The Endocrine Pancreas: Regulation of Carbohydrate Metabolism

The Endocrine Pancreas
Regulation of Carbohydrate
Metabolism
Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Pancreatic Anatomy
Gland with both exocrine and endocrine

functions
15-25 cm long
60-100 g
Location: retro-peritoneum, 2nd lumbar
vertebral level
Extends in an oblique, transverse position
Parts of pancreas: head, neck, body and
tail
Pancreas
Head of Pancreas
Includes uncinate process

Flattened structure, 2 3 cm thick
Attached to the 2nd and 3rd portions of
duodenum on the right
Emerges into neck on the left
Border b/w head and neck is determined
by GDA insertion
SPDA and IPDA anastamose between the
duodenum and the right lateral border
Neck of Pancreas
2.5 cm in length
Straddles SMV and PV
Antero-superior surface supports the
pylorus
Superior mesenteric vessels emerge from
the inferior border
Posteriorly, SMV and splenic vein
confluence to form portal vein
Posteriorly, mostly no branches to pancreas
Body of Pancreas
Elongated, long structure

Anterior surface, separated from stomach
by lesser sac
Posterior surface, related to aorta, lt.
adrenal gland, lt. renal vessels and upper
1/3rd of lt. kidney
Splenic vein runs embedded in the post.
Surface
Inferior surface is covered by transverse
mesocolon
Tail of Pancreas
Narrow, short segment

Lies at the level of the 12th thoracic
vertebra
Ends within the splenic hilum
Lies in the splenophrenic ligament
Anteriorly, related to splenic flexure of
colon
May be injured during splenectomy (fistula)
Pancreatic Duct
Main duct (Wirsung) runs the entire length of

pancreas
Joins CBD at the ampulla of Vater
2 4 mm in diameter, 20 secondary branches
Ductal pressure is 15 30 mm Hg (vs. 7 17
in CBD) thus preventing damage to panc.
duct
Lesser duct (Santorini) drains superior portion
of head and empties separately into 2nd
portion of duodenum
Arterial Supply of Pancreas
Variety of major arterial sources (celiac,

SMA and splenic)
Celiac Common Hepatic Artery
Gastroduodenal Artery Superior
pancreaticoduodenal artery which
divides into anterior and posterior
branches
SMA Inferior pancreaticoduodenal
artery which divides into anterior and
posterior branches
Arterial Supply of Pancreas
Anterior collateral arcade between

anterosuperior and anteroinferior PDA
Posterior collateral arcade between
posterosuperior and posteroinferior PDA
Body and tail supplied by splenic artery by
about 10 branches
Three biggest branches are
Dorsal pancreatic artery

Pancreatica Magna (midportion of body)
Caudal pancreatic artery (tail)
Pancreatic Arterial Supply
Venous Drainage of
Pancreas
Follows arterial supply

Anterior and posterior arcades drain
head and the body
Splenic vein drains the body and tail
Major drainage areas are
Suprapancreatic PV
Retropancreatic PV
Splenic vein
Infrapancreatic SMV
Ultimately, into portal vein
Venous Drainage of the Pancreas
Lymphatic Drainage
Rich periacinar network that drain

into 5 nodal groups
Superior nodes
Anterior nodes
Inferior nodes
Posterior PD nodes
Splenic nodes
Innervation of Pancreas
Sympathetic fibers from the splanchnic

nerves
Parasympathetic fibers from the vagus
Both give rise to intrapancreatic
periacinar plexuses
Parasympathetic fibers stimulate both
exocrine and endocrine secretion
Sympathetic fibers have a predominantly
inhibitory effect
Innervation of Pancreas
Peptidergic neurons that secrete

amines and peptides (somatostatin,
vasoactive intestinal peptide, calcitonin
gene-related peptide, and galanin
Rich afferent sensory fiber network
Ganglionectomy or celiac ganglion
blockade interrupt these somatic fibers
(pancreatic pain)
Pancreatic Hormones, Insulin and

Glucagon, Regulate Metabolism
Production of Pancreatic
Hormones by Three Cell Types
Alpha cells produce glucagon.

Beta cells produce insulin.
Delta cells produce somatostatin.
Islet of Langerhans Cross-section
Three cell types are

present, A (glucagon
secretion), B (Insulin
secretion) and D
(Somatostatin secretion)
A and D cells are located
around the perimeter
while B cells are located
in the interior
Venous return
containing insulin flows
by the A cells on its way
out of the islets
Pancreatic Hormones, Insulin and

Glucagon, Regulate Metabolism
Figure 22-8: Metabolism is controlled by insulin and glucagon
Structure of Insulin
Insulin is a polypeptide hormone,

composed of two chains (A and B)
BOTH chains are derived from
proinsulin, a prohormone.
The two chains are joined by disulfide
bonds.
Roles of Insulin
Acts on tissues (especially liver, skeletal

muscle, adipose) to increase uptake of
glucose and amino acids.
- without insulin, most tissues do not
take in glucose and amino acids well
(except brain).
Increases glycogen production (glucose

storage) in the liver and muscle.
Stimulates lipid synthesis from free fatty

acids and triglycerides in adipose tissue.
Also stimulates potassium uptake by cells
The Insulin Receptor
The insulin receptor is composed of two

subunits, and has intrinsic tyrosine kinase
activity.
Activation of the receptor results in a cascade of
phosphorylation events:
phosphorylation of
insulin responsive
substrates (IRS)
RAS
RAF-1
MAP-K
MAP-KK
Final
actions
Specific Targets of Insulin

Action: Carbohydrates
Increased activity of glucose transporters.
Moves glucose into cells.
Activation of glycogen synthetase.
Converts glucose to glycogen.
Inhibition of phosphoenolpyruvate
carboxykinase. Inhibits
gluconeogenesis.
Specific Targets of Insulin

Action: Lipids
Activation of acetyl CoA carboxylase.

Stimulates production of free fatty acids
from acetyl CoA.
Activation of lipoprotein lipase (increases
breakdown of triacylglycerol in the
circulation). Fatty acids are then taken
up by adipocytes, and triacylglycerol is
made and stored in the cell.
lipoprotein
lipase
Regulation of Insulin Release
Major stimulus: increased blood glucose

levels
- after a meal, blood glucose increases
- in response to increased glucose,
insulin is released
- insulin causes uptake of glucose into
tissues, so blood glucose levels decrease.
- insulin levels decline as blood glucose
declines
Insulin Action on Cells:

Dominates in Fed State Metabolism
glucose uptake in most cells

(not active muscle)
glucose use and storage
protein synthesis
fat synthesis
Insulin Action on Cells:

Dominates in Fed State Metabolism
Insulin: Summary and Control Reflex

Loop
Other Factors Regulating

Insulin Release
Amino acids stimulate insulin release (increased

uptake into cells, increased protein synthesis).
Keto acids stimulate insulin release (increased
glucose uptake to prevent lipid and protein
utilization).
Insulin release is inhibited by stress-induced increase
in adrenal epinephrine
- epinephrine binds to alpha adrenergic receptors on
beta cells
- maintains blood glucose levels
Glucagon stimulates insulin secretion (glucagon has
opposite actions).
Structure and Actions of

Glucagon
Peptide hormone, 29 amino acids

Acts on the liver to cause breakdown of
glycogen (glycogenolysis), releasing glucose
into the bloodstream.
Inhibits glycolysis
Increases production of glucose from amino
acids (gluconeogenesis).
Also increases lipolysis, to free fatty acids for
metabolism.
Result: maintenance of blood glucose levels
during fasting.
Mechanism of Action of
Glucagon
Main target tissues: liver, muscle, and

adipose tissue
Binds to a Gs-coupled receptor, resulting
in increased cyclic AMP and increased
PKA activity.
Also activates IP3 pathway (increasing
Ca++)
Glucagon Action on Cells:

Dominates in Fasting State
Metabolism
Glucagon prevents hypoglycemia by cell

production of glucose
Liver is primary target to maintain blood
glucose levels
Glucagon Action on Cells: Dominates in

Fasting State Metabolism
Targets of Glucagon Action
Activates a phosphorylase, which cleaves off a

glucose 1-phosphate molecule off of glycogen.
Inactivates glycogen synthase by
phosphorylation (less glycogen synthesis).
Increases phosphoenolpyruvate carboxykinase,
stimulating gluconeogenesis
Activates lipases, breaking down triglycerides.
Inhibits acetyl CoA carboxylase, decreasing free
fatty acid formation from acetyl CoA
Result: more production of glucose and
substrates for metabolism
Regulation of Glucagon
Release
Increased blood glucose levels inhibit

glucagon release.
Amino acids stimulate glucagon release
(high protein, low carbohydrate meal).
Stress: epinephrine acts on betaadrenergic receptors on alpha cells,
increasing glucagon release (increases
availability of glucose for energy).
Insulin inhibits glucagon secretion.
Other Factors Regulating

Glucose Homeostasis
Glucocorticoids (cortisol): stimulate

gluconeogenesis and lipolysis, and
increase breakdown of proteins.
Epinephrine/norepinephrine: stimulates
glycogenolysis and lipolysis.
Growth hormone: stimulates
glycogenolysis and lipolysis.
Note that these factors would
complement the effects of glucagon,
increasing blood glucose levels.
Hormonal Regulation of
Nutrients
Right after a meal (resting):

- blood glucose elevated
- glucagon, cortisol, GH, epinephrine low
- insulin increases (due to increased glucose)
- Cells uptake glucose, amino acids.
- Glucose converted to glycogen, amino acids
into protein, lipids stored as triacylglycerol.
- Blood glucose maintained at moderate levels.
Nutrients
A few hours after a meal (active):

- blood glucose levels decrease
- insulin secretion decreases
- increased secretion of glucagon, cortisol, GH,
epinephrine
- glucose is released from glycogen stores
(glycogenolysis)
- increased lipolysis (beta oxidation)
- glucose production from amino acids
increases (oxidative deamination;
gluconeogenesis)
- decreased uptake of glucose by tissues
- blood glucose levels maintained
Turnover Rate
Rate at which a molecule is broken down and

resynthesized.
Average daily turnover for carbohydrates is 250
g/day.
Some glucose is reused to form glycogen.
Only need about 150 g/day.
Average daily turnover for protein is 150 g/day.
Some protein may be reused for protein synthesis.
Only need 35 g/day.
9 essential amino acids.
Average daily turnover for fats is 100 g/day.
Little is actually required in the diet.
Fat can be produced from excess carbohydrates.
Essential fatty acids:
Linoleic and linolenic acids.
Regulation of Energy
Metabolism
Energy reserves:
Molecules that
can be oxidized for
energy are derived
from storage
molecules
(glycogen, protein,
and fat).
Circulating
substrates:
Molecules absorbed
through small
intestine and
carried to the cell
for use in cell
respiration.
Insert fig. 19.2
Pancreatic Islets (Islets of

Langerhans)
Alpha cells secrete glucagon.
Stimulus is decrease in blood

[glucose].
Stimulates glycogenolysis
and lipolysis.
Stimulates conversion of
fatty acids to ketones.
Beta cells secrete insulin.
Stimulus is increase in blood

[glucose].
Promotes entry of glucose
into cells.
Converts glucose to
glycogen and fat.
Aids entry of amino acids
into cells.
Energy Regulation of
Pancreas
Islets of Langerhans contain 3 distinct

cell types:
cells
cells
Secreteglucagon.
Secreteinsulin.
cells
Secrete somatostatin.
Regulation of Insulin and

Glucagon
Mainly regulated by blood

[glucose].
Lesser effect: blood [amino acid].
Regulated by negative feedback.
Glucose enters the brain by

facilitated diffusion.
Normal fasting [glucose] is 65105
mg/dl.

Glucagon
(continued)
When blood [glucose] increases:
Glucose binds to GLUT2 receptor

protein in cells, stimulating the
production and release of insulin.
Insulin:
Stimulates skeletal muscle cells and

adipocytes to incorporate GLUT4
(glucose facilitated diffusion carrier)
into plasma membranes.
Promotes anabolism.
Oral Glucose Tolerance Test
Measurement
of the ability of
cells to
secrete insulin.
Ability of insulin
to lower blood
glucose.
Normal
persons rise in
blood [glucose]
after drinking
solution is
reversed to
normal in 2 hrs.
Insert fig. 19.8

Glucagon
Parasympathetic nervous system:
Sympathetic nervous system:
Stimulates insulin secretion.
GLP-1:
Stimulates glucagon secretion.
GIP:
CCK:

Glucagon Secretion
(continued)
Glucose homeostasis Putting it all

together
Insulin
Beta cells
of pancreas stimulated
to release insulin into
the blood
High blood
glucose level
STIMULUS:
Rising blood glucose
level (e.g., after eating
a carbohydrate-rich
meal)
Body
cells
take up more
glucose
Liver takes
up glucose
and stores it as
glycogen
Homeostasis: Normal blood glucose level

(about 90 mg/100 mL)
Blood glucose level

rises to set point;
stimulus for glucagon
release diminishes
Figure 26.8
Blood glucose level

declines to a set point;
stimulus for insulin
release diminishes
Liver
breaks down
glycogen and
releases glucose
to the blood
STIMULUS:
Declining blood
glucose level
(e.g., after
skipping a meal)
Alpha
cells of
pancreas stimulated
to release glucagon
into the blood
Glucagon
Metabolism
Absorptive state:
Absorption of energy.
4 hour period after eating.
Increase in insulin secretion.
Postabsorptive state:
Fasting state.
At least 4 hours after the meal.
Increase in glucagon secretion.
Absorptive State
Insulin is the major hormone that

promotes anabolism in the body.
When blood [insulin] increases:
Promotes cellular uptake of glucose.

Stimulates glycogen storage in the liver and
muscles.
Stimulates triglyceride storage in adipose
cells.
Promotes cellular uptake of amino acids and
synthesis of proteins.
Postabsorptive State
Maintains blood glucose

concentration.
When blood [glucagon] increased:
Stimulates glycogenolysis in the liver

(glucose-6-phosphatase).
Stimulates gluconeogenesis.
Skeletal muscle, heart, liver, and
kidneys use fatty acids as major source
of fuel (hormone-sensitive lipase).
Stimulates lipolysis and ketogenesis.
Effect of Feeding and Fasting

on Metabolism
Insert fig. 19.10
Diabetes Mellitus
Chronic high blood [glucose].

2 forms of diabetes mellitus:
Type I: insulin dependent diabetes

(IDDM).
Type II: non-insulin dependent
diabetes (NIDDM).
Comparison of Type I and

Type II Diabetes Mellitus
Insert table 19.6
Type I Diabetes Mellitus
cells of the islets of Langerhans are

destroyed by autoimmune attack which may
be provoked by environmental agent.
Killer T cells target glutamate decarboxylase in the

cells.
Glucose cannot enter the adipose cells.
Rate of fat synthesis lags behind the rate of

lipolysis.
Fatty acids converted to ketone bodies, producing

ketoacidosis.
Increased blood [glucagon].
Stimulates glycogenolysis in liver.
Consequences of Uncorrected
Deficiency in Type I Diabetes Mellitus
Insert fig. 19.11
Type II Diabetes Mellitus
Slow to develop.
Genetic factors are
significant.
Occurs most often in
people who are
overweight.
Decreased sensitivity
to insulin or an
insulin resistance.
Obesity.
Do not usually
develop ketoacidosis.
May have high blood
[insulin] or normal
[insulin].
Insert fig. 19.12
Treatment in Diabetes
Change in lifestyle:
Increase exercise:
Increases the amount of membrane GLUT-4

carriers in the skeletal muscle cells.
Weight reduction.
Increased fiber in diet.
Reduce saturated fat.
Hypoglycemia
Over secretion
of insulin.
Reactive
hypoglycemia:
Caused by an
exaggerated
response to a
rise in blood
glucose.
Occurs in
people who are
genetically
predisposed to
type II
diabetes.
Insert fig. 19.13
Metabolic Regulation
Anabolic effects of insulin are

antagonized by the hormones of
the adrenals, thyroid, and anterior
pituitary.
Insulin, T3, and GH can act

synergistically to stimulate protein
synthesis.

The Endocrine Pancreas: Regulation of Carbohydrate Metabolism

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The Endocrine Pancreas

Gland with both exocrine and endocrine

Includes uncinate process

Elongated, long structure

Narrow, short segment

Main duct (Wirsung) runs the entire length of

Arterial Supply of Pancreas

Variety of major arterial sources (celiac,

Arterial Supply of Pancreas

Anterior collateral arcade between

Dorsal pancreatic artery

Pancreatic Arterial Supply

Follows arterial supply

Ultimately, into portal vein

Venous Drainage of the Pancreas

Rich periacinar network that drain

Sympathetic fibers from the splanchnic

Peptidergic neurons that secrete

Pancreatic Hormones, Insulin and

Alpha cells produce glucagon.

Islet of Langerhans Cross-section

Three cell types are

Pancreatic Hormones, Insulin and

Figure 22-8: Metabolism is controlled by insulin and glucagon

Insulin is a polypeptide hormone,

Acts on tissues (especially liver, skeletal

Increases glycogen production (glucose

Stimulates lipid synthesis from free fatty

Also stimulates potassium uptake by cells

The Insulin Receptor

The insulin receptor is composed of two

Specific Targets of Insulin

Specific Targets of Insulin

Activation of acetyl CoA carboxylase.

Regulation of Insulin Release

Major stimulus: increased blood glucose

Insulin Action on Cells:

glucose uptake in most cells

Insulin Action on Cells:

Insulin: Summary and Control Reflex

Other Factors Regulating

Amino acids stimulate insulin release (increased

Structure and Actions of

Peptide hormone, 29 amino acids

Main target tissues: liver, muscle, and

Glucagon Action on Cells:

Glucagon prevents hypoglycemia by cell

Glucagon Action on Cells: Dominates in

Targets of Glucagon Action

Activates a phosphorylase, which cleaves off a

Increased blood glucose levels inhibit

Other Factors Regulating

Glucocorticoids (cortisol): stimulate

Right after a meal (resting):

A few hours after a meal (active):

Rate at which a molecule is broken down and

Some glucose is reused to form glycogen.

Only need about 150 g/day.

Average daily turnover for protein is 150 g/day.

Some protein may be reused for protein synthesis.

Only need 35 g/day.

9 essential amino acids.

Average daily turnover for fats is 100 g/day.