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1. Endocrine Physiology
Part-4
Assist. Prof. Dr. Muthanna I. Al-Ezzi
Ph.D. Physiology
M.Sc. Physiology
[email protected]
[email protected]
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2. The Endocrine Pancreas
Regulation of Carbohydrate
Metabolism

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Pancreas

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Pancreas as an Organ of
Internal Secretion
•The islet cells of the pancreas were
described by Langerhans in 1869.
•In 1889 Von Mering and
Minkowski demonstrated that the
removal of the pancreas in the
dog led to sugar appearing in the
urine, which is diabetes mellitus.

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•Early attempts to isolate insulin
were unsuccessful, because insulin
is a protein and is destroyed by the
trypsinogen present in the
pancreatic juice secreting cells.
•However, if the pancreatic duct is
tied, these cells degenerate and
then insulin can be extracted from
the gland.

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•Insulin has been synthesized. It is a
protein built up of 51 amino acid units
in two coupled chains. Chain A
contains 21 amino acid units and has a
molecular weight of 2,750. Chain B
contains 30 amino acid units and has a
molecular weight of 3,700.
•Insulin is produced by the β-cells of the
islet tissue. It is thought to be stored as
a zinc compound. Insulin facilitates the
entry of glucose into cells.

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•A deficiency leads to a high blood
sugar, fatigue and loss of weight.
•An excess leads to a low blood sugar,
irritability, sweating and a sensation
of hunger, and ultimately to coma
due to the low blood sugar.
•Insulin is the antidiabetic hormone
and is used to treat diabetes mellitus.

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•Being a protein it is inactive by
mouth and has to be given by
injection. It restores the ability to
use glucose and fats.
•The excessive breakdown of protein
ceases.
•The blood glucose level is lowered
as the glucose is converted to liver
and muscle glycogen and utilized as
a source of heat and energy.

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•The ketosis disappears as the
ketone bodies are metabolized
in the presence of the
carbohydrate metabolism.
•Glucose and ketone bodies
disappear from the urine.

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•The physiological importance of a
second hormone glucagon
produced by the α-cells of the islet
tissue has yet to be evaluated.
•It raises the blood glucose level
probably by mobilizing the liver
glycogen in much the same way
as does adrenaline.

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Pancreatic Hormones, Insulin and Glucagon,
Regulate Metabolism

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Production of Pancreatic Hormones by
Three Cell Types
Alpha cells produce glucagon.
Beta cells produce the hormones
insulin and amylin.
Delta cells produce the hormones
gastrin and somatostatin.
F cells produce hormone
pancreatic polypeptide

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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

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Pancreatic Hormones, Insulin and Glucagon,
Regulate Metabolism
Figure 22-8: Metabolism is controlled by insulin and glucagon

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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.

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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).

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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.

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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

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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.

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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

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Insulin: Summary and Control
Reflex Loop

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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).

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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.

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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
++
)

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
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

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Glucagon Action on Cells: Dominates in
Fasting State Metabolism

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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

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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.

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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.

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Function - Dysfunction of
Endocrine Pancreas
(Diabetes)

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Both an exocrine and endocrine organ.
Cells with exocrine function release an
alkaline fluid containing sodium
bicarbonate and enzymes →
pancreatic duct → small intestine.
Pancreatic “juice” aids in breakdown
and digestion of food in the small
intestine.
Pancreatic exocrine cells = acinar cells.
Anatomy of the pancreas:

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Endocrine Function
oCells of the Islet of Langerhans
synthesize and release hormones into the
circulation.
oHormones travel through the
bloodstream to target tissues (especially
liver and muscle).
oAt the target cells, hormones bind specific
receptors and cause cell changes that
control metabolism.

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Pancreatic endocrine cells regulate
carbohydrate, fat, protein metabolism

Alpha cells – secrete the hormone
glucagon.

Beta cells – secrete the hormones
insulin and amylin.

Delta cells – secrete the hormones
gastrin and somatostatin.

F cells – secrete hormone pancreatic
polypeptide.

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Beta Cells

Synthesize pre-proinsulin, a protein.
This is cleaved by enzymes
→proinsulin, then cleaved again →
insulin.

Insulin is the biologically active
hormone that is released into the
bloodstream.

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Insulin secretion is controlled
through several mechanisms:

Chemically – high levels of glucose and
amino acids in the blood.

Hormonally – beta cells are sensitive to
several hormones that may inhibit or
cause insulin secretion.

Neurally – stimulation of the
parasympathetic nervous system
causes insulin to be secreted.

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Insulin secretion is decreased by:
•Decreased blood glucose
concentration.
•Increased blood insulin
concentration.
•Sympathetic stimulation.

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Insulin

Transported through the blood to target tissues where
it binds to specific receptors.

The binding of insulin to target cells:

Acts as a biochemical signal to the inside of the cell.

Overall, cell metabolism is stimulated.

There is increased glucose uptake into the cell.

Regulation of glucose breakdown within the cell.

Regulation of protein and lipid breakdown within
the cell.

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
Blood glucose is decreased because
insulin causes glucose to leave the
bloodstream and enter the
metabolizing cells.

With the exception of brain, liver and
erythrocytes, tissues require membrane
glucose carriers.

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Disorder ‑ Diabetes mellitus

The single most common endocrine
disorder – group of glucose
intolerance disorders.

Incidence is estimated at 1-2% of the
North American population.

Many of these cases are
undiagnosed.

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Diabetes mellitus
 Historically ‑ distinguished by weight loss,
excessive urination, thirst, hunger:
Excessive urination= Polyuria
Excessive thirst = Polydipsia
Excessive hunger = Polyphagia
Modern characterization is by
hyperglycemia and other metabolic
disorders.

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Modern classifications

Type 1 or IDDM ‑ Insulin Dependent
Diabetes Mellitus.

Type 2 or NIDDM ‑ Non‑Insulin Dependent
Diabetes Mellitus.

GDM ‑ Gestational Diabetes Mellitus.

Other Types of Diabetes Mellitus.

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
Accounts for 10% all DM in the Western
world ~10-15% have parent or sibling with
the disease. Peak age of diagnosis = 12
years.

Genetic/environmental/autoimmune factors
destroy beta cells.

Believed abrupt onset – now
immunomarkers and preclinical symptoms
have been discovered.
Type 1 or IDDM

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
Disequilibrium of hormones produced by
islets of Lagerhans : low insulin and high
glucagon.

Ratio insulin/glucagons apparently
controls metabolism of glucose and fats.

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Clinical Manifestations
Glucose in urine:
-Because when insulin is not present,
glucose is not taken up out of the blood
at the target cells.
-Blood glucose is very highly increased →
increased glucose filtered and excreted in
the urine (exceeds transport maximum).
-Weight loss - Patient eats, but nutrients
are not taken up by the cells and/or are
not metabolized properly.

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Clinical Manifestations (Cont.)
-Osmotic diuresis results in fluid loss.
-Loss of body tissue by metabolism of fats
and proteins.
-Polyuria, polydipsia, pholyphagia,
Ketoacidosis:

Fats and proteins are metabolized
excessively, and byproducts known as
ketone bodies are produced. These are
released to the bloodstream and cause:

Decreased pH (so increased acidity).

Compensations for metabolic acidosis.

Acetone given off in breath.

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Type 2 or NIDDM

More common than IDDM, often
undiagnosed.

It has a slow onset.

Most common in those >40 years, though
children are being diagnosed more
regularly.

May be genetic .

Obesity is the greatest risk factor for
this disease, and is related to increased
incidence in children.

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
NIDDM → insulin resistance in target
cells.

See decreased β cell responsiveness →
Decreased insulin secreted by β
cells.

Also abnormal amount of glucagon
secreted.

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These effects may be due to:
1. Abnormally functioning β cells.
2. Decreased β cell mass.
3. Or a combination of both 1 and 2.
4. Target cell resistance to insulin, Due to:
1) Decreased number of insulin receptors.
2) Postreceptor events may be
responsible.
3) Cells “burn out” and become
insensitive.

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
Overweight, hyperlipidemia common
(but these are precursors, not
symptoms).

Recurrent infections.

Visual changes, paresthesias, fatigue.
Clinical manifestations

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•Due to increased hormone secretion
during pregnancy.
•Seen if patient has predisposition.
•If previous or potential glucose
intolerance has been noted.
•Important ‑ increased mortality risk for
mother, child
Gestational Diabetes

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Complications of Diabetes Mellitus
Acute:

Hypoglycemia = rapid decrease in plasma
glucose = insulin shock.

Neurogenic responses – probably due to
decreased glucose to hypothalamus.

Symptoms include:
-Tachycardia, palpitations, tremor, pallor .
-Headache, dizziness, confusion.
-Visual changes.

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Ketoacidosis: Involves a precipitating event:
-Increased hormones released w/ trauma 
increased glucose produced by the body’s cells.
-This “antagonizes” the effects of any glucose
present, which leads to :
•Increased ketones in blood.
•Acid/base imbalance.
•Polyuria, dehydration.
•Electrolyte disturbances.
•Hyperventilation.
•CNS effects.
•Acetone on breath.

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Chronic Complications of DM
Neuropathies = nerve dysfunctions →
slowing of nerve conduction. In these
patients, see:
-Degeneration of neurons →Sensory,
motor deficits →Muscle atrophy,
paresthesias.
-Depression.
-G.I. problems, as muscle motility
decreased.
-Sexual dysfunction.

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
Microvascular disease:
-Chronic diabetes w/ improper glucose
metabolism → thickening of the
basement membrane of capillaries,
particularly in the eye and the kidney.
-As the capillary changes in this way, →
Decreased tissue perfusion.
-So ischemia → hypoxia.

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In the eye:
-The retina is metabolically quite active, so
hypoxia here is a big problem .
-So, the following events can be seen:
•Retinal ischemia →
•Formation of microaneurisms, hemorrhage,
tissue infarct, formation of new vessels,
retinal detachment.

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In the kidney:
-Diabetes is the most common cause
of end ‑ stag renal disease.
-Injured glomeruli (glomerulosclerosis)
In these patients, the following
signs can be seen:
•Proteinuria (protein is excreted into
the urine) → Generalized body
edema, hypertension.

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Macrovascular disease:
-Atherosclerosis .
-Plaque formation increases → Increased
risk of coronary artery disease, so
increased risk of myocardial infarction.
-Increased risk of congestive heart
failure.
-Stroke.
-Peripheral vascular disease, that’s why
diabetic patients face problems with
their lower legs and feet.
-Increased risk of infections.