2. • Diabetes mellitus derived from Greek word for fountain
and the latin word from honey.
• when hyperglycemia increase it lead to polyuria,
ploydipsia, ketonuria, and weigth loss. Over time can lead
to hypertension, heart disease, renal failur, blindness
neurophathy, stroke.
3. INTRODUCTION:
Insulin is a peptide hormone, produced by beta cells
of the pancreas, and is central to regulating
carbohydrate and fat metabolism in the body. Insulin
causes cells in the liver, skeletal muscles, and fat
tissue to absorb glucose from the blood. In the liver
and skeletal muscles, glucose is stored as glycogen,
and in fat cells (adipocytes) it is stored as
triglycerides. When control of insulin levels fails,
diabetes mellitus can result. As a consequence,
insulin is used medically to treat some forms of
diabetes mellitus.
6. Insulin
The insulin plays an important role in storing the
excess energy. In the case of excess
carbohydrates, it causes them to be stored as
glycogen mainly in the liver and muscles.
All the excess carbohydrates that cannot be stored
as glycogen are converted under the stimulus of
insulin into fats and stored in the adipose tissue.
7. Insulin
In the case of proteins, insulin has a direct effect in
promoting amino acid uptake by cells and
conversion of these amino acids into protein.
In addition, it inhibits the breakdown of the
proteins that are already in the cells.
Anabolic
8.
9. STRUCTURE OF INSULIN
v Human insulin consists of 51aa in
two chains connected by 2 disulfide
bridges (a single gene product
cleaved into 2 chains during post-
translational modification).
v T1/2~5-10 minutes, degraded by
Glutathione-insulin
transhydrogenase (insulinase)
which cleaves the disulfide links.
v Bovine insulin differs by 3aa,
pork insulin differs by 1aa.
v Insulin is stored in a complex
with Zn2+ions.
10. BIOSYNTHESIS OF INSULIN:
Insulin is synthesized as
proinsulin in pancreatic β-
cells. It contains a signal
peptide which directs the
nascent polypeptide chain to
the rough endoplasmic
reticulum. Then it is cleaved
as the polypeptide is
translocated into lumen of
the RER, forming proinsulin.
Proinsulin is transported to
the trans-Golgi network
(TGN) where immature
granules are formed.
Proinsulin undergoes
maturation into active
insulin through action of
cellular endopeptidases
known as prohormone
convertases (PC1 and PC2),
as well as the exoprotease
carboxypeptidase E. The
endopeptidases cleave at 2
positions, releasing a
fragment called the C-
peptide, and leaving 2
peptide chains, the B- and A
- chains, linked by 2
disulfide bonds. The
cleavage sites are each
located after a pair of basic
residues and after cleavage
these 2 pairs of basic
residues are removed by
the carboxypeptidase. The C
-peptide is the central
portion of proinsulin, and
the primary sequence of
proinsulin goes in the order
"B-C-A”
The resulting mature insulin
is packaged inside mature
granules waiting for
metabolic signals (such as
leucine, arginine, glucose
and mannose) and vagal
nerve stimulation to be
exocytosed from the cell into
11. EFFECT OF INSULIN ON GLUCOSE UPTAKE AND
METABOLISM
Insulin binds
to its
receptor
Starts many
protein
activation
cascades
glycogen
synthesis
These include
translocation of
Glut-4 transporter
to the plasma
membrane and
influx of glucose
glycolysis triglyceride
12. Insulin release
qwhen Glucose get bind to
the receptor and cause.
qThis lead to increase ATP
which close ATP
depended K+ channel and
open Ca+ valtage ligant by
depolarization of the
membrane.
qAs the concentration of
Ca+ increase in to
intracelular
Cause insulin resale from
the granules
13. MOA
Insulin acts on specific receptors located on the cell
membrane of practically every cell, but their density
depends on the cell type: liver and fat cells are very
rich.
The insulin receptor is a combination of four subunits
held together by disulfide linkages:
Two alpha subunits that lie entirely outside the cell
membrane
Two beta subunits that penetrate through the
membrane, protruding into the cell cytoplasm
14.
15. metoblism
Insulin binds with alpha
↓
beta unit autophosphorylated
↓
tyrosine kinase
↓
phosphorylation of multiple other intracellular
enzymes including a group called
insulin-receptor substrates (IRS)
16. MECHANISM OF ACTION of the receptor :
v The insulin receptor is a receptor
tyrosine kinase (RTK) . Consisting of 2
extracellular α and 2 transmembrane β
subunits linked together by disulfide
bonds, orienting across the cell
membrane as a heterodimer
v It is oriented across the cell membrane
as a heterodimer.
v The α subunits carry insulin binding
sites, while the β subunits have tyrosine
kinase activity.
17. MECHANISM OF ACTION:
qAfter insulin bend to the
receptor by Alpha subunit and
influence B sub unit to cause
mutation and phosphorlation of
tyrosin kinase to the active form
which direcated to the
cytoplasmic protien of (IRS) inslin
receptor substrate
qIRS bind to other active kinase
(phosphatidylionsitol-3- kinase as
reasult transation of Glucose
transport
(GLUT4) to the cell membran and
result increase glucose up take
18.
19. DEGRADATION OF INSULIN:
The internalized receptor-insulin complex is
either degraded intercellularly or returned
back to the surface from where the insulin is
released extracellularly. The relative
preponderance of these two processes differs
among different tissues: maximum
degradation occurs in liver, least in vascular
endothelium.
20. FATE OF INSULIN
▲ Insulin is distributed only extracellularly. It is a peptide; gets
degraded in the g.i.t. if given orally.
▲ Injected insulin or that released from the pancreas is metabolized
primarily in liver and to a smaller extent in kidney and muscles.
▲ Nearly half of the insulin entering portal vein from pancreas is
inactivated in the first passage through liver.
▲ Thus, normally liver is exposed to a much higher concentration (4-8
fold) of insulin than other tissues.
▲ During biotransformation the disulfide bonds are reduced- A and B
chains are separated. These are further broken down to the constituent
amino acids
22. Diabetes
• People who do not produce the necessary amount
of insulin have diabetes. There are two general
types of diabetes.
– The most severe type, known as Type I or
juvenile-onset diabetes, is when the body does
not produce any insulin. Due to immune
response,ketoacidosis more comman
–Type II diabetics produce some insulin, but it is
either not enough or their cells do not respond
normally to insulin. This usually occurs in obese
or middle aged and older people.
–Gestation diabitese :in pregnancy (metformin)
–Prediabetes : (FPG 100-125) LEAD TO TYPEII
23. Diabetes complication
Short complication
• Hyperglacymia
• Hypoglacymia
Long complication
• Macrovascular :-
(hypertention – heart falier and
stock)
• Microvascular Damage
v Retinopathy
v Nephropathy
v Sensory and motor neuropathy
v Autonomic
neuropathy(Gastroparesis)
v Amputation secondary infection
v Erectile dysfunction
24. Carbohydrate Metabolism – Muscle
Immediately after a high-carbohydrate meal, the glucose that is absorbed
into the blood causes rapid secretion of insulin
The normal resting muscle membrane is only slightly permeable to glucose,
except when the muscle fiber is stimulated by insulin – so during much of the
day, muscle tissue depends not on glucose for its energy but on fatty acids
Moderate or heavy exercise – exercising muscle fibers become more
permeable to glucose even in the absence of insulin
Few hours after a meal because of insulin – Glucose stored as muscle
GLYCOGEN – used during anaerobic exercise
25. Carbohydrate Metabolism - Liver
Glucose absorbed after a meal to be stored almost immediately in the liver
in the form of glycogen - Between meals – liver glycogen – glucose.
1. Insulin inactivates liver phosphorylase - enzyme that causes liver
glycogen to split into glucose. This prevents breakdown of the glycogen
that has been stored in the liver cells.
2. It increases the activity of the enzyme glucokinase, which is one of the
enzymes that causes the initial phosphorylation of glucose after it diffuses
into the liver cells - phosphorylated glucose cannot diffuse back through
the cell membrane.
26. Carbohydrate Metabolism - Liver
3. Insulin also increases the activities of the enzymes that
promote glycogen synthesis, including glycogen synthase -
polymerization of the monosaccharide units to form the
glycogen
4. Enzyme glucose phosphatase inhibited
5. Glycolysis (oxidation of glucose) is increased in muscle &
liver by activating enzyme phosphofructokinase
27. Carbohydrate Metabolism - Liver
Glucose Is Released from the Liver Between Meals
1. The decreasing blood glucose causes the pancreas to decrease its insulin
secretion.
2. Stopping further synthesis of glycogen in the liver and preventing
further uptake of glucose by the liver from the blood.
3. The lack of insulin along with increase of glucagon, activates the
enzyme phosphorylase, which causes the splitting of glycogen into glucose
phosphate.
4. The enzyme glucose phosphatase, becomes activated by the insulin lack
and causes the phosphate radical to split away from the glucose
28. Carbohydrate Metabolism
When the quantity of glucose entering the liver cells is more than can
be stored as glycogen, insulin promotes the conversion of all this
excess glucose into fatty acids – triglycerides in VLDL - adipose tissue
and deposited as fat
Insulin also inhibits gluconeogenesis & glycogenolysis. Thus inhibiting
glucose production
Insulin decreases the release of amino acids from muscle and other
extrahepatic tissues and in turn the availability of these necessary
precursors required for gluconeogenesis
29. Fat Metabolism - Liver
Insulin increases the utilization of glucose by most of the body’s tissues
– fat sparer.
Promotes fatty acid synthesis in liver from excess glucose
1. Insulin increases the transport of glucose into the liver cells –
extra glucose via glycolytic pathway – pyruvate – acetyl CoA –
fatty acids
2. Energy from glucose via citric acid cycle - excess of citrate and
isocitrate ions - activates acetyl CoA carboxylase – acetyl CoA to
form malonyl CoA
30. Fat Metabolism – Adipose Tissue
Fat storage in adipose tissue
1. Fatty acids (triglycerides) are then transported from the
liver by way of the blood lipoproteins to the adipose cells.
2. Insulin activates lipoprotein lipase - splits the triglycerides
again into fatty acids, a requirement for them to be absorbed
into the adipose cells - again converted to triglycerides and
stored
31. Fat Metabolism – Adipose Tissue
- Insulin promotes glucose transport through the cell membrane
into the fat cells - large quantities of alpha glycerol phosphate
- supplies the glycerol that combines with fatty acids to form
the triglycerides
- Insulin inhibits the action of hormone-sensitive lipase – no
hydrolysis of the triglycerides stored in the fat cells - release
of fatty acids from the adipose tissue into the circulating blood
is inhibited
32. Fat Metabolism
Insulin deficiency - free fatty acid becomes the main energy
substrate used by essentially all tissues of the body besides the
brain – ketoacidosis – coma, death
The excess of fatty acids in the plasma also promotes liver
conversion of some of the fatty acids into phospholipids and
cholesterol - atherosclerosis
33. Protein Metabolism and Growth
1. Insulin stimulates transport of many of the amino acids into the
cells
2. Insulin increases the rate of transcription of selected DNA genetic
sequences
3. Insulin increases the translation of mRNA
4. Insulin inhibits the catabolism of proteins
5. In the liver, insulin depresses the rate of gluconeogenesis - conserves
the amino acids in the protein stores of the body
Insulin deficiency – enhanced urea excretion in the urine - protein wasting
– weakness
Insulin and Growth Hormone Interact Synergistically to Promote
Growth
35. Effects of insulin on various tissues
Adipose issue
Increased glucose entry
Increased fatty acid synthesis
Increased glycerol phosphate synthesis
Increased triglyceride deposition
Activation of lipoprotein lipase
Inhibition of hormone-sensitive lipase
Increased K+ uptake
Muscle
Increased glucose entry
Increased glycogen synthesis
Increased amino acid uptake
Increased protein synthesis in ribosomes
Decreased protein catabolism
Decreased release of gluconeogenic amino acids
Increased K+ uptake
36. Effects of insulin on various tissues
Liver
Decreased ketogenesis
Increased protein synthesis
Increased lipid synthesis
Decreased gluconeogenesis
Increased glycogen synthesis
General
Increased cell growth
37. Insulin also increase in the secretion of HCL
by parietal cells in the stomach via vagus
nerve
Insulin test is done to check whether
vagotomy is complete or not, as in case of
treatment of peptic ulcer
38.
39. Fasting level of blood glucose of 80 to 90 mg/100
ml, the rate of insulin secretion is minimal — 25
ng/kg of body weight per minute
41. DIABETES MELLITUS
Insulin is effective in all
forms of diabetes mellitus
and is a must for type 1
cases, as well as for post
pancreatectomy diabetes
and gestational diabetes.
Many type 2 cases can be
controlled.
Insulin therapy is generally
started with regular insulin
given s.c. before each major
meal. The requirement is
assessed by testing urine or
blood glucose levels .
DIABETIC KETOACIDOSIS
(DIABETIC COMA)
Regular insulin is used
to rapidly correct the
metabolic
abnormalities.
Usually within 4-6 hours
blood glucose reaches 300
mg/dl. Then the rate of
infusion is reduced to 2-3
U/hr
HYPEROSMOLAR
(NONKINETIC
HYPERGLYCAEMIC COMA)
This usually occurs in
elderly type 2 cases. The
cause is obscure.
The general principles of
treatment are the same as
for ketoacidotic coma, except
that faster fluid replacement
is to be instituted as alkali is
usually not required.
CONCLUSION:
