Download Insulin

PHYSIOLOGY OF
PANCREAS
S. Sh. Sadr MD
Professor of Tehran University
Department of Physiology
General Informations
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W : 50 – 75 gr
Langerhans Islet : 0.5 – 1.5 million
Histology :
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α : 20 – 30 % ; Glucagon (around of islet)
β : 60 – 80 % ; Insulin (center of islet)
δ : 8 % ; Sumatostatin & Gastrin (between α, β)
PP or F : variable ; pancreatic polypeptide)
Insulin
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W : 6000 d
51 aa (A chain = 21, B chain = 30)
Pro-insulin : 9000 d, 84 aa (= 51+33)
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C-peptide : 33 aa
Store : 4 u/kg (in adult = 200 u)
Gene on short arm of Chr. 11
Secretion of Insulin
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1- Basal secretion :
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Continuous, 1 u/h
2- Stimulated secretion :
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IV Glu. : peak : after 3 – 5 min = 8 – 10 x BS
Oral Glu. : peak : after 0.5 – 1 h = 6 – 8 x BS
Insulin response to Glu. Infusion shows a rapid
first phase of release followed by a fall and a later
slower second phase
Metabolism of Insulin
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Half life : 6 min
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When insulin is secreted into the blood, it
circulates almost entirely in an unbound form
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Each hepatic passage : 40 – 50 % inactivation
Mechanism of Action
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Receptor :
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W = 300,000 d
2α (extracellular) + 2β(intracellular)
Insulin + α subunit → autophosphorilation of β
subunit → tyrosine kinase activity
↓ cAMP
↑ Glycogenesis, lipogenesis and Pr. Synthesis
↓ Glycogelolysis, lipolysis, proteolysis,
gluconeogenesis and ketogenesis
Effects of Insulin
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Metabolism of Carbohydrates :
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↑ Glu. Uptake from plasma
Facilitates Glu. entrance into cells
↓ rate of release of Glu. From liver by :
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By Inhibiting glycogenolysis
By Stimulating glycogen synthesis
By Stimulating Glu. Uptake
By Stimulating glycolysis
By indirectly inhibiting glycogenesis via inhibition of fatty acid
mobilization from adipose tissue
Insulin is necessary for entrance of Glu. Into the most of cells
(Except of CNS, intestine epithelium, pancreas cells and renal tubul epithelium)
Effects of Insulin
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Metabolism of Carbohydrates :
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Effect on Liver:
 Glu. Uptake from plasma
 ↑ glycogenesis
 ↓ glycogenolysis
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↓ glyconeogenesis
Glu. Converting to fatty acids
Effect on Muscles:
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Most of day time: fatty acid
At rest: glu. resistant
during sport: needs glu. for providing energy
After meal: rapid glu. Transport into muscle cells
Effects of Insulin
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Metabolism of Proteins:
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↑ transport of aa into hepatic and muscle cells (unrelated
but may be related to Na/K pump activity)
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Val
Leu
Ile
Tyr
Phe
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↑ synthesis of protein
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↓ proteolysis
to glu. transport
Effect of Insulin on Protein
Metabolism and on Growth
Insulin Promotes Protein Synthesis and
Storage.
1 . Insulin stimulates transport of many of
the amino acids into the cells
2. Insulin increases the translation of
messenger RNA
3. Insulin also increases the rate of
transcription of selected DNA genetic
sequences in the cell nuclei
4. Insulin inhibits the catabolism of proteins
5. In the liver, insulin depresses the rate of
gluconeogenesis
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Insulin Deficiency Causes Protein Depletion and
Increased Plasma Amino Acid
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Insulin and Growth Hormone Interact
Synergistically to Promote Growth
Effects of Insulin
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Metabolism of Lipids:
 ↓ lipolysis
 ↑ synthesis of fatty acids in liver
As a result:
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Effect on growth:
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Insulin is an Anabolic Hormone
In embryonic life, Insulin is the most important hormone for
embryonic growth.
Effect on Glucagon:
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Insulin refuses glucagon secretion
The end effects of Insulin
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1. Within seconds after insulin binds with its membrane
receptors, the membranes of about 80 percent of the body’s cells
markedly increase their uptake of glucose.
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2. The cell membrane becomes more permeable to many of
the amino acids, potassium ions, and phosphate ions,causing
increased transport of these substances into the cell
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3. Slower effects occur during the next 10 to 15 minutes to
change the activity levels of many more intracellular metabolic
enzymes.
• 3. Slower effects occur during the next 10 to 15
minutes to change the activity levels of many more
intracellular metabolic enzymes
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4. Much slower effects continue to occur for hours
and even several days. They result from changed rates
of translation of messenger RNAs at the ribosomes to
form new proteins and still slower effects from changed
rates of transcription of DNA in the cell nucleus
Insulin Secretion
Increased by
Decreased by
D-glucose
Glucagon-like
Fasting
Galactose
peptide I
Gasteric inhibitory
polypeptide
Secretin
Cholecystokinin
Vagal activity
Acetylcholine
β-adrenergic activity
Sulfounylurea drugs
Exercise
Mannose
Glyceraldehyde
Protein:
Arg,
Lys, Leu, Ala
Ketoacids
Free fatty acids
Potassium
Calcium
Glucagon
Endurance
training
Somatostatin
Galanin
Pancreastatin
Interleukine I
α2-adrenergic
activity
Prostaglandin E2
Diazoxide
Glucagon
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Single chain polypeptide 29 aa
3485 d
α cells
Entro-glucagon:
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Larger molecule
Half life = 6 min
Hepatic and renal metabolizing
Glomerule infiltration
Effects of Glucagon
(Completely against Insulin effects)
 Metabolism of Carbohydrates :
 ↑ glycogenolysis in liver
 ↑ glyconeogenesis (slow process)
 Inhibition of glycogen synthesis in liver
 Metabolism of Lipids :
 ↑ lipolysis
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Other effects:
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β cell stimulation
Catecholamine secretion stimulation
↑ heart muscle contractility
↑ bile and calcitonin secreton
Glucagon Causes Glycogenolysis
and Increased Blood Glucose
Factors Influencing Glucagon
Release
Stimulation
Amino
acids
Gastrointestinal
polypeptide hormones
Catecholamine (exercise)
Growth Hormone
Glucocorticoid
Inhibition
Glucose
Insulin
Free
fatty acids
Pancreas Islets Control
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Effective agents:
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Metabolites
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Hormones
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Neural factors
Pancreas Islets Control
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Metabolites:
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Glucose: ↑ insulin, ↓ glucagon and
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hypothalamic effects
Amino acids: Arg, lys and Leu
aa. amplifies glu. effect on insulin secretion
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Lipids:
Fatty acids and Ketons: inhibitory effects on α
cells and stimulatory effect on β cells.
Pancreas Islets Control
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Hormones:
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GI hormones:
 oral glu. increases insulin more than IV glu.
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Gastrin
Secretin
CCK
GIP
Entroglucagon
Gastrin, CCK and GIP, ↑ glucagon secretion.
glucagon
Other hormones: GH, Thyroxin, Glucocorticoids, SS
Pancreas Islets Control
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Neural factors:
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α2 adrenergic: ↓ insulin
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β adrenergic: ↑ insulin
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Parasympathetic, dopamine, serotonin and PG : ?
Somatostatin
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δ cells
Polypeptide with 14 aa
Half life = 2 min
All of the factors related to digestion and
absorption stimulates SS. secretion:
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↑ glu.
↑ aa
↑ fatty acids
↑ GI hormones
Effects of Somatostatin
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Insulin and glucagon secretion inhibition
(local effect)
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↓ gastric, duodenal and biliary bladder motility
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↓ GI secretions and absorption
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GH inhibitor
Blood Sugar Control
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Normal FBS = 70 – 100 mgr/100cc
1 hour after eating = 120 – 140 mgr/100cc
Control Mechanism:
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Liver
Insulin and glucagon
Hypoglycemia
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Early
Late
Blood Sugar Control
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↑ BS:
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↑ extracellular osmotic pressure → cellular
dehydration
Excretion in urine → osmotic dieresis →
polydipsia and polyuria signs → dehydration
↓ BS:
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Cerebral cells, retina and testicular epithelium
Diabetes Mellitus (pathophysiology)
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↓ insulin :
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↓ metabolism of gu. in cells
↑ fatty acids from lipid storages
Protein emptying in tissues
Abnormalities:
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Glu. excretion in urine: > 180 mgr/100cc
Intra and extra cellular dehydration: shock
Acidosis and Coma: metabolism changing from
carbohydrate to lipid
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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.
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Chronic high glucose concentration also causes damage
to many other tissues.
Peripheral neuropathy,
( which is abnormal function of peripheral nerves)
Autonomic nervous system dysfunction
These abnormalities can result in impaired
cardiovascular reflexes
Impaired bladder control
Decreased sensation in the extremities
Other symptoms of peripheral nerve damage.
Hypertension
(secondary to renal injury)
Atherosclerosis
( secondary to abnormal lipid metabolism)
Diabetes Mellitus Causes Increased
Utilization of Fats and
Metabolic Acidosis.
Rapid and deep breathing
Clinical Characteristics of DM
type I and type II
Type I
Type II
Age at Beginning
Usually under 20
Usually above 40
Body Mass
↓ (Thin) abnormal
Obese
↓ or empty
Normal to ↑ at
beginning
Plasma Insulin
Plasma Glucagon ↑ it can be suppressed
↑, resistant to
suppression
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↑
Insulin Susceptibility
Normal
↓
Treatment
Insulin
↓ Weight, Insulin,
Drugs*
Plasma Glucose
Insulin Resistance: Causes
1)
2)
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Obesity and Overweight
Glucocorticoid excess (Cushing syndrome)
↑ GH
Pregnancy and GDM
PCO
Lipodystrophy
Insulin Receptor Ab
Insulin Receptor Mutation
Hemochromatosis
Metabolic Syndrome
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Obesity
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Insulin Resistance
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Fasting Hyperglycemia
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Lipid Disorders (↑ TG and ↓ HDL)
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Hypertension
Obesity, insulin resistance and
metabolic syndrome are usually
present before DM II