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Islets of Langerhans, which form the endocrine
portion of the pancreas, are scattered throughout the organ and
consist of richly vascularized globular masses of cells, which in the
human pancreas are estimated to total from 200,000 to 2 million cells.
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Six distinct cell
types have been identified and correlated with hormone synthesis and
storage.
Alpha cells,
which contain glucagons, and beta cells, in which insulin is
localized, have been best characterized.
The two types of delta cells, D and D1 (which secrete somatostatin and vasoactive intestinal
polypeptide, respectively), and pancreatic polypeptide-secreting cells
have been less well studied.
The enterochromaffin cells, which
secrete the vasoactive amine serotonin (5-hydroxytryptamine), are a
minor component of the istet cell population and are demonstrable by
their capacity for staining with potassium dichromate.
The cellular
composition of islets varies in the different anatomic subdivisions as
follows: In the head the ratios of the component cells are
beta > polypeptide-secreting >delta >alpha as contrasted with the body and
tail, where the ratios are beta >alpha >delta >polypeptide-secreting.
Alpha
cells are localized in the outer rim of the islets and constitute 15%
to 20% of the total islet cell population.
In the alpha cells,
glucagons, like insulin and other hormones, is synthesized as a
prohormone, proglucagon, with a molecular of 19,000 daltons.
Before
export the prohormone is cleaved to active hormone, a 3500-dalton
product.
Glucagon glycogenolysis and gluconeogenesis, thereby raising
the blood glucose level.
Its secretion is stimulated by hypoglycemia,
by the ingestion of a low-carbohydrate-high-protein meal, and by an
intravenous infusion of amino acids.
By virtue of these responses by alpha cells, glucagons, together with insulin serves to maintain fuel
homeostasis.
At least two precursor peptides of proglucagon apparently
constitute separate regions of the molecule.
These are called glicentins 1 and 2 and have been localized to the secretory granules
in alpha cells.
Radioimmunoassay of glucagons in serum reveals several
species, of which only the 3500-dalton variety appears to be
biologically active.
Larger species, weighing 9000 daltons and 16,000
daltons, respectively, represent forms of the incompletely cleaved
prohormone.
It is noteworthy that in patients with a rare condition
called familial hyperglucagonemia, in whom the level of serum glucagon
may be 10 times normal, 85% of the hormone consists of molecular forms
higher than 9000 daltons.
Beta cells comprise the largest population,
60% to 70%, of cells in islets.
They are distributed throughout the
islet when visualized by their affinity for certain stains, such as aldehude fuchsin or pseudoisoocyanin, or by specific antibody to
insulin.
By electron microscopy the insulin is resolved into
characteristic polygonal and rhomboidal crystals enclosed in secretory
vesicles.
The synthesis and secretion pathway for insulin can be
considered as a general model for the other islet cell types.
Insulin
is synthesized in the rough endoplasmic reticulum of beta cells as a
single chain precursor molecule, termed proinsulin, with a
molecular weight of about 9000 daltons. This molecule is transferred
by an ATP-dependent process to Golgi membrane system, where it is
packaged into smooth-surfaced microvesicles, and continuing in the
secretory granules, Zn2+ is added
to the proinsulin molecule, after which it is progressively cleaved by
membrane-bound proteases into equimolar amounts of insulin and the
peptide that connects the A and B chains of insulin (C-peptide).
The
mature secretory granules, guided by the microtubules, migrate
centripetally in the cytoplasm until they fuse with the plasma
membrane and are extruded into the extracellular space, a process
termed exocytosis.
The final release involves an influx of Ca2+ ions into the cell.
As is true for a large number of other intracellular processes, cAMP participates in the insulin
secretory process.
However, the
major obligatory stimulus for insulin secretion is the binding of
glucose to glucose receptors on surface of the beta cell.
Delta cells are fewer in number and slightly
larger than alpha cells.
Like alpha cells, delta cells tend to be
localized at the periphery of islets.
They are situated between the alpha and the beta cells so that the three cell types are often
contiguous.
Delta cells secrete somatostatin, a 1600-dalton peptide
identical to that discovered earlier in the hypothalamus that inhibits
the pituitary release of growth hormone.
Somatostatin synthesized in
the islets inhibits secretion by alpha and beta cells and one type(D1)
of delta cell, acinar cells of the exocrine pancreas, and certain
hormone-secreting cells in the gastrointestinal tract.
Coupled with
the topographical cell-cell relations noted earlier, these hormonal
interactions suggest that somatostatin plays a regulatory role in alpha
and beta cell secretion, which is reflected in the high stability of
glucose homeostasis.
D1 cells
are smaller than the other islet cell types and are rare in the islets
of normal human pancreas.
They synthesize a 3800-dalton peptide termed vasoactive intestinal polypeptide, a molecule that has also been
localized in ganglion cells and nerve fibers of the pancreas, gut, and
brain.
Vasoactive intestinal polypeptide induces glycogenolysis and
hyperglycemia, as does glucagons, and in addition regulates the tone,
motility, and ion and water secretion by epithelial cells of the
gastrointestinal tract.
The latter function is mediated by its ability
to activate adenyl cyclase, thus leading to the production of cAMP.
Pancreatic polypeptide-producing cells are
located primarily in the islets of the head of the pancreas and
synthesize a 4300-dalton polypeptide, which appears to have variable
and opposed functions.
These include stimulation of the secretion of
enzymes from the gastric mucosa and inhibition of a variety of
functions, such as smooth muscle contraction in the intestine and
gallbladder, production of gastric acid, and secretion by the exocrine
pancreas and biliary system.
Enterochromaffin cells, identified by
their capacity for reducing ammoniacal silver and for staining by
potassium dichromate, are rare components of the islet cell population
in the head of the pancreas.
They synthesize serotonin, a vasoactive
amine that causes vasodilatation and increased permeability of the
venular capillaries, and the 2700-dalton peptide motilin, which
stimulates motility of gastric smooth muscle, and increased the tone
of the sphincter at the gastroesophageal junction.
Visit:
Pancreatic Pathology Online
;
Anatomy of Normal Pancreas
;
The Apud Concept.
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