Endocrine functions of the

pancreas
Control of blood sugar
 Pancreas
• It has digestive functions
• Secretes 2 important hormones
• INSULIN
• GLUCAGON
• Secretes other hormones, such as Amylin,
somatostatin., and pancreatic polypeptide
 Physiologic anatomy of the Pancreas
• Two major types of tissues
• 1) Acini → secrete digestive juices in the duodenum
• 2) Islets of Langerhans→ secrete insulin & glucagon in
blood
• Islet of Langerhans → aplha cells, beta cells & delta
cells
• Beta cells→ 60% of cells, secrets insulin & amylin
• Alpha cells→ 25% of cells, secrete glucagon
• Delta cells→ 10% of cells, somatostatin
• Others → PP cells secrete pancreatic polypeptide
 Insulin & its metabolic effects
• First isolated from the pancreas in 1922 by
Banting and Best
• Associated with blood sugar
• Has effects on carbohydrates metabolism
• Affects fat and protein metabolism also
Insulin Is a Hormone Associated with
Energy Abundance
• Abundance of energy giving foods in diet
(carbohydrates), secretes insulin
• Causes excessive carbohydrates to be stored
as glycogen mainly in the liver & muscles
• Some store as fats (in adipose tissues) &
under the stimulus of insulin
• Also promotes amino acids uptake &
conversion of amino acids into proteins
 Insulin Chemistry and Synthesis
• Human insulin has a molecular weight of 5808.
• It is composed of two amino acid chains,
connected to each other by disulfide linkages.
• When the two amino acid chains are split apart,
the functional activity of the insulin molecule is
lost.
• Preproinsulin(ribo)→ proinsulin (ER) → insulin
(GA)
• plasma half-life averages only about 6 minutes,
so it is mainly cleared from the circulation within
10 to 15 minutes.
 Activation of Target Cell Receptors by Insulin and the
Resulting Cellular Effects
• Insulin binds to the α-subunit of its receptor, which causes
autophosphorylation of the β-subunit receptor, which in turn induces
tyrosine kinase activity.
• The receptor tyrosine kinase activity begins a cascade of cell
phosphorylation that increases or decreases the activity of enzymes,
including insulin receptor substrates(IRS)
• IRS mediate the effects on glucose, fat, and protein metabolism. For
example, glucose transporters are moved to the cell membrane to
assist glucose entry into the cell.
• Immediately after a high-carbohydrate meal, the glucose that is
absorbed into the blood causes rapid secretion of insulin, which in turn
causes rapid uptake, storage, and use of glucose by almost all tissues
of the body, but especially by the muscles, adipose tissue, and liver.
 Insulin Promotes Muscle Glucose Uptake and
Metabolism

• During much of the day, muscle tissue depends

not on glucose for its energy but on fatty acids
because the normal resting muscle membrane is
only slightly permeable to glucose, except when
the muscle fiber is stimulated by insulin
• Under two conditions muscles utilize large
amounts of glucose
• 1) during moderate or heavy exercise
• 2) during few hours after a meal
• Abundant glucose transported into the muscle
cells is stored as muscle glycogen
 Insulin Promotes Liver Uptake, Storage, and Use of
Glucose

• insulin is to cause most of the glucose absorbed

after a meal to be stored almost immediately in
the liver in the form of glycogen.
• The mechanism of glucose uptake & storage in
the liver:
• 1) insulin inactivates liver phosphorylase (split
glycogen → glucose)
• 2) ↑uptake of glucose from blood by the liver via
glucokinase
• 3) ↑activites of the enzymes that promote
glycogen synthesis → glycogen synthase
 Glucose Is Released from the Liver
Between Meals
• Low glucose level between the meal causes liver to
release glucose back into circulating blood;
• 1) ↓blood glucose →↓insulin secretion
• 2) lack of insulin reverses effects of glycogen storage
• 3) activates phosphorylase to split glycogen → glucose
phosphate
• 4) glucose phosphatase → causes phosphate radical to
split away from the glucose
• Liver removes glucose from the blood when in excess
after a meal & return it into the blood when blood
glucose concentration falls between meals
 Insulin Promotes Conversion of Excess Glucose into
Fatty Acids and Inhibits Gluconeogenesis in the Liver

• When the quantity of glucose entering the liver

cells is more, insulin promotes the conversion of
all this excess glucose into fatty acids.
• These packaged as triglycerides in VLDL and
transported by blood to the adipose tissue and
deposited as fat.
• Insulin also inhibits gluconeogenesis.
 Lack of Effect of Insulin on Glucose
Uptake and Usage by the Brain
• Insulin has little effect on uptake or use of
glucose in brain (permeable to glucose)
• Brain cells use only glucose for energy and can
use other energy substrates, such as fats, only
with difficulty.
• It is essential that the blood glucose level always
be maintained above a critical level
• When the blood glucose falls too low, symptoms
of hypoglycemic shock develop, characterized by
progressive nervous irritability that leads to
fainting,
 Effect of Insulin on Carbohydrate
Metabolism in Other Cells
• Insulin increases glucose transport into and
glucose usage by most other cells of the body
• The transport of glucose into adipose cells
mainly provides substrate for the glycerol
portion of the fat molecule.
• Therefore, indirectly insulin promotes
deposition of fat in these cells.
 Effect of Insulin on Fat Metabolism

• Insulin Promotes Fat Synthesis and Storage

• Insulin has several effects that lead to fat storage
in adipose tissue.
• Insulin increases the utilization of glucose by
body
• Insulin promotes fatty acid synthesis, in liver cells
• Fatty acids are then transported from the liver by
way of the blood lipoproteins to the adipose cells
to be stored
 Role of Insulin in Storage of Fat in the Adipose Cells

• Insulin has two other essential effects that are

required for fat storage in adipose cells:
• 1. Insulin inhibits the action of hormone-sensitive
lipase → causes hydrolysis of the triglycerides
already stored in the fat cells.
• 2. Insulin promotes glucose transport through
the cell membrane into the fat cells to forms
large quantities of a-glycerol phosphate.
• a-glycerol phosphate supplies the glycerol that
combines with fatty acids to form the
triglycerides (storage form of fat)
 Insulin Deficiency Increases Use of Fat for Energy

• All aspects of fat breakdown and use for providing

energy are greatly enhanced in the absence of insulin.
• This occurs even normally between meals when
secretion of insulin is minimal, but it becomes extreme
in diabetes mellitus .
• Insulin Deficiency Causes Lipolysis of Storage Fat and
Release of Free Fatty Acids.
• Consequently, the plasma concentration of free fatty
acids begins to rise within minutes.
• This free fatty acid then becomes the main energy
substrate used by essentially all tissues of the body
besides the brain.
 Insulin Deficiency Increases Plasma Cholesterol and
Phospholipid Concentrations

• The excess of fatty acids in the plasma associated with

insulin deficiency also promotes liver conversion of
fatty acids → phospholipids and cholesterol
• These two substances, along with excess triglycerides
formed at the same time in the liver, are then
discharged into the blood in the lipoproteins, so the
plasma lipoproteins increase
• This high lipid concentration—especially the high
concentration of cholesterol—promotes the
development of atherosclerosis in people with serious
diabetes.
 Excess Usage of Fats During Insulin
Lack Causes Ketosis and Acidosis
• Insulin lack also causes excessive amounts of acetoacetic
acid in the liver cells.
• ↓ utilization of acetoacetic acid in the peripheral tissues.
• Some of the acetoacetic acid is also converted into b-
hydroxybutyric acid and acetone.
• These two substances, along with the acetoacetic acid, are
called ketone bodies, and their presence in large quantities
in the body fluids is called ketosis.
• In severe diabetes the acetoacetic acid and the β-
hydroxybutyric acid can cause
severe acidosis and coma, which may lead to death.
•
 Insulin Promotes Protein Synthesis and Storage
• During the few hours after a meal proteins are also
stored in the tissues by insulin
• 1. Insulin stimulates transport of many of amino acids
into the cells, eg valine, leucine, isoleucine, tyrosine,
andphenylalanine.
• 2. Insulin increases the translation of mRNA, thus
forming new proteins
• 3. Insulin also increases the rate of transcription of
selected DNA, forming increased quantities of RNA and
still more protein synthesis
• 4. Insulin inhibits the catabolism of proteins
• 5. In the liver, insulin depresses the rate of
gluconeogenesis.
Insulin and Growth Hormone Interact
Synergistically to Promote Growth
• Because insulin is required for
the synthesis of proteins, it is as
essential for growth of an
animal as growth hormone is.
• A combination of these
hormones causes dramatic
growth.
• Thus, it appears that the two
hormones function
synergistically to promote
growth each performing a
specific function that is
separate from that of the other.
Mechanisms of Insulin Secretion
• The beta cells have a large number
of glucose transporters (GLUT 2) that
permit a rate of glucose influx that is
proportional to the blood concentration
• glucose is phosphorylated to glucose-6-
phosphate by glucokinase.
• The glucose-6-phosphate is
subsequently oxidized to form
adenosine triphosphate (ATP), which
inhibits the ATP-sensitive potassium
channels of the cell.
• opening voltage-gated calcium channels
produces an influx of calcium that
stimulates fusion of the docked insulin-
containing vesicles with the cell
membrane and secretion of insulin into
the extracellular fluid by exocytosis.
 Glucagon
• Glucagon is also called the hyperglycemic
hormone
• Most of the actions of Glucagon are achieved by
activation of Adenylyl Cyclase in hepatic cell
membrane
• The binding of glucagon to hepatic receptors
results in activation of adenylyl cyclase and
generation of the second messenger cyclic AMP,
• which in turn activates protein kinase, leading to
phosphorylation that results in the activation or
deactivation of a number of enzymes.
 Glucagon Causes Glycogenolysis and Increased Blood
Glucose Concentration
• The most dramatic effect of glucagon is its ability to cause glycogenolysis
in the liver, which in turn increases the blood glucose concentration
within minutes.
• It does this by the following complex cascade of events:
• 1. Glucagon activates adenylyl cyclase in the hepatic cell membrane,
• 2. Which causes the formation of cyclic adenosine monophosphate,
• 3. Which activates protein kinase regulator protein,
• 4. Which activates protein kinase,
• 5. Which activates phosphorylase b kinase,
• 6. Which converts phosphorylase b into phosphorylase a,
• 7. Which promotes the degradation of glycogen into glucose-1-phosphate,
• 8. Which is then dephosphorylated; and the glucose is released from the
liver cells.
Glucagon Increases Gluconeogenesis
• effect of glucagon to increase the rate of
amino acid uptake by the liver cells and then
the conversion of many of the amino acids to
glucose by gluconeogenesis.
• activation of the enzyme system for
converting pyruvate to phosphoenolpyruvate,
a rate-limiting step in gluconeogenesis.
 Other Effects of Glucagon
• the most important effect is that glucagon activates
adipose cell lipase,making increased quantities of fatty
acids available to the energy systems of the body.
• Glucagon also inhibits the storage of triglycerides in
the liver helps make additional amounts of fatty acids
available for the other tissues of the body.
• Glucagon in high concentrations also (1) enhances the
strength of the heart; (2) increases blood flow in some
tissues, especially the kidneys; (3) enhances bile
secretion; and (4) inhibits gastric acid secretion.
 Regulation of Glucagon Secretion
• a decrease in the blood
glucose concentration from
its normal fasting level of
about 90 mg/100 ml of
blood down to
hypoglycemic levels can
increase the plasma
concentration of glucagon
severalfold.
• Conversely, increasing the
blood glucose to
hyperglycemic levels
decreases plasma glucagon.
• Increased Blood Amino • Exercise Stimulates
Acids Stimulate Glucagon Glucagon Secretion
Secretion
• High concentrations of • One of the factors that
amino acids, as occur in might increase glucagon
secretion in exercise is
the blood after a protein increased circulating
meal (especially the amino acids. Other
amino factors, such as β-
acids alanine and arginine adrenergic stimulation of
), stimulate the secretion the islets of Langerhans,
of glucagon may also play a role.
• which promotes rapid
conversion of the amino
acids to glucose, thus
making even more
glucose available to the
tissues.
 Somatostatin Inhibits Glucagon and
Insulin Secretion
• The delta cells of the islets of Langerhans secrete
the hormone somatostatin, a 14 amino acid
polypeptide that has an extremely short half-life
of only 3 minutes in the circulating blood.
• (1) increased blood glucose,
• (2) increased amino acids,
• (3) increased fatty acids, and
• (4) increased concentrations of several of the
gastrointestinal hormones released from the
upper gastrointestinal tract in response to food
intake.
• In turn, somatostatin has multiple inhibitory
effects as follows:
• 1. Somatostatin acts locally within the islets of
Langerhans themselves to depress the
secretion of both insulin and glucagon.
• 2. Somatostatin decreases the motility of the
stomach, duodenum, and gallbladder.
• 3. Somatostatin decreases both secretion and
absorption in the gastrointestinal tract.
 Summary of Blood Glucose
Regulation
• 80 and 90 mg/100 ml of blood in the fasting
person each morning before breakfast
• 120 to 140 mg/100 ml during the first hour or so
after a meal
• rapidly back to the control level, usually within 2
hours after the last absorption of carbohydrates.
• 1. The liver functions as an important blood
glucose buffer system.
• Both insulin and glucagon function as important
feedback control systems for maintaining a normal
blood glucose concentration.
• Also, in severe hypoglycemia, low blood glucose →
hypothalamus → sympathetic nervous system →
epinephrine(adrenal glands) → release of glucose
from the liver to protect against severe
hypoglycemia.
• Prolonged hypoglycemia → GH & cortisol secretion
→ ↓ glucose utilization by the cells & ↑ fats
utilization → blood glu concentration normal
 Importance of Blood Glucose Regulation

• Glucose is the only nutrient that normally can be used by

the brain, retina, and germinal epithelium of the gonads in
sufficient quantities to supply them optimally with their
required energy.
• Therefore, it is important to maintain the blood glucose
concentration at a sufficiently high level to provide this
necessary nutrition.
• It is also important that the blood glucose concentration not
rise too high for four reasons:
• (1) Glucose → ↑osmotic pressure (ECF) , and if the glucose
concentration rises to excessive values → cellular
dehydration.
• (2) An excessively high level of blood glucose
concentration causes loss of glucose in the
urine.
• (3) Loss of glucose in the urine → osmotic
diuresis → deplete the body fluids and
electrolytes.
• (4) Long-term increases in blood glucose may
cause damage to many tissues, especially to
blood vessels.
 Diabetes Mellitus

• Diabetes mellitus is a syndrome of impaired carbohydrate, fat,

and protein metabolism caused by either lack of insulin
secretion or decreased sensitivity of the tissues to insulin.
There are two general types of diabetes mellitus:
• Type I Diabetes
• Type II Diabetes
• The basic effect either type of Diabetes on glucose metabolism
is to prevent the efficient uptake and utilization of glucose by
most cells of the body, except those of the brain.
• As a result, blood glucose concentration ↑, cell utilization of
glucose falls ↓, and utilization of fats and proteins ↑.
 • Type II diabetes
• Type II diabetes, also
• Type I diabetes called non-insulin-
dependent diabetes
• Type I diabetes, also mellitus (NIDDM), is
called insulin-dependent initially caused by
diabetes decreased sensitivity of
mellitus (IDDM), is target tissues to the
caused by lack of insulin metabolic effect of
secretion. insulin. This reduced
sensitivity to insulin is
often called insulin
resistance.
 Type I Diabetes—Deficiency of Insulin Production by
Beta Cells of the Pancreas
• Injury to the beta cells of the pancreas or diseases that impair
insulin production can lead to type I diabetes.
• Viral infections or autoimmune disorders
• Hereditary
• Type I diabetes may develop abruptly, over a period of a few
days or weeks, with three principal sequelae:
• (1) increased blood glucose,
• (2) increased utilization of fats for energy and for formation of
cholesterol by the liver, and
• (3) depletion of the body’s proteins.
• The lack of insulin ↓ peripheral glucose utilization and ↑glucose
production, ↑plasma glucose to 300 to 1200 mg/100 ml.
 Increased Blood Glucose Causes
Loss of Glucose in the Urine
•when the blood glucose concentration rises
above 180 mg/100 ml, a level that is called the
blood “threshold” for the appearance of glucose
in the urine.
•When the blood glucose level rises to 300 to
500 mg/100 ml—100 or more grams of glucose
can be lost into the urine each day.
 Increased Blood Glucose Causes
Dehydration
• Very high levels of blood glucose (sometimes as high as 8 to
10 times normal in severe untreated diabetes) can cause
severe cell dehydration throughout the body.
• Increased osmotic pressure in the extracellular fluids causes
osmotic transfer of water out of the cells.
• The overall effect is massive loss of fluid in the urine, causing
dehydration of the extracellular fluid, which in turn causes
compensatory dehydration of the intracellular fluid,
• Thus, polyuria(excessive urine excretion), intracellular and
extracellular dehydration, and increased thirst are classic
symptoms of diabetes.
 Chronic High Glucose Concentration Causes Tissue
Injury

• When blood glucose is poorly controlled over long periods in

diabetes mellitus, blood vessels in multiple tissues throughout
the body begin to function abnormally and undergo structural
changes that result in inadequate blood supply to the tissues.
• This in turn leads to increased risk for heart attack, stroke, end-
stage kidney disease, retinopathy and blindness, and ischemia
and gangrene of the limbs.
• Peripheral neuropathy, and autonomic nervous system
dysfunctionare can result in impaired cardiovascular reflexes,
impaired bladder control, decreased sensation in the
extremities, and other symptoms of peripheral nerve damage.
 Diabetes Mellitus Causes Increased Utilization
of Fats and Metabolic Acidosis
• ↑ fat metabolism in diabetes →↑ the release of keto acids
(acetoacetic acid and β-hydroxybutyric acid)
• As a result, the patient develops severe metabolic
acidosis from the excess keto acids, which, in association
with dehydration due to the excessive urine formation, can
cause severe acidosis.
• This leads rapidly to diabetic coma and death unless the
condition is treated immediately with large amounts of
insulin.
 Diabetes Causes Depletion of the
Body’s Proteins
• Failure to use glucose for energy leads to
increased utilization and decreased storage of
proteins and fat.
• Therefore, a person with severe untreated
diabetes mellitus suffers rapid weight loss
and asthenia (lack of energy) despite eating
large amounts of food (polyphagia).
Type II Diabetes—Resistance to the Metabolic Effects
of Insulin

• More common than type I (90-95%)

• Occurs after age 30 (adult –onset diabetes)
• But affects younger individuals too
↓
OBESITY
 Obesity, Insulin Resistance, and “Metabolic
Syndrome” Usually Precede Development of Type II
Diabetes
• Type II diabetes, associated with increased plasma insulin
concentration (hyperinsulinemia).
• This occurs as a compensatory response by the pancreatic
beta cells for diminished sensitivity of target tissues to the
metabolic effects of insulin, a condition referred to as insulin
resistance.
• ↓ insulin sensitivity → impairs carbohydrate utilization and
storage, ↑ blood glucose & ↑ insulin secretion.
• Impaired insulin signaling → lipid accumulation in tissues such
as skeletal muscle and liver secondary to excess weight gain.
• Insulin resistance is part of a cascade of disorders that is often
called the “metabolic syndrome.”
• Some of the features of the metabolic syndrome include
• (1) obesity, especially accumulation of abdominal fat;
• (2) insulin resistance;
• (3) fasting hyperglycemia;
• (4) lipid abnormalities, such as increased blood triglycerides and
decreased blood high-density lipoprotein-cholesterol; and (5)
hypertension.
• All of the features of the metabolic syndrome are closely related
to accumulation of excess adipose tissue in the abdominal cavity
around the visceral organs.
• Polycystic ovary syndrome (PCOS), for example, is associated
with marked increases in ovarian androgen production and
insulin resistance and is one of the most common endocrine
disorders in women, affecting approximately 6 percent of all
women during their reproductive life.
• insulin resistance and hyperinsulinemia are found in
approximately 80 percent of affected women. The long-term
consequences include increased risk for diabetes mellitus,
increased blood lipids, and cardiovascular disease.
• Excess formation of glucocorticoids (Cushing’s
syndrome) or growth hormone (acromegaly) also decreases
the sensitivity of various tissues to the metabolic effects of
insulin and can lead to development of diabetes mellitus.
Clinical Characteristics of Patients with Type I and Type II Diabetes Mellitus

thiazolidinediones,
metformin,
sulfonylureas,
insulin
 Insulinoma—Hyperinsulinism
• Excessive insulin production occasionally
occurs from an adenoma of an islet of
Langerhans.
• About 10 to 15 percent of these adenomas are
malignant, and occasionally metastases from
the islets of Langerhans spread throughout the
body, causing tremendous production of
insulin by both the primary and metastatic
cancers.
 Insulin Shock and Hypoglycemia
• Central nervous system normally derives essentially all its energy from
glucose metabolism.
• However, if high levels of insulin cause blood glucose to fall to low values,
the metabolism of the central nervous system becomes depressed.
• Consequently, in patients with insulin-secreting tumors or in patients with
diabetes who administer too much insulin to themselves, the syndrome
called insulin shock may occur
• As the blood glucose level falls into the range of 50 to 70 mg/100 ml, various
forms of hallucinations result, but more often the patient simply experiences
extreme nervousness, trembles all over, and breaks out in a sweat.
• blood glucose level falls to 20 to 50 mg/100 ml, clonic seizures and loss of
consciousness are likely to occur. As the glucose level falls still lower, the
seizures cease and only a state of coma remains.
• administration of glucagon (epinephrine) can cause glycogenolysis in the
liver and thereby increase the blood glucose level extremely rapidly.