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Endocrine function
of
pancreas
Dorota Nowak MD, PhD
Internal Medicine Specialist
Dept. of Physiology
University of Medical Sciences
Alfa cells – secrete glucagon
Beta cells – secrete insulin
Delta cells – secrete somatostatin
PP cells – secrete pancreatic polypeptide
Somatostatin – first found in hypothalamus as hormone which inhibits
growth hormone secretion.
It inhibits secretion of insulin and glucagon.
It decreases motility of stomach, duodenum, gollbladder.
It decreases secretion and absorbtion in gastrointestinal tract.
Factors that stimulate secretion:
- increased blood glucose
Factors that inhibit secretion
- increased blood amino acids
- increased blood free fatty acids
- CCK
Pancreatic polypeptide – inhibits secretion of digestive juices from
pancreas
Secretion of pancreatic polypeptide is stimulated by increased blood amino acids
Insulin and glucagon control especially
energetic status of the body
Sources of energy
ATP is produced from:
1. Combusion of carbohydrates / predominate in physiological condition/ –
this occurs in cytoplasm through the anaerobic process of glycolysis
and in the cell mitochondria through the aerobic citric acid /Krebs/ cycle.
2. Combusion of fatty acids in the cell mitochondria by beta oxydation
and citric acid cycle
3. Combusion of proteins, which requires hydrolysis to amino acids and
degradation of the amino acids to intermediate compounds of
the citric acid cycle – acetyl coenzyme A
--------------------
Reciprocal influence of pancreatic hormones secretion
Insulin is a small protein.
It is composed of two amino acid chains, connected to each other by disulfide linkages.
Insulin is synthesized in the beta cells, by the
usual cell machinery for protein synthesis.
Insulin is synthesized as prepro hormon.
It is cleaved in endoplasmic reticulum
to form proinsulin.
Most of proinsulin is cleaved in Golgi apparatus
into insulin and C peptide, which are packeged
in the secretory granules.
C peptide is released from pancreas in a 1:1 ratio
with insulin. Serum amounts of C peptide are
good indicator of insulin production.
Insulin circulates in unbound form. It has a plasma half-life time only about 6 min.
Mechanism of insulin secretion from pancreas after stimulation
of beta cell by glucose
Glucose influx into beta cell through
glucose transporter- GLUT 2
Phosphorylation of glucose
Oxidation of G-6-P which increases
concentration of ATP
ATP inhibits the ATP-sensitive
potassium channels of the cells
Closure of the potassium channels depolarizes the cell
membrane, thereby opening voltage-gated calcium channels.
This produces an influx of calcium that stimulates fusion of
insulin-containing vesicles with cell membrane and secretion of insulin
by exocytosis
GLUT- glucose transporter
GLUT 1 is present in renal epithelial cells
GLUT 2 is present in ß cells of pancreas (glucose sensor),
intestinal and renal epithelial cells
GLUT 3 – in brain, kidneys, placenta (basal glucose uptake)
GLUT 4 – in muscle, adipose tissue, liver (insulin-stimulated
glucose uptake)
Increase in plasma insulin concentration after a suden increase in blood glucose / two to three
times the normal range/.
Plasma insulin concentration increases almost 10-fold within 3-5 min after
elevation of blood glucose. This results from release of preformed insulin.
After about 15 minutes insulin secretion rises second time. This increase
results both from additional release of preformed insulin and from activation of
the enzyme system that synthesizes insulin.
Regulation of insulin secretion
Factors that increase insulin
secretion
blood glucose
amino acids (arginine,leucine)
fatty acids
gastrointestinal hormones (gastrin,
cholecystokinin, secretin, GIP)
glucagon, cortisol, GH
parasymphatetic stimulation-Ach
insulin resistance, obesity
sulfonylurea drugs (glyburide)
Factors that decrease insulin
secretion
↓ blood glucose
somatostatin
norepinephrine, epinephrine
alfa adrenergic stimulation
insulin
↓ potassium plasma
concentration
The target cell for glucose = the cell which has insulin receptor in cell membrane
Insulin binds with alfa subunits of
insulin receptor at target cell.
Insulin receptors are present in: adipose tissue, muscle, liver
Insulin receptors are not present in the neurons and red blood cells
The end effects of insulin receptor stimulation at target cell are as
follow
Insulin binds with alfa subunits of
insulin receptor at target cell.
It causes autophosphorylation of
beta subunit.
Autophosphorylation of the beta
subunit activates a local tyrosine
kinase
Tyrosine kinase phosphorylates
intracellular enzymes which are
called insulin-receptor substrates
/IRS/
The end effects of insulin receptor stimulation at target cell are as
following:
1. The uptake of glucose increases in 80% of body cells. It results from
translocation of intracellular vesicles to the cell membranes. These
vesicles carry in their own membranes glucose transport proteins GLUT
4, which bind with the cell membrane and facilitate glucose uptake.
(within seconds)
2.The cell membrane becomes more permeable to amino acides and
potasium ions (within seconds)
3. Slower effects occur during next 15 minutes to change activity of many
metabolic enzymes (within minutes)
4. Much slower effects result from changed rates of translation of
messenger RNAs at the ribosome to form new proteins
(after hours and days)
5. Much slower effects result from changed rate of transcription of DNA in
the cell nucleus to remold cellular enzymatic machinery
(after hours and days)
Carbohydrate metabolism in the muscle
During much of the day muscle depends on fatty acids for it energy. However,
under two conditions do use large amounts of glucose. There are:
1. during exercise and
2. few hours after the meal.
The amount of insulin that is secreted between meals is too small to promote
glucose entry into the cells.
The glucose transported into the cell is phosphorylated and becomes
a
substrate for all the usual carbohydrate metabolic functions.
If
the muscle are not exercising after the meal, the most of the glucose is stored
in the form of muscle glycogen.
Effect of insulin in enhancing the concentration of glucose inside muscle cells.
The control – absence of insulin
Carbohydrate metabolism in the liver
Insulin promotes glucose uptake in the liver cells.
Insulin promotes glucose storage in the liver, because
it stimulates synthesis of glycogen.
When the quantity of glucose entering the liver cells is more
than can be stored as glycogen insulin promotes the
convertion of glucose into fatty acids.
Carbohydrate metabolism in the liver
Insulin promotes liver uptake and storage of glucose, because
Insulin increases activity of glucokinase-it causes initial phosphorylation of
glucose. Phosphorylated glucose cannot diffuse back through cell membrane.
Insulin inhibits glucose phosphatase, enzyme which catalyses
dephosphorylation of glucose (4)
Insulin increases activity of glycogen synthetase (7)
Insulin inhibits glycogen phosphorylase – enzyme that causes liver
glycogen to split into glucose (6)
The net effects of all these actions is to increase the amount of glycogen in the
liver
Insulin also inhibits
gluconeogenesis
by inhibition of
enzymes required
for
gluconeogenesis.
Glucose is released from the liver between meals
Decrease in blood glucose concentration causes the pancreas
to decrease its insulin secretion.
The lack of insulin stops glycogen synthesis.
The lack of insulin activates glycogen phosphorylase, which causes the
splitting of glycogen (6).
The lack of insulin activates glucose-6-phosthatase, enzyme which
catalyses dephosphorylation of glucose and glucose diffuses to the
blood (4).
Fat metabolism in the liver
When the quantity of glucose entering the liver cells is more than can
be stored as glycogen insulin promotes the conversion of glucose into
fatty acids.
The fatty acids and triglycerides may be packed in very-low-density
lipoproteins and transported into adipose tissue.
Insulin inhibits ketoacids formation. It decreases fatty acids degradation
and provides less acetyl CoA substrate for ketoacid formation.
Fat metabolism
Insulin promotes conversion of glucose into fatty acids. Fatty acids are synthesized within the
liver and are used to form triglycerides. Fatty acids and triglycerides are packed in very-lowdensity lipoproteins.
Insulin activates lipoprotein lipase –the enzyme, which is present in the capillary walls, which
splits triglycerides into fatty acids. Fatty acids are absorbed into adipose tissue.
When the insulin is not available storage of fatty acids in adipose tissue is almost blocked.
Insulin inhibits the action of hormone-sensitive lipase /enzyme which is present in fat cells
and causes hydrolysis of triglycerides already stored in fat cells/ – insulin inhibits release of
fatty acids from adipose tissue.
.
Blood
Lipoprotein lipase
. Triglycerides
FFA
Adipose tissue
Hormone sensitive lipase
Triglycerides
FFA
to
blood
Effect of insulin on fat metabolism in adipose tissue
1. Insulin promotes transport of glucose into the fat cells.
Glucose is also used for synthesis of fatty acids and glycerol
in adipose cells.
Effects of insulin on protein metabolism and growth
Insulin promotes protein synthesis and storage.
1. Insulin stimulates transport of amino acids into cells
/valine, leucine, tyrosine/
2. Insulin increases the translation of messenger RNA, thus
forming new proteins
3. Insulin increases the rate of transcription of DNA
4. Insulin inhibits catabolism of proteins
5. Insulin depresses the rate of gluconeogenesis
Insulin is an anabolic hormone.
Effect of insulin and growth hormone on growth in rat.
Brain
The brain cells are permeable to glucose and can use glucose
without the intermediation of insulin.
Neurons use only glucose for energy.
When blood glucose falls too low /below 50 mg/ 100ml/
symptoms of hypoglycemic shock develop.
Effects of hypoglicemia
Glucose concentration
in plasma
mg/dl
90
Inhibition of insulin secretion
75
.
Secretion of glucagon, epinephrin, growth hormone, stimulation of
sympathetic nervous system. Palpitation, sweating, nervous irritability occur
60
Secretion of cortisol, disturbances of cognitive processes
45
Lethargy
30
Coma
Convulsions
15
Persistent lesion of central nervous system, death
0
Factors and conditions that increase or decrease glucagon secretion
Stimulation of glucagon secretion
Ihibition of glucagon secretion
↓ blood glucose
↑ blood glucose
↑ blood amino acids (arginine)
↑ blood FFA
CCK, gastrin
stimulation of beta-adrenergic
. receptors (epinephrin,
norepinephrin)
acetylocholina
exercises
stress
inflamation
cortisol
↑ blood ketons
somatostatin
insulin
Approximate plasma glucagon concentration at different blood
glucose level
The effects of glucagon
Glucagon in physiological conditions acts on the liver and adipose
tissue.
1. Glucagon increases blood glucose concentration
- causes breakdown of liver glycogen /glycogenolysis/
- increases gluconeogenesis in the liver.
2.Glucagon increases blood fatty acids and ketoacids concentration
- activates hormone sensitive lipase
- fatty acids degradation (caused by glucagon) increases
formation of ketoacids
Glucagon in very high concentration
-
enhances the strength of the heart contraction
-
increases blood flow in some tissue /kidney/
-
inhibits gastric acid secretion
Glucagon increases gluconeogenesis and glycogenolysis in the liver.
Glucagon increases glycogenolysis by the following cascade of events:
1.Glucagon activates adenyl cyclase in the
liver
2.Adenyl cyclase causes formation of
c-AMP
3.c-AMP activates protein kinase
4.Protein kinase activates phosphorylase
Phosphorylase promotes degradation of
glycogen into glucose-1-phosphate
Glucose-1-phosphate is dephosphorylated
and glucose diffusis into extracellular fluid
INSULIN
GLUCAGON
↑ glycogenesis
↑ glycogenolysis
↓ gluconeogenesis
↑ gluconeogenesis
↑ fat synthesis
↑ lipolysis
↓ keton bodies plasma
. concentration
.
hormone which stores
energy
.
hormone which stimulates
storage of carbohydrates
↑ keton bodies plasma
.
concentration
.
hormone which releases
energy
.
hormone which stimulates
release of carbohydrates
proteins
proteins
lipids
lipids
„stress hormone”
Diagnosis of diabetes mellitus
-Fasting blood glucose – normally 80 -100 mg/100ml
upper limit of normal level 110 mg/100 ml
-Glucose tolerance test : fasting person ingests 1 g of glucose per
kilogram of body weight
Glucose tolerance curve in a normal person and in patient with diabetes .
Fasting blood
glucose
Glucose tolerance
test (after 2 hours)
Diabetes mellitus
≥ 126 mg%
≥ 200 mg%
Impaired glucose
tolerance
< 126 mg%
140 mg% - 200 mg%
Impaired fasting
glucose
100 mg% - 126 mg%
< 140 mg%
Normal
< 100 mg%
< 140 mg%
Recommendation for diagnosis of diabetes mellitus
Diagnosis of diabetes mellitus
Aceton breath – concentration of acetoacetic acid in the blood
increases. It is converted to acetone which is volatile and
appears in expired air.
Keto acids can be detected in the urine.
Monitoring diabetic control
Long-term, objective assessment of the degree of diabetic control utilizes
periodic measurement of glycosylated hemoglogin (hemoglobin A Ic).
It is present in normal persons, but increases several fold in the presence of
hyperglycemia.
Normal values in nondiabetic subjects reaches 6% of hemoglobin
In poorly controlled patients is above 10% of hemoglobin
The percent of glycosylated hemoglobin gives an estimate of diabetic control
for the preceding 6 to 10 weeks.
Diabetes mellitus is the syndrom of impaired metabolism of
carbohydrates, fats and proteins.
Diabetes mellitus is caused by lack of insulin secretion or by decreased
sensitivity of the tissues to insulin.
There are two types of diabetes mellitus
1. Type I – insulin-dependent diabetes mellitus IDDM is caused by lack of
insulin secretion
1. Type II – non-insulin-dependent diabetes mellitus NIDDM is caused by
decreased sensitivity of target tissues to the metabolic effects of insulin.
This reduced sensitivity to insulin is often called insulin resistance.
Type I diabetes
Type II diabetes
Pathogenesis
Injury to the beta cells of pancreas
or diseases that impair insulin
production / viral infection,
autoimmune disorders /
Metabolic syndrom may precede
diabetes mellitus type II .
Some of the features of metabolic
syndrom include:
obesity
insulin resistance
fasting hyperglycemia
lipid abnormalities / increased blood
triglycerides, decreased HDL
cholesterol /
hypertension
Insuline resistance may be caused by
adnormalities of the signaling
pathways that link receptor activation
with multiple cellular effects or by
decreased number of insulin receptors
in skeletal muscle, liver and adipose
tissue in obese.
Type I diabetes
Type II diabetes
Onset of symptoms
Onset of symptoms may be
Symptoms begin more gradualy.
abrupt.
Diagnosis is frequently made when
Ketoacidosis may be the first
an elevated plasma glucose is found
symptom which is diagnosed.
in routine laboratory examination.
It begins before age of 40,
It begins in persons older then 40
ofen in childhood or adolescence.
Type I diabetes
Type II diabetes
Body habitus
Normal or wasted
Obese
Symptoms
increased thirst
polyuria
increased appetite
ketoacidosis
hyperosmolar coma
Metabolic effects
decreased utilization of glucose for energy
increased utilization of fats for energy
depletion of the body’s proteins
Type I diabetes
Type II diabetes
Plasma glucose concentration
Hight
Hight
Plasma insulin concentration
Low or absent
Hight
Type I diabetes
Type II diabetes
Treatment
Insulin
Caloric restriction and exercises to
reduce body weight.
Drugs that increase insulin sensitivity
/thiazolidinediones, metformin/
Drugs that cause additional release of insulin
/sulfonylureas/
Later stages of diabetes may required insulin
treatment
Effects of hypoinsulinemia
Decreased capture of
Protein catabolism
Stimulation of lipolysis
glucose by tissues
Hyperglycemia
Increase of amino acids
glucosuria
concentration in plasma,
osmotic diuresis
loss of nitrogen with urine
loss of electrolytes
Dehydration,
acidosis
Coma,
death
Increase of FFA concentration
in plasma, ketogenesis,
ketonuria
Increased blood glucose can cause severe cell dehydration.
The increased osmotic pressure in the extracellular fluid
causes osmotic transfer of water out of the cells.
In addition loss of glucose in the urine causes osmotic diuresis
(the osmotic effect of glucose in the renal tubules greatly
decreases tubular reabsorption of fluid).
Massive loss of fluid in the urine causes dehydration of the
extracellular fluid. Extracellular fluid dehydration causes
compensatory dehydration of the cells.
Diabetes mellitus causes increased utilization of fats which
increases release of ketoacids such as acetoacetic acid into the
plasma more rapidly than ketoacids can be oxidized by the
cells.
As a result, the patient develops severe metabolic acidosis.
This leads rapidly to diabetic coma and death unless condition
is treated immediately with large amounts of insulin.
Lipid metabolism in patient with diabetes mellitus
Conversion of acetyl-CoA into malonyl-CoA is impaired. Molecules of acetyl-CoA
condense to form molecules of acetoacetic acid. Acetoacetic acid is also
converted into beta-hydroxybutyric acid and acetone. These substances diffuse
freely through the cell membrane and are transpoted by the blood to the
peripheral tissue – ph of body fluids decreases.
Tissue injury in diabetes
The precise mechanisms that causes tissue injury in diabetes
are not well understood, but they probably involve effects of:
- metabolic abnormalities on proteins of endothelial cells and
vascular smooth muscle cells
- hypertension secondary to renal injury
- atherosclerosis secondary to abnormal lipid metabolism
( ↑ blood cholesterol concentration )
all of it amplify the tissue damage caused by
the elevated glucose
Injury of the vessels causes inadequate blood supply to the
tissues. This in turn leads to increased risk for:
-Heart attack
-Stroke
-Kidney disease
-Retinopathy and blindness
-Ischemia and gangrene of the limbs
-Peripheral neuropathy
Effects of hypoglicemia
Glucose concentration
in plasma
mg/dl
90
Inhibition of insulin secretion
75
Secretion of glucagon, epinephrin, growth hormone, stimulation of
.
sympathetic nervous system. Palpitation, sweating, shakenees,
……….dizzinees, nervousnees occur
60
Secretion of cortisol, disturbances of cognitive processes
45
Lethargy
30
Coma
Convulsions
15
Persistent lesion of central nervous system, death
0
.
Treatment of the patients with hypoglicemia
Severe hypoglicemia (unconsciousness, convulsions)
-Intravenous administration of glucose /usually brings the patient out of shock
within a minute/
-Intravenous administration of potassium ions
-Administration of glucagon or epinephrine /less effectively/, which stimulates
glycogenolysis
Moderate hypoglicemia
- Ingestion of glucose