BIOC 313

Chapter 7

Hormones of the Pancreas

Pancreas

The pancreas contains two distinctly different tissues.

1- Exocrine tissue and associated ducts
Produce an alkaline fluid loaded with digestive enzymes
which is delivered to the small intestine to facilitate
digestion of foodstuffs.
2- Endocrine cells
Scattered throughout the exocrine tissue are several
hundred thousand clusters of endocrine cells which
produce the hormones insulin and glucagon.
Endocrine Pancreas

The endocrine portion of the pancreas has many small clusters

of cells called islets of Langerhans

Pancreatic islets house of four major cell types:

• α-cells (Alpha): secrete the hormone glucagon
• β-cells (Beta): produce insulin
• δ-cells (Delta): secrete the hormone somatostatin
• F cells: secrete pancreatic polypeptide
 It is produced by -cells of
islets:

• Insulin is an anabolic peptide hormone

secreted by pancreatic β cells.
• Controls the conversion of blood glucose
to insoluble glycogen, which is stored in
Insulin the liver.
• Increases metabolic rate by stimulating
cellular glucose uptake.
• Increases protein synthesis in some cells.

It is composed of 2
peptide chain and
3 disulphide bonds
 Chemical
structure of
insulin
•Insulin is a polypeptide
hormone (51 amino acids), Connecting peptide
with a M. Wt. of about 5.8 Proinsulin
kDa. structure
•It is composed of two
chains held together by
disulfide bonds (after
removal of connecting
peptide (C-peptide):
 α-chain (21 amino acids)
 β- chain (30 amino
acids)
Biosynthesis of insulin

• Insulin is produced in beta cells which

constitute 75% of the islets of Langerhans of
the pancreas.
• The insulin mRNA is translated as a single
chain precursor called preproinsulin.
• Signal sequence at the N-terminal of
preproinsulin are cleaved in endoplasmic
reticulum to form proinsulin.
Proinsulin consists of three domains:
• β- chain (N-terminal),
• α-chain (C-terminal) and
• C-peptide in the middle
The proinsulin is transferred to Golgi apparatus
where it undergoes proteolysis to give insulin
and c-peptide.
 • Insulin and free C-peptide are packaged in
the Golgi into secretory granules which
accumulate in the cytoplasm.
• Insulin is secreted from the cell by
exocytosis and diffuses into blood.

Biosynthesi • C-peptide is also secreted into blood in

equal amounts to the insulin protein.
s of insulin • Serum amount of C-peptide is good
indicator of internal insulin production.
• C-peptide has recently been discovered to
have biological activity itself; the activity is
apparently confined to an effect on the
muscular layer of the arteries.
Secretion

• β-cells in the islets of Langerhans release insulin under the

influence of various substances such as glucose, amino acids
and fatty acids.
A. The stimulation of insulin secretion by glucose requires
several steps:
1. Glucose is diffused into β-cells through GLUT2 transporter.
2. Phosphorylation of glucose by glucokinase, and synthesis of
ATP.
Secretion

3. Increased level of ATP induces the closing of ATP-dependent

potassium channels and the cessation of potassium exit.
4. This leads to membrane depolarization and Ca2+ influx.
5. The entry of Ca2+ elicits the activation of phospholipase C
allowing the release of Ca2+ from the ER (endoplasmic
reticulum)
6. Significantly increased amounts of calcium in the cells causes
release of previously synthesized insulin, which has been stored
in secretory vesicles
 Ewa Świderska
Ewa Świderska

Figure: Insulin release. Glucose is transported into β-cells via GLUT2 in an insulin-independent way with concentration
gradient. Then, glucose is phosphorylated by glucokinase to glucose-6-phosphate, which allows for its inclusion to
metabolic processes and ATP production. Raised ATP level triggers accumulation of K+ ions along with membrane
depolarization. The latter activates Ca2+ channels, leading to increased concentration of Ca2+ ions inside the cell and
consequent release of insulin from vesicles.
Świderska E. et.al., 2018; Role of PI3K/AKT Pathway in Insulin-Mediated Glucose Uptake.
Secretion

B. Amino acids from ingested proteins. Three amino acids

(alanine, glycine and arginine) act similarly to glucose.
C. Fatty acids and ketonic bodies.
D. Acetylcholine released from parasympathetic nervous
system which triggers insulin release through
phospholipase C.
E. Gastrointestinal hormones released by intestinal mucosa
that act through the mechanism of adenylate cyclase, such
as secretin.
Insulin receptors

• Insulin is a hydrophilic
hormone, secreted in
plasma with no special
transport proteins.
• It interacts with cell
surface receptors on
target cells.
• The insulin receptor is
a transmembrane
receptor that is
activated by insulin.
 • It belongs to the large class of tyrosine
kinase receptors.
• Two α-subunits and two β-subunits
make up the insulin receptor. The β-
subunits pass through the cellular
membrane and are linked by disulfide
Insulin bonds.

receptors • The α- and β- subunits are encoded by

a single gene (INSR).
• The insulin receptor has also been
designated CD220 .
Mechanism of insulin action

• The effects of insulin on glucose metabolism vary depending

on the target tissue.
• Insulin facilitates entry of glucose into muscle, adipose and
several other tissues through a family of transporters.
• The major transporter used for uptake of glucose (called
GLUT4) which is made available in the plasma membrane
through the action of insulin.
 In the absence of insulin
• GLUT4 are present in cytoplasmic
vesicles, where they are useless for
transporting glucose.

Mechanis In the presence of insulin

• Binding of insulin to its receptors leads
m of rapidly to fusion of those vesicles with the
plasma membrane and insertion of the
insulin glucose transporters, giving the cell an
ability to efficiently take up glucose.
action • When blood levels of insulin decrease and
insulin receptors are no longer occupied,
the glucose transporters are recycled back
into the cytoplasm.
Mechanism of insulin action

Role of insulin in transport of Organ Glucose

glucose into adipose tissue, transporter
skeletal muscles and heart
through GLUT4: Brain, erythrocyte GLUT1
Adipocyte, skeletal GLUT4
- Insulin induces transfer of muscles and
GLUT4 from their intracellular myocardium
pool to the outer membrane
surface of these tissues. Liver, pancreas GLUT2
Increased GLUT4 in the surface Gut and kidney GLUT3
of these tissues leads to increase
glucose transport.
Mechanism of insulin action

Effect of insulin on glucose

uptake and metabolism:
• Insulin binds to its receptor which
in turn starts many protein
activation cascades.
• These include, translocation of
GLUT-4 transporter to the plasma
membrane and influx of glucose,
glycogen synthesis, glycolysis and
fatty acid synthesis.
Mechanism of insulin action
• Insulin is a multitask protein involved, among others, in the regulation
of carbohydrate and lipid metabolism.
• It is responsible for energy storage through accelerating glycogen
synthesis and lipogenesis.
• Insulin is also involved in phenomena connected with cell survival.
Table: Metabolic functions of insulin
Upregulation Downregulation

Carbohydrate metabolism Glucose uptake via GLUT4 Glycogenolysis

Glycogen synthesis Gluconeogenesis
Glycolysis
Conversion of pyruvate to acetyl CoA

Lipid metabolism Fatty acid synthesis Lipid oxidation

Triglyceride synthesis Triglycerides breakdown
Cholesterol synthesis
Protein metabolism Transcription of proteins involved Transcription of proteins
energy stores generation involved in energy stores release
 Action of Insulin on Actions of Insulin on Actions of Insulin on the
Adipose Tissue Muscle Liver
• Stimulates glucose • Stimulates glucose • Stimulates glucose
uptake uptake uptake
• Stimulates glycolysis • Stimulates glycolysis • Stimulates glycolysis
• Stimulates • Stimulates • Stimulates
lipogenesis glycogenesis glycogenesis
Actions of
• Inhibits lipolysis and
ketogenesis
• Inhibits
glycogenolysis
• Inhibits
glycogenolysis
Insulin on • Inhibits FFA uptake
and oxidation
• Inhibits
gluconeogenesis
Muscle • Stimulates
proteogenesis
• Stimulates
lipogenesis
• Inhibits proteolysis • Inhibits lipolysis
• Stimulates
cholesterol synthesis
Figure. Critical actions and pathways controlled by insulin.
Degradation of insulin

• Once an insulin molecule has bound to the receptor and exerted

its action, it may be released back into the extracellular
environment, or it may be degraded by the cell.
• Degradation normally involves endocytosis of the insulin-receptor
complex followed by the action of insulin degrading enzyme.
• Most insulin molecules are degraded by liver cells.
• Insulin is inactivated by enzymatic bio-transformations: hydrolyze
by metalloproteinases and reduction by Glutathione insulin
transhydrogenase, i.e. cleavage of disulfide bonds of insulin
separating it into 2 inactive polypeptides .
Glucagon

• It is produced from -
cells of islets
pancreas
• Controls the conversion
of insoluble glycogen to
glucose in the liver.
Chemical structure of glucagon

• Glucagon is composed of
single peptide chain and no
disulphide bond.
• It contains 29-amino acids.
• Its M. Wt. is about 3.5 kDa.
• Glucagon binds to the
glucagon receptor, a G
protein-coupled receptor
located in the plasma
membrane.
 Glucagon helps maintain the level of glucose in
the blood.

It is the signal of fasting (released under the

influence of low glucose level).

Glucagon When glucagon binds to the glucagon

receptors on liver, it stimulates the
Action glycogenolysis.

It induces gluconeogenesis.

Glucagon also regulates the rate of glucose

production through lipolysis.
 • It is produced from δ-cells of
islets.

• Somatostatin, also known as

Somatostatin growth hormone-inhibiting
hormone (GHIH), is a peptide
hormone that regulates the
endocrine system.
•It is induced by low pH.
 Chemical Structure of Somatostatin

• Somatostatins are peptides, initially

synthesized as a large precursor
molecule that undergoes tissue-specific
enzymatic degradation to yield either
somatostatin-14 or somatostatin-28.

• Natural somatostatins have only short

half-lives (<3 min).
 Somatostatin is classified as an
inhibitory hormone, whose
actions are spread to different
parts of the body:
 Inhibits the release of growth
hormone

Action of  Inhibits the release of thyroid-

stimulating hormone (TSH)
Somatostatin  It suppresses the release of
various gastrointestinal
hormones
 It suppresses the release of
pancreatic hormones
 It suppresses the exocrine
secretory action of pancreas
Bioc 313