Lect V Hormonal Regulation of Metabolism

The Endocrine Pancreas
Regulation of Carbohydrate
Metabolism
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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 (role in
potassium homeostasis).
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 beta-adrenergic
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.
Hormonal Regulation of 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). Insert fig. 19.2
 Circulating
substrates:
 Molecules absorbed
through small
intestine and carried
to the cell for use in
cell respiration.
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:
 a cells:
 Secrete glucagon.
 b cells:
 Secrete insulin.
 D 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 65–105
mg/dl.

Glucagon (continued)
 When blood [glucose] increases:

 Glucose binds to GLUT2 receptor protein in
b 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 b
cells to secrete
insulin. Insert fig. 19.8
 Ability of insulin
to lower blood
glucose.
 Normal person’s
rise in blood
[glucose] after
drinking solution
is reversed to
normal in 2 hrs.

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

Glucagon Secretion (continued)
 Glucose homeostasis – Putting it all together

Body
cells
Insulin take up more
glucose
Beta cells
of pancreas stimulated
to release insulin into
the blood Liver takes Blood glucose level
up glucose declines to a set point;
High blood and stores it as stimulus for insulin
glucose level glycogen release diminishes
STIMULUS:
Rising blood glucose
level (e.g., after eating
a carbohydrate-rich
meal) Homeostasis: Normal blood glucose level
(about 90 mg/100 mL) STIMULUS:
Declining blood
glucose level
(e.g., after
skipping a meal)
Blood glucose level

rises to set point; Alpha
stimulus for glucagon cells of
release diminishes pancreas stimulated
to release glucagon
into the blood
Liver
breaks down
glycogen and Glucagon
releases glucose
Figure 26.8 to the blood
Hormonal Regulation of
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

 b 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
b 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 Insert fig. 19.12
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].
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
Insert fig. 19.13
response to a
rise in blood
glucose.
 Occurs in people
who are
genetically
predisposed to
type II diabetes.
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.

Lect V Hormonal Regulation of Metabolism

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Lect V Hormonal Regulation of Metabolism

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The Endocrine Pancreas

 Gland with both exocrine and endocrine

 Includes uncinate process

 Elongated, long structure

 Main duct (Wirsung) runs the entire length of

Arterial Supply of Pancreas

 Variety of major arterial sources (celiac, SMA

Arterial Supply of Pancreas

 Anterior collateral arcade between

Pancreatic Arterial Supply

Venous Drainage of Pancreas

Venous Drainage of the Pancreas

 Rich periacinar network that drain into 5

 Sympathetic fibers from the splanchnic nerves

 Peptidergic neurons that secrete amines

Pancreatic Hormones, Insulin and Glucagon,

Production of Pancreatic Hormones

Islet of Langerhans Cross-section

 Three cell types are

Pancreatic Hormones, Insulin and Glucagon,

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

The Insulin Receptor

Specific Targets of Insulin

Increased activity of glucose transporters.

Activation of glycogen synthetase. Converts

Specific Targets of Insulin

Regulation of Insulin Release

Insulin Action on Cells:

  glucose uptake in most cells

Dominates in Fed State Metabolism

Insulin: Summary and Control Reflex

Other Factors Regulating Insulin

Structure and Actions of

 Main target tissues: liver, muscle, and adipose

Glucagon Action on Cells:

 Glucagon prevents hypoglycemia by  cell

Glucagon Action on Cells: Dominates in Fasting

Targets of Glucagon Action

Regulation of Glucagon Release

 Increased blood glucose levels inhibit glucagon

Other Factors Regulating

Hormonal Regulation of Nutrients

Hormonal Regulation of Nutrients

Pancreatic Islets (Islets of

Energy Regulation of Pancreas

 Islets of Langerhans contain 3 distinct

Regulation of Insulin and

Regulation of Insulin and

 When blood [glucose] increases:

Oral Glucose Tolerance Test

Regulation of Insulin and

Regulation of Insulin and

 Glucose homeostasis – Putting it all together

Blood glucose level

Effect of Feeding and Fasting on

Insert fig. 19.10

 Chronic high blood [glucose].

Comparison of Type I and Type

Insert table 19.6

Type I Diabetes Mellitus

Consequences of Uncorrected Deficiency

Insert fig. 19.11

Type II Diabetes Mellitus