Endocrine Physiology

The Endocrine Pancreas

Pan-creas!

• Greek: “pan”
= all; “creas”
= flesh
• Pancreas is
like a fish!
Head, body,
and tail.
• Important
anatomical
relationships
 Pancreas: two major roles

2) Endocrine

• Produce enzymes
that CHOP (digest
(digest))
food
• Control the sugar
levels in the body
1) Exocrine
A closer look: Endocrine
Pancreatic cells
Islets of
Langerhans! Islets of
Langerhans has
!! FOUR major
cell types:
1) Alpha cell
2) Beta cell
3) Gamma cell
(PP cell)
4) Delta cell
Pancreas

• A triangular gland, which has both exocrine and

endocrine cells, located behind the stomach
• Strategic location
• Acinar cells produce an enzyme-rich juice used
for digestion (exocrine product)
• Pancreatic islets (islets
(islets of Langerhans)
Langerhans)
produce hormones involved in regulating fuel
storage and use.
Super Fun and Totally Cool Mnemonic

• In
Insul
sulin
in gets glucose in
into
to cells
(so that they can use it or store it)

• Glu
Gluca
cagon
gon is for when the glu
glucose
cose is gon
gonee
(and you need to mobilize storage)
Functional Anatomy

• The pancreas,
which lies
parallel to and
beneath the
stomach is a
large
compound
gland with most
of its internal
structure
similar to that
of the salivary
glands
The Endocrine Pancreas
Islets of Langerhans

• 1 million islets
• 1-2% of the pancreatic mass
• Beta (β) cells produce insulin
• Alpha (α) cells produce glucagon
• Delta (δ) cells produce somatostatin
• F cells produce pancreatic polypeptide
The pancreas, in
Islet of Langerhans in the pancreas.
addition to its
digestive functions,
secretes two important
hormones:
1. Insulin (Beta cells;
60%).
2. Glucagon (Alpha
cells; ~25%).
that are crucial for
normal regulation of
glucose, lipid, and
protein metabolism.
Also Somatostatin is
secreted by delta cells (Figure 78-1. Copyright 2011, WB Saunders Elsevier, All
Rights Reserved
Islets of Langerhans
Insulin

• Hormone of nutrient abundance

• A protein hormone consisting of two amino acid
chains linked by disulfide bonds
• Synthesized as part of proinsulin (86 AA) and
then excised by enzymes, releasing functional
insulin (51 AA) and C peptide (29 AA).
Insulin Structure

1- Large polypeptide 51 AA (MW 6000)

2- Two chains linked by disulfide bonds.

A chain (21 AA)

B chain (30 AA)
3 disulfide bonds.
Insulin Structure
Protein and Polypeptide Synthesis and
Release
Insulin Synthesis

• insulin gene( chro-11) encodes a large precursor

of insulin (preproinsulin)
• During translation, the signal peptide is cleaved
(proinsulin)
• During packaging in granules by Golgi,
proinsulin is cleaved into insulin and C peptide
Insulin Synthesis

DNA (chromosome 11) in β cells

mRNA

Preproinsulin (signal peptide, A chain,

B chain, and peptide C)

proinsulin

insulin
Insulin Synthesis
Insulin Synthesis

• Insulin synthesis is stimulated by glucose or

feeding and decreased by fasting
• Threshold of glucose-stimulated insulin secretion
is 100 mg/dl.
• Glucose rapidly increase the translation of the
insulin mRNA and slowly increases transcription
of the insulin gene
Glucose is the primary stimulator of insulin
secretion
Regulation of Insulin Secretion
Pancreas and Glucose Homeostasis
Regulation of Insulin Secretion

• No insulin is produced when plasma glucose

below 50 mg/dl
• Half-maximal insulin response occurs at 150 mg/
dl
• A maximum insulin response occurs at 300 mg/dl
• Insulin secretion is biphasic:
• Upon glucose stimulation– an initial burst of
secretion (5-15 min.)
• Then a second phase of gradual increment that
lasts as long as blood glucose is high
Insulin secretion is biphasic and MOA OF
INSULIN.
Insulin Action: Visual Aid

Recall: insulin
is
anabolic
Glucose Transport

• GLUT2 (liver, pancreas .Bidirectional.)

• GLUT4, insulin sensitive transporter (muscle,
adipose tissue. Unidirectional)
• GLUT3 (brain)
Insulin Mechanism

Insulin – Receptor Complex

↓
p- IRS
↓ ↓
PI-3 kinase G-Ras

Akt/PK -B
MAPK
↓
Gene Expression
Principle Actions of Insulin

A. Rapid action – increase trans port glucose,

A.A,K+ Into Insulin sensitive cells. B.
Intermediate Effect- 1.Stimulation of protein
synthesis and inhibition of protein
degradation. 2.Activation of glycolytic enzymes
and gluconeogenic enzymes C.
Delays Effect – Increase in mRNA for lipogenic
enzymes and other enzymes
Tyrosine kinase receptors are a family of receptors with a similar
structure. They each have a tyrosine kinase domain (which
phosphorylates proteins on tyrosine residues), a hormone binding domain,
and a carboxyl terminal segment with multiple tyrosines for
autophosphorylation. When hormone binds to the extra cellular domain
the receptors aggregate.
When the receptors aggregate, the tyrosine kinase domains
phosphorylate the C terminal tyrosine residues.
This phosphorylation produces binding sites for proteins with
SH2 domains. GRB2 is one of these proteins. GRB2, with SOS
bound to it, then binds to the receptor complex. This causes
the activation of SOS.
Activated ras then causes the activation of a cellular kinase
called raf-1.
Raf-1 kinase then phosphorylates another cellular kinase
called MEK. This cause the activation of MEK.
Activated MEK then phosphorylates another protein kinase called MAPK
causing its activation. This series of phosphylating activations is called a
kinase cascade. It results in amplification of the signal.
 Adapted from: Dr. Donald F. Slish,
Biological Sciences Department,
Plattsburgh State University, Plattsburgh,
NY.

Among the final targets of the kinase cascade are transcriptions factors (fos and
jun showed here). Phosphorylation of these proteins causes them to become active
and bind to the DNA, causing changes in gene transcription.
 Adapted from: Dr. Donald F. Slish,
Biological Sciences Department,
Plattsburgh State University, Plattsburgh,
NY.

Among the final targets of the kinase cascade are transcriptions factors (fos and
jun showed here). Phosphorylation of these proteins causes them to become active
and bind to the DNA, causing changes in gene transcription.
Insulin Action on Cells:

• Insulin is the hormone of abundance.

• The major targets for insulin are:
• liver
• Skeletal muscle
• adipose tissue
• The net result is fuel storage
Insulin Action on Carbohydrate
Metabolism:
Liver:
• Stimulates glucose oxidation
• Promotes glucose storage as glycogen
• Inhibits glycogenolysis
• Inhibits gluconeogenesis

Muscle:
• Stimulates glucose uptake (GLUT4)
• Promotes glucose storage as glycogen
Insulin Action on Carbohydrate
Metabolism :

Adipose Tissue:
• Stimulates glucose transport into adipocytes
• Promotes the conversion of glucose into
triglycerides and fatty acids
Glycogen Synthesis

• Short term storage of glucose

• Activates glycogen synthase
• Inhibit glycogen phosphorylase
• Glycolysis is also stimulated by insulin
Protein Synthesis and Degradation

• Insulin promotes protein accumulation:

1. Stimulates amino acid uptake
2. Increases the activity of protein synthesis
3. Inhibits protein degradation
Action of insulin on Liver:
Action of insulin on Muscle:
Action of insulin on Fat:
Lipogenic and antilipolytic in ADIPOSE
TISSUE

• Insulin promotes lipogenesis and inhibits

lipolysis
• Promotes formation of α-glycerol phosphate
and fatty acid synthesis
• Stimulates fatty acid synthase (FAS)
• Inhibits hormone sensitive lipase (HSL)
• Activates lipoprotein lipase (LPL)
Insulin action (summary):

Dominates in Fed State

Metabolism

• ↑ glucose uptake in most cells

• ↑ glucose use & storage
• ↑ protein synthesis
• ↑ fat synthesis
Insulin: Summary
Glucagon

• A 29-amino-acid polypeptide hormone that is a

potent hyperglycemic agent
• Produced by α cells in the pancreas
• Its major target is the liver, where it promotes:
• Glycogenolysis – the breakdown of glycogen
to glucose
• Gluconeogenesis – synthesis of glucose from
lactic acid and noncarbohydrates
• Release of glucose to the blood from liver cells
SYNTHESIS

DNA in α cells

mRNA

Preproglucagon

proglucagon

glucagon
 Glucagon
Mechanism of action

The action of
glucagon is mediated
by the activation of
adenylate cyclase
cAMP activates
cascade of enzyme
reactions.
Glucago
n
Signalin
g
Glucagon Regulation

• Glucagon secretion is stimulated by:

Low blood glucose
Amino acid ingestion
Epinephrine
• Glucagon secretion is inhibited by:
High blood glucose
Insulin
Glucagon: Principle Actions

• Increases blood glucose

Triggers glycogen breakdown in liver (glycogenolysis)
Activates glucose production pathways (gluconeogenesis)
• Elicits breakdown of stored lipids (lipolysis)
Glycerol used in gluconeogenesis
Free fatty acids can be made into ketone bodies
• Amino acid metabolism
Taken up by liver; used in gluconeogenesis
• Theme: glucagon engages energy reserves
 Control of
Glucagon
secretion and Adipose
↑
Effect Triglyceride
breakdown
↑ Fatty
acids
Exercis ↓ Triglyceride storage
e
Amino
acids
Pancre
as Liver
Alpha ↑ Glycogen
breakdown ↑ Blood
cellsEpinephri
↑ Glucose synthesis glucose
ne
↑ Glucose release
(stress)

Brain
No
effect

Feedbac
k
Glucagon
- Polypeptide hormone secreted by α-cells of
the pancreatic cells
- (29a.a of 1 chain)
- Glucagon, epinephrine, cortisol, growth
hormone have opposite action of insulin.
- α-cells respond to many stimuli that signal
of hypoglycemia
* Glucagon secretion increased by:
1) Low glucose level is the primary stimulus
for glucagon release.
2) a.a stimulate both insulin and glucagon
Glucagon prevents hypoglycemia that
occurs after a protein meal.
3) Epinephrin: released from adrenal
medulla increases the release of glucagon
regardless the concentration of glucose in
the blood.
Factors Affecting Glucagon Secretion:
Glucoregulatory systems
- humans have two overlapping glucose-regulating systems that activated by
hypoglycemia.
A) The islets of langerhans that release glucagon.
B) receptors in hypothalamus that respond to low glucose level.
hypothalamic glucoreceptors activate the release of ACTH and GH.

Glucagon, epinephrine, cortisol and GH have opposite action of insulin.

*Glucagon and epinephrine: hypoglycemia is combated by decrease release of
insulin and increase secretion of glucagon, epinephrine, cortisol and GH.
- glucagon and epinephrine are important in short term regulation of blood-
glucose level
Glucagon: Increases the hepatic glycogenolysis and increases gluconeogensis.
Epinephrine: Increases glycogenolysis, increases lipolysis, decreases Insulin
secretion decreases the uptake of glucose by peripheral cells.
*Cortisol and growth hormone
- play a role in long term management of glucose metabolism.
Glucagon Action on Cells:
Insulin & Glucagon Regulate Metabolism
The Regulation of Blood Glucose
Concentrations
Feed/Fast Cycle Summarized

The key is that insulin and

glucagon
work in tandem to maintain
blood
glucose levels in response to
food
intake, or lack thereof.
Different forms of diabetes
mellitus
 Diabetes Mellitus (DM)

• A serious disorder of carbohydrate metabolism

• Results from hyposecretion or hypoactivity of
insulin
• The three cardinal signs of DM are:
• Polyuria – huge urine output
• Polydipsia – excessive thirst
• Polyphagia – excessive hunger and food
consumption
Diabetes Mellitus Type I

• Type 1: beta cells destroyed- no insulin

produced→
produced →chronic fasted state, "melting flesh",
ketosis, acidosis, glucosurea, diuresis & coma
Diabetes Mellitus: Type II a Group of
Diseases

• Over 15 million diabetics in USA- 10% type I,

90% type II
• More common is some ethnic groups
• Insulin resistance keeps blood glucose too
high
• Chronic complications: atherosclerosis,
renal failure& blindness
Diabetes Mellitus: Type II a Group of
Diseases
GTT
Symptoms of Diabetes Mellitus
Diabetes Mellitus (DM)
Pancreas and Glucose Homeostasis

• Glucose regulation works in a system of

organs