Transcript No Slide Title

Secretion of insulin from
pancreas b cells:
A Case Study of Exocytosis
and Cell Signaling
Cultured Mouse Pancreatic Islets
(10x magnification).
Provided by David Zhiyong Gao,
Ph.D.
Designed by Leonardo Da Vinci
in 1501, this figure is an exact
representation of clathrin as it
appears in coated pits.
Exocytosis Case Study:
Secretion of insulin from pancreas b cells
Cultured Mouse Pancreatic Islets
(10x magnification).
Insulin is a peptide
hormone that regulates
glucose uptake and
metabolism.
Provided by David Zhiyong Gao, Ph.D.
In diabetes mellitus (sweet urine), insulin
secretion by ß-cells of islets of Langerhans is
deficient or absent.
Insulin Monomer Structure
51 amino acid residues
a and ß chain
disulfide bonds connect the two chains
The amino acid
sequence of
bovine insulin.
Insulin is stored in
crystalline
structures made up
of insulin hexamers
containing two Zn2+
ions.
This figure was
created using RasMol
by Roger Sayle.
Cultured Mouse Pancreatic Islets
(10x magnification).
Pancreatic islets are scattered
throughout the pancreas.
There are about 1 million islets, Provided by David Zhiyong Gao, Ph.D.
comprising 1 to 2% of the total volume
of the pancreas.
Islets have a central core of insulin
producing ß-cells surrounded by cells
that produce other pancreatic
hormones such as glucagon (alphacells), somatostatin (D or delta-cells),
and pancreatic polypeptide (F or PP
cells).
In type 2 diabetes,
beta cells fail to secrete
insulin normally in
response to glucose.
About 16 million people or 6% of the US population has
diabetes.
Of those, type 2 diabetes is by far the most common.
The number of people with type 2 diabetes is
predicted to increase as the population grows older.
Exocytotic membrane fusion
occurs by a highly conserved
mechanism that involves
membrane vesicles and
membrane proteins.
TEM Showing Exocytosis of
the Contents of a Secretory
Vesicle
Figure source:
http://tidepool.st.usm.edu/crs
wr/exocytosis.html
Members of the SNARE, Sec1p, and Rab families are
involved in the docking and fusion of transport vesicles
to target membranes.
Time Out 2
Botulinum toxin: Types A and E
cleave SNAP 25 (synaptosomal
associated protein) a highly conserved
protein known to be involved in
exocytosis. Type C cleaves syntaxin, a
synaptic membrane protein also involved
in exocytosis.
Role of NSF in membrane fusion
NSF is a
molecular
chaperone
that induces
conformation
al change into
its targets
syntaxin and,
to a lesser
extent,
SNAP-25.
Model for membrane fusion
Figure source:
http://www.mpibpc.gwdg.de/abteilungen/190/fusmodel.html
How does this happen with
insulin secretion?
Preproinsulin is synthesized and inserted
across the rough endoplasmic reticulum
membrane membrane. (A proprotein, is one
that is made in an inactive form and later
activated by the cell.)
http://www.accessexcel
lence.org/AB/GG/exocy
tosis.html
The prepeptide is cleaved to form the
active hormone and packaged in the Golgi
apparatus into secretory vesicles.
There are about 15,000 secretory vesicles
(in this case, they are called secretory
granules) per cell. This is about a 5-day
supply in a normal human.
Figure from “Access Excellence” http://www.accessexcellence.org/AB/GG/exocytosis.html
Time Out
Mistletoe extract (Viscum album) has
a long history as a traditional
treatment for diabetes.
Mistletoe exerts its
antidiabetic effect
by stimulating insulin
secretion.
Cell Signaling Case Study:
Secretion of insulin from pancreas b cells
In general, signaling by cell-surface
receptors initiates a cascade of
biochemical events that result changes
in the metabolism of the cell.
Insulin is secreted in
response to elevated blood
concentrations of glucose.
How does glucose stimulate insulin secretion
from b cells of the pancreas?
Glucose metabolism produces cellular
ATP,
which closes the ATP-sensitive
potassium channel;
then the voltage-dependent L-type Ca2+
channels open.
Ca2+ from the extracellular space (and
intercelluar stores) leads to the
exocytosis of insulin.
Overwhelming evidence supports the idea that
glucokinase is the major regulator of glucose metabolism,
allowing it to function as the glucose sensor of the ß-cell.
Figure source:
http://mcb1.ims.abdn.ac.
uk/teaching/courses/mo
dules/Ercs.html
Signaling is about
communication
between different
groups of cells and
tissues…how one
group of cells informs
another group of cells
what to do.
Signal transduction refers to how the presence of an
extracellular signal can produce a change in the
intracellular state of the cell without the initial signal
crossing the membrane.
Signal transduction
systems
Ca2+/calmodulin
adenylate cyclase/cAMP
NO
PLC/PKC
PI/IP3/DAG
membrane receptors
G proteins
steroid hormones
How does insulin work?
INSULIN ACTS TO STORE NUTRIENTS.
(carbohydrates, fats and protein)
It is the only hormone that does this. A lack of
insulin is fatal.
Insulin acts on three major organs, the
liver, muscle and adipose tissue..
Insulin is not needed for glucose transport into the
brain, red blood cells, liver, renal medulla or active
muscle.
Review
1.Compare the structures, locations and functions of
preproinsulin and insulin.
2. Outline the events from translation of the preproinsulin
gene to exocytosis of insulin.
3. Describe the mechanisms by which glucose promotes insulin
secretion.
4. Identify the components of insulin secretion that are
defective in type II diabetes mellitus.