells, preprosomatostatin
(116 residues) is similarly processed to prosomato-
statin (92 residues) before conversion to the active,
14-amino-acid form of somatostatin (SRIF-14,
1.5 kDa). In PP cells, pancreatic polypeptide (36 resi-
dues, 4.3 kDa) also appears to be produced from a
larger, 95-amino-acid, prohormone form. In the in-
testine, the posttranslational processing of progluca-
gon and prosomatostatin differs, yielding as major
products glucagon-like peptide-1[7-36]-amide (GLP-
1[7-36]-amide) and the 28-amino-acid form of soma-
tostatin (SRIF-28), respectively.
Regulation of Secretion
0011 A wide range of nutrients, hormones, and neurotrans-
mitters are capable of influencing the secretion of
insulin, glucagon, somatostatin, and pancreatic poly-
peptide (Tables 1 and 2). In the case of insulin, the
major physiological regulator of b cell function is
the prevailing plasma glucose concentration. Other
metabolizable nutrients can mimic the stimulatory
action of glucose, but these other agents basically
act as modulators of the glucose response.
0012 Insulin acting locally within the islet is an influen-
tial inhibitor of glucagon secretion. Glucose inhib-
ition of glucagon secretion is thus attributable in
large part to concomitant stimulation of the b cell
with the release of insulin. g-Aminobutyric acid
(GABA), cosecreted with insulin from the b cell, has
also been suggested to contribute to inhibition of
a
2
cells. The paradoxical ability of amino acids and
food-activated elements of the enteroinsular axis to
stimulate glucagon as well as insulin secretion is often
considered to offer protection from hypoglycemia
that might result from the marked stimulation of
insulin release. An alternative interpretation is that
the stimulation of glucagon release serves to promote
insulin secretion by paracrine interaction within
the islet. Other situations associated with secretion
of glucagon include hypoglycemia, starvation, and
stress. In these circumstances, glucagon serves to
mobilize nutrient fuels from body stores to meet
immediate energy requirements.
Nutrient Regulation of Insulin Secretion
0013Although many factors influence the secretion of
pancreatic hormones, the regulation of insulin secre-
tion is particularly critical for normal metabolism
and maintenance of good health. b cell dysregulation
leading to deficient insulin secretion results in
impaired glucose tolerance, hyperglycemia and type
2 diabetes (also known as noninsulin-dependent dia-
betes mellitus). Hypersecretion of insulin may result
in life-threatening hypoglycemia, as observed in cer-
tain individuals with an islet cell tumor (insulinoma).
0014Nutrients exert direct and indirect effects on insulin
secretion. Thus, in addition to the direct stimulatory
actions of glucose, amino acids, and fatty acids on the
b cell, the ingestion of food and absorption of nutri-
ents trigger neural and hormonal elements of the
enteroinsular axis (Figure 2). Activation of the para-
sympathetic nerve innervating the islets liberates
acetylcholine from nerve terminals close to b cells.
Stimulation of intestinal endocrine cells leads to the
secretion of GLP-1[7–36]-amide, gastric-inhibitory
polypeptide (GIP) and cholecystokinin (CCK). These
agents are powerful insulin secretagogs at raised
glucose concentrations, and they markedly augment
the direct stimulatory actions of glucose and other
nutrients.
0015The mechanisms through which nutrients and
enteroinsular stimuli trigger insulin secretion from b
cells involve elevation of [Ca
2þ
]
i
and sensitization of
the exocytotic process to normal stimulatory action
of [Ca
2þ
]
i
(Figure 3). Metabolizable nutrients, includ-
ing glucose, certain amino acids, and fatty acids, act
by virtue of the ability of the b cell to metabolize these
substances with the generation of adenosine triphos-
phate (ATP). ATP generation results in closure of
ATP-sensitive potassium channels (K
ATP
) channels in
HORMONES/Pancreatic Hormones 3153