ENDOCRINE PANCREAS

Kristienne O. Apostol, M.D.

Physiologic Anatomy of the
Pancreas
EXOcrine


organized into acini

produce digestive
enzymes secreted
into duodenum
 Peptidases
 Lipases
 Amylases
 Nucleases
Physiologic Anatomy of the
Pancreas
ENDOcrine


Organized into Islets

of Langerhans
Produce hormones
secreted into the
hepatic portal
vein
 Insulin
 Glucagon
 Somatostatin
 Pancreatic polypeptide

Physiologic Anatomy of the
Endocrine Pancreas
Form about 2% of the pancreas
Comprised of 1-2 million Islets
More plentiful in the tail than in
the body and head
Physiologic Anatomy of the
Endocrine Pancreas
Types of cells in the


Islets:
1.Alpha cells (A cells) ISLET: a functional


 25% ; glucagon-secreting syncytium

2.Beta cells (B cells)  Alpha, beta and
 60% ; insulin-secreting delta cells form
3.Delta cells (D cells) a paracrine
 10% ; somatostatin-
control system
secreting 

4.Pancreatic polypeptide
cells (PP or F cells)
 5%

INSULIN
Product of Beta cells

FUNCTION of Insulin
Coordinates use of fuels by tissues by
favoring ANAbolism
ANA
Promotes storage when metabolic
fuels are in abundance (“hormone of
energy storage”)
synthesis of glycogen, TAG and
protein when carbohydrates,
fatty acids and amino acids are in
excess
Most important regulator of glucose
homeostasis
Insulin BIOSYNTHESIS
Stimulated by plasma glucose
>3.9mmol/L (70mg/dL)
Enhance protein translation and
processing
Also stimulated by amino acids (esp.
arginine)
 Insulin BIOSYNTHESIS
C-peptide:
connecting
peptide that
remains after
cleavage of
proinsulin to
insulin
 Essential to
proper insulin
folding
 Produced in
amounts
equimolar to
insulin
 Longer plasma
half-life than
Insulin BIOSYNTHESIS
Insulin SECRETION
 Primary stimuli
Carbohydrates
Amino acids
Fatty acids and Keto acids


 Secondary stimuli
Gastrointestinal hormones
Parasympathetic stimulation
Glucagon

Stimulation of Insulin Secretion by...
Carbohydrates
monosaccharides that can be metabolized
(e.g. hexose, triose) are more potent
stimuli than those that cannot (e.g.
mannose)

PRINCIPAL STIMULUS: GLUCOSE
 Stimulation of Insulin Secretion by...
Carbohydrates

o n - in su lin d e p e n d e n t R a te - lim itin g ste p

Stimulation of Insulin Secretion by...
Carbohydrates
Action of GLUCOSE on insulin
secretion is biphasic
Initial response: release of
preformed insulin
Prolonged response: release of
newly synthesized insulin
Stimulation of Insulin Secretion by...
Amino, Fatty and Keto Acids
Amino acids

A lso g e n e ra te AT P
 Arginine w h e n m e ta b o lize d
 lysine A T P clo se s A T P -
 Leucine ... se n sitive K +
Fatty acids
 ch a n n e ls ... 
 Short- and long- insulin
exocy tosis
chain
S tro n g ly p o te n tia te
Keto acids


 Acetoacetate
g lu co se stim u lu s
 3-
hydroxybutyrat
e
Stimulation of Insulin Secretion by...
Gastrointestinal Hormones
Gastrin R e le a se d a fte r a
Secretin p e rso n e a ts a m e a l
C a u se “ a n ticip a to ry ”
CCK
in cre a se in in su lin
Gastric In cre a se C a 2+ influx
inhibitory through voltage-gated
peptide Ca2+ channels
Also strongly
potentiate glucose and
amino acid stimulus
Stimulation of Insulin Secretion by...
Parasympathetics
Islets are innervated by branches
of the right vagus nerve
Causes insulin release only when
glucose levels are elevated
Stimulation of Insulin Secretion by...
Parasympathetics
PIP2

ACh +
+ PLC
M4
receptor
Ca2+ from DAG
endoplasmic IP 3
reticulum into
cytoplasm Insulin
exocytosis
Stimulation of Insulin Secretion by...
Glucagon
ATP

Glucagon Adenylyl
+ + cyclase
receptor

Increase . . .
cAMP
intracellular
Ca2+
Insulin
exocytosis
Insulin DEGRADATION
Insulin half-life: 5-6 minutes
Allows for rapid changes in its
circulating levels and effects
Degraded by insulinase
50% in liver before entering
systemic circulation
Insulin SECRETORY PROFILE
Pulsatile release of insulin
Small secretory outbursts every 10
mins
Greater amplitude oscillations every 80-
150 mins
Major stimuli of insulin secretion (meal
intake) induce large bursts of insulin
secretion
Rapid four to five-fold increase (2-3 mins)
Followed by decrease halfway down (5-
10 mins)
then a greater continuing increase (2-3
Insulin SECRETION
Inhibitors


Starvation (hypoglycemia)
Sympathetic stimulation
Stress, trauma
Exercise
Largely overrides the influence of the
plasma glucose concentration in
emergency situations
somatostatin
 Inhibition of Insulin Secretion by...
Sympathetics
α2 adrenergic
 β2 adrenergic
Inhibits adenylyl Activates adenylyl
cyclase ... cyclase ...
INHIBITS insulin STIMULATES insulin
secretion secretion

N E T E F F E C T : inhibitionof insulinsecretion
Insulin MECHANISM
OF ACTION

Mechanism #1

Mechanism #2

Mechanism #3
EFFECTS of Insulin on...
CARBOHYDRATE METABOLISM
Promotes storage and use of glucose in
especially in the liver, adipose tissue and
muscles
Liver


Increase In cre a se g lyco lysis

glycogenesis In cre a se a m o u n t o f
 Activate of glycogen g lu co kin a se ,
synthase p h o sp h o fru cto kin a se
, pyruvate kinase
Decrease
D e cre a se
glycogenolysis
 Inactivate glycogen g lu co n e o g e n e sis
phosphorylase in d ire ctly

EFFECTS of Insulin on...
CARBOHYDRATE METABOLISM
Muscles
  Adipose Tissue
Increase glycogenesis Increase glycolysis
Decrease INCREASE GLUCOSE
glycogenolysis UPTAKE
Increase glycolysis
INCREASE GLUCOSE
UPTAKE
 EFFECTS of Insulin on...
CARBOHYDRATE METABOLISM

Muscles &


Adipose Tissue

Increase glucose
uptake
on glucose uptake and
insulin ...
Main insulin-DEpendent glucose transporter:
GLUT4
Adipose tissue, skeletal and cardiac muscles
Major insulin-INdependent tissues:
Nerve cells, RBCs, liver, epithelial cells of
the kidney and intestine, cornea, lens of the
eyes

Physiologic
significance?
Clinical
significance?
EFFECTS of Insulin on...
FAT METABOLISM
Promotes fat synthesis and storage in the
liver and adipose tissue

Liver
Increase fatty acid synthesis
Activate acetyl CoA carboxylase
Increase TAG synthesis
Increase glycerol precursor (glucose)
Increase fatty acids substrates by increasing
amount of lipoprotein lipase

EFFECTS of Insulin on...
FAT METABOLISM
 Adipose Tissue
Increase fatty acid synthesis
Increase TAG synthesis
DECREASE LIPOLYSIS
Inactivate hormone-sensitive lipase

EFFECTS of Insulin on...
PROTEIN METABOLISM
Promotes protein synthesis and
storage
S tim u la te tra n sp o rt o f a m in o a cid s in to
ce lls
In cre a se m R N A tra n sla tio n
In cre a se ra te o f D N A tra n scrip tio n
In h ib it p ro te o lysis
In cre a se a m in o a cid su b stra te s b y
su p p re ssin g g lu co n e o g e n e sis
Other Insulin EFFECTS

On POTASSIUM BALANCE


Stimulates movement of extracellular K+

into insulin-sensitive cell (muscle and
hepatic tissue)
Stimulate Na+-K+ ATPase pump
EFFECTS of Insulin
Rapid (seconds)
 Increased transport of glucose, amino acids,
and K+ into insulin-sensitive cells
Intermediate (minutes)
 Increase protein synthesis
 Decrease protein degradation
 Increase glycolysis and glycogenesis
 Decrease of glycogenolysis
Long-term effects
 Promotion of cell growth
GLUCAGON
Product of Alpha cells

FUNCTION of Glucagon
Coordinates use of fuels by tissues by
favoring CATAbolism
CATA
Mobilizes energy stores (“hormone of
energy release”)
Opposes many of the actions of
insulin
Glucagon SECRETION
Stimuli


Starvation (hypoglycemia)
Amino acids
Gastrointestinal hormones (CCK,
gastrin)
Cortisol
Sympathetic stimulation
 Stimulation of Glucagon Secretion by...
Sympathetics
α2 adrenergic
 β2 adrenergic


Inhibits adenylyl Activates adenylyl

cyclase ... cyclase ...
INHIBITS glucagon STIMULATES
secretion glucagon secretion

E T E F F E C T : stimulation of glucagon secretio

Stimulation of Glucagon Secretion by...
Sympathetics
secreted with...
Stress, trauma
Exercise
Largely overrides the influence of the
plasma glucose concentration in
emergency situations
Glucagon SECRETION
Inhibitors


Glucose
Free fatty acids, keto acids
Insulin
Somatostatin
 Glucagon
MECHANISM OF
ACTION

Mechanism #1
- direct de- or activation of enzymes by phospho

Mechanism #2
- alter gene expression
EFFECTS of Glucagon on...
CARBOHYDRATE METABOLISM
Promotes mobilization of carbohydrate stores in
the liver
MAJOR EFFECT
Liver


Decrease D e cre a se g lyco lysis

glycogenesis In a ctiva te a n d
 Inactivate of d e cre a se a m o u n t o f
glycogen g lu co kin a se ,
synthase p h o sp h o fru cto kin a se ,
p yru va te kin a se
Increase
In cre a se
glycogenolysis
 Activate glycogen g lu co n e o g e n e sis
phosphorylase A ctiva te fru cto se 1 , 6 -
b isp h o sp h a ta se a n d
Other Glucagon EFFECTS
On FAT METABOLISM...


Decrease fatty acid synthesis

 Inactivate acetyl CoA carboxylase
Increase lipolysis (TAG degradation)
 Activate hormone-sensitive lipase in
adipocytes
Increase ketogenesis indirectly
 Increased fatty acids from increased lipolysis
overwhelm oxidative capacity of the liver
 INSULIN and GLUCAGON:
Major Regulators of Fuel
Metabolism
Major controlling factor: plasma glucose


concentration

Pre fe rs FAT Prefers

for energy CARBOHYDRATES
for energy
Somatostatin
Product of Delta cells

Somatostatin
SECRETION:
SECRETION practically stimulated by
all related to food ingestion
blood glucose
amino acids
fatty acids
several GI hormones
Somatostatin
EFFECTS:
EFFECTS inhibitory
Depress secretion of insulin, glucagon*
and even PP
Decrease motility of the stomach,
duodenum and gallbladder
Decrease digestive enzyme secretion
and absorption in the GIT
FUNCTION:
FUNCTION Extend the period of time over
which food nutrients are assimilated into
the blood
Prevent rapid exhaustion of food

Pancreatic Polypeptide
Product of PP cells

Pancreatic Polypeptide
SECRETION:
Stimulated by cholinergics, fasting,
exercise and acute hypoglycemia
Inhibited by somatostatin and glucose
EFFECTS:
EFFECTS
Inhibit secretion of insulin and
somatostatin
Inhibits trypsinogen and bicarbonate
secretion (affects exocrine pancreas)
FUNCTION:
FUNCTION
Slow down digestive process
Islet as a functional
syncytium ...
Other Hormones affecting
Fuel Metabolism
The Counterregulatory Hormones

Two systems activated by
hypoglycemia:
1.Islets of Langerhans
2.Hypothalamically-mediated system
 Activate sympathetic nervous

system
 Release ACTH and growth

hormone by the anterior

pituitary
The Counterregulatory
Hormones
1.Glucagon
2.Catecholamines
3.Cortisol
4.Growth
hormone
Counter the effects of insulin on
glucose use
The Counterregulatory Hormones
CATECHOLAMINES
To g e th e r w ith g lu ca g o n , co m p rise th e
m o st im p o rta n t a cu te sh o rt-te rm
g lu co re g u la to ry m e ch a n ism s

 EFFECTS:
Promotes mobilization of stored carbohydrates
Suppresses mobilization of stored fats
Inhibits insulin secretion
Decrease insulin-dependent peripheral
glucose utilization
The Counterregulatory Hormones
CORTISOL
P la y a ro le in lo n g - te rm re g u la tio n o f
g lu co se m e ta b o lism
A lte rs g e n e e xp re ssio n

EFFECTS:


Promotes gluconeogenesis
 Promotes mobilization of amino acids
Promotes mobilization of stored fats
Promote fat utilization
 Decrease insulin-dependent peripheral glucose
utilization
The Counterregulatory Hormones
GROWTH HORMONE
Play a role in long-term regulation
of glucose metabolism
Alter gene expression

EFFECTS :
Promote fat utilization
Decrease peripheral glucose
utilization
MENTAL EXERCISE
 Diabetes Mellitus
Diabetes Mellitus

PATHOLOGY
Absolute or relative
insulin deficiency
coupled with some
glucagon excess

Protein Carbohydrate Fat

metabolism? metabolism? metabolism?
END.