Insulin and Glucagon

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Insulin and Glucagon
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Pancreas
Exocrine pancreas
Endocrine pancreas
Insulin Glucagon Somatostatin
Pancreatic polypeptide
Digestive enzymes
The pancreas contains two distinctly different
tissues. The bulk of the mass is exocrine tissue
and associated ducts which produce an alkaline
fluid with digestive enzymes that is delivered to
the small intestine. Scattered throughout the
exocrine tissues are clusters of endocrine cells
which produce, among others, the hormones insulin
and glucagon.
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Cell types in the endocrine pancreatic Islets of
Langerhans
Cell types
Secretory Products
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Beta cells usually occupy the central portion of
an islet and are surrounded by alpha and delta
cells.
Three Islets of Langerhans in the pancreas of a
horse
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Synthesis and secretion of insulin
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Processing of Insulin
Preproinsulin
Preproinsulin is a long-chain polypeptide (MW
11,500) produced by mRNA-directed translation in
the rough endoplasmic reticulum.
Proinsulin
Preproinsulin is cleaved immediately after
synthesis to proinsulin (MW 9000). Proinsulin is
transported to the Golgi and packaged into
secretory granules.
Insulin and C peptide
Maturation of the secretory granule involves
proteolytic cleavage of proinsulin into insulin
and C peptide. Normal mature secretory granules
contain these in equimolar amounts and only small
quantities of proinsulin.
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Proinsulin consists of a single chain of 86 amino
acids which includes the A and B chains of
insulin, and a connecting segment of 35 amino
acids.
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Insulin hexamer with two Zn atoms
The hexameric form of insulin is thought to exist
in the secretory granules of the pancreatic B
cells.
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Glucose Transporters
All cells require proteins to transport glucose
across the lipid bilayers into the cytosol. The
intestine and kidney have an energy dependent
Na/glucose cotransporter. All other cells have
non-energy dependent transporters that facilitate
diffusion of glucose from a higher concentration
to a lower concentration across cell membranes.
At least five facilitative glucose transporters
have been described, and these have different
affinities for glucose (GLUT1, GLUT2, GLUT3,
GLUT4, and GLUT5).
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Human glucose transporters
Affinity for glucose
Transporter
Major sites of expression
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GLUT1 is present in all tissues especially brain
vascular system (blood-brain barrier). Its high
affinity for glucose ensures adequate uptake even
at low blood glucose levels (basal levels).
GLUT3 is the main neuronal glucose transporter.
It has a very high affinity for glucose and is
responsible for transferring glucose from the
cerebrospinal fluid into neuronal cells.
GLUT2 has a low affinity for glucose. It is the
major transporter in the liver and pancreatic B
cells. This insures that insulin is secreted
only when blood glucose levels are high. It also
prevents hepatic uptake when levels are basal or
low as during fasting.
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GLUT4 is found in two major insulin-targeted
tissues, muscle and adipose tissue. It is not
present to a great extent on the cell surface
until an insulin signal relocates these
transporters to the cell membrane. Thus GLUT4
functions primarily after a high carbohydrate
meal when insulin is secreted. GLUT5 appears to
function biochemically as a fructose transporter.
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Stimulus for insulin secretion
Glucose is the most potent simulate to pancreatic
B cells for insulin secretion. Glucose enters B
cells through GLUT2 (low affinity for glucose).
The metabolism of glucose is apparently required
for insulin secretion. The rate limiting step
for glucose utilization in the B cells is
phosphorylation to glucose-6-phosphate by the
low-affinity enzyme glucokinase.
Glucose induces cAMP formation in B cells.
However, increased cAMP will not induce insulin
in the absence of glucose.
Insulin release also requires Ca2 ( microtubules
that contract in response to Ca2 may play a role
in the ejection of insulin granules).
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Multiphasic response of the in vitro perfused
pancreas during constant stimulation with glucose
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Insulin Receptors
Insulin action begins with the binding to
specific cell surface receptors.
Insulin receptors are membrane glycoproteins
composed of two subunits a larger a subunit
which extends beyond the cell surface and is
involved in the binding of insulin, and a smaller
b subunit which is predominately intracellular
and contains tyrosine kinase activity.
Upon insulin binding, signal transduction results
in autophosphorylation of the receptor tyrosine
kinase. This now activated complex, interacts
with and phosphorylates a network of as many as
nine intracellular proteins.
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The insulin receptor is a tyrosine-specific kinase
Upon insulin binding, signal transduction causes
autophosphorylation of the receptor, activating
the complex. The target proteins, IRS-1 and
IRS-2, are then phosphorylated.
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The immediate targets for the activated insulin
receptor tyrosine kinase are insulin receptor
substrate-1 (IRS-1) and insulin receptor
substrate-2 (IRS-2). IRS-1 becomes the point of
nucleation for a complex of proteins that carry
the signal from the insulin receptor to end
targets in both the cytosol and the nucleus.
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Abbreviations used in previous figure
IRS-1 insulin receptor substrate-1 PI-3K
phosphatidylinositiol 3-kinase (phosphorylates
phosphatidylinositol-4,5-bisphosphate (PIP2) to
form phosphatidylinositol-3,4,5-trisphsophate
(PIP3). PKB protein kinase B PDK1 a protein
kinase GSK3 glycogen synthase kinase 3 GS
glycogen synthase GluT4 glucose transporter 4
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Metabolic effects of insulin
The major function of insulin is to promote
storage of ingested nutrients. Blood glucose is
converted to glycogen (muscle and liver) and into
triacylglycerols (adipose tissue).
Liver
Promotes glucose storage as glycogen Increases
triglyceride synthesis and VLDL
formation Inhibits glycogen breakdown Inhibits
conversion of fatty acids and amino acids to keto
acids Inhibits conversion of amino acids to
glucose
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Muscle
Increases ribosomal protein synthesis Increases
amino acids uptake Increases glucose
transport Increases glycogen synthesis and
inhibits glycogen breakdown
Adipose tissue
Increases triglyceride storage Inhibits
intracellular lipase Promotes uptake of fatty
acids Increases glucose transport Reduces fatty
acid flux to the liver
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Metabolic effects of insulin
Metabolic effect
Target enzyme
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Glucagon
Synthesized in the A cells of the Islets of
Langerhans, the precursor molecule, proglucagon,
is composed of 160 amino acids. Within this
prohormone are several other peptides connected
in tandem glicentin-related polypeptide
(GRPP) glucagon glucagon-like peptide-1
(GLP-1) glucagon-like peptide-2 (GLP-2)
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Levels of GLP-1 and GLP-2 both increase after
meals. A truncated derivative of GLP-1 (residues
7-37) is an extremely potent stimulator of
pancreatic B cells. This molecule is thought to
be the major physiological gut factor which
potentiates glucose-induced insulin secretion.
Intact GLP-1 and GLP-2 do not stimulate insulin
secretion.
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Tissue specific secretory products of human
proglucagon
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Secretion of glucagon
The release of glucagon is controlled primarily
through suppression by glucose and insulin.
Glucagon secretion is inhibited by glucose. This
may be direct, or indirect via the release of
insulin and somatostatin.
Several hours after the intake of dietary
carbohydrates, blood glucose levels fall below
4.5 mM and trigger the secretion of glucagon.
Basically, this signal says glucose is gone.
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Other substances that stimulate glucagon
release catecholamines (epinephrine) the
gastrointestinal hormones (cholecystokinin,
gastrin, and gastrin-inhibitory
peptide) glucocorticoids (cortisol)
High levels of fatty acids are associated with
suppression of glucagon release.
Many amino acids stimulate glucagon release
Arginine releases both insulin and
glucagon Leucine, a good stimulant for insulin
release, does not release glucagon. Alanine
stimulates glucagon primarily.
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Glucagon Receptors
The liver is one of the major target organs for
glucagon. Glucagon binds to hepatic receptors in
the cell membrane and stimulates adenylyl cyclase
and thus increases the intracellular
concentration of cAMP.
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Metabolic effects of glucagon
Glucagon acts to maintain fuel availability in
the absence of dietary glucose.
Glucagon stimulates the breakdown of stored
glycogen, maintains hepatic output of glucose
from amino acid precursors (gluconeogenesis), and
promotes hepatic output of ketone bodies from
fatty acid precursors (ketogenesis).
Uptake of alanine by liver cells is facilitated
by glucagon and fatty acids are directed away
from reesterification to triacylglycerols and
toward ketogenic pathways.
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Metabolic effects of glucagon
Metabolic effect
Target enzyme
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Blood glucose, insulin, and glucagon levels after
a high carbohydrate meal.
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Release of insulin and glucagon after a high
protein meal (100 grams of protein after an
overnight fast)
Insulin levels do not increase nearly as much as
after a high carbohydrate meal. Glucagon
increases above fasting levels.