1. Basics of Insulin
Dr. Chintan Parmar
- Assistant Professor
- Dept. of physiology
- KIMS & RF
- Dt.: 17 / 07 / 2014

2. Outline
- Introduction
- Brief history
- Chemistry and Synthesis
- Mechanism of action
- Physiologic functions
- Mechanisms of Secretion
- Factors affecting Secretion

3. Intro. - The Pancreas
Digestive + Endocrine functions
Insulin and Glucagon - crucial for normal regulation of
glucose, lipid and protein metabolism
(1) the acini, which secrete digestive juices into the
duodenum,
(2) the islets of Langerhans, which secrete insulin and
glucagon directly into the blood - three major types of
cells; alpha, beta and delta cells + PP cells
Beta cells – 60 % - insulin, Alpha – 25 % - glucagon,
Delta – 10 % - somatostatin, PP - pancreatic polypeptide

5. Insulin
Insulin is the first hormone to be isolated,
purified, crystallized & synthesized.
Insulin secretion is associated with energy
abundance.
When there is great abundance of energy-
giving foods in the diet, especially excess
amounts of carbohydrates, insulin is
secreted in great quantity.

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. HistoryInsulin was first isolated from the pancreas in 1922 by
Banting and Best, and almost overnight the outlook
for the severely diabetic patient changed from one of
rapid decline and death to that of a nearly normal
person.
Children dying from diabetic ketoacidosis were kept
in large wards, often with 50 or more patients in a
ward, mostly comatose. Grieving family members
were often in attendance, awaiting the (until then,
inevitable) death.
In one of medicine's more dramatic moments, Banting,
Best and Collip went from bed to bed, injecting an
entire ward with the new purified extract. Before they
had reached the last dying child, the first few were
awakening from their coma, to the joyous exclamations

9. Frederick Banting joined by Charles Best,
1924
The Nobel Prize committee in 1923 credited the practical
extraction of insulin to a team at the University of Toronto
and awarded the Nobel Prize to two men: Frederick Banting
and J.J.R. Macleod. They were awarded the Nobel Prize in
Physiology or Medicine in 1923 for the discovery of insulin.
Banting, insulted that Best was not mentioned, shared his
prize with him, and Macleod immediately shared his with

10. Insulin Chemistry and Synthesis
Insulin is a small protein; - has a molecular weight of
5808. It is composed of two amino acid chains
connected to each other by disulfide linkages
Beta cells - beginning with translation of the insulin
RNA by ribosomes attached to the ER to form an insulin
preprohormone (11500) - cleaved in the ER to form a
proinsulin (9000) - further cleaved in the Golgi
apparatus to form insulin - secretory granules
unbound form; it has a plasma half-life that averages
only about 6 minutes - degraded by the enzyme
insulinase mainly in the liver, to a lesser extent in the
kidneys and muscles

11. C – peptide (Connecting Peptide) has no biological activity,
but its estimation in plasma serves as an useful index for the
endogenous production of insulin.

12. MOA
Insulin first binds with and activates a membrane
receptor protein (300,000)
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

13. MOA
Insulin binds with alpha
↓
beta unit autophosphorylated
↓
tyrosine kinase
↓
phosphorylation of multiple other intracellular enzymes
including a group called
insulin-receptor substrates (IRS)

15. MOAWithin seconds, the membranes of about 80
per cent of the body’s cells markedly increase
their uptake of glucose.
This is especially true of muscle cells,
adipose cells & liver cells but is not true of
most neurons in the brain
The cell membrane becomes more
permeable to many of the amino acids, K ions
and phosphate ions, causing increased
transport of these substances into the cell

16. MOA
Slower effects occur during the next 10 to 15
minutes to change the activity levels of many more
intracellular metabolic enzymes
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

17. Physiologic
functions of
Insulin

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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

28. 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

30. Confused ???
Here is the summary…

31. 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

32. Effects of insulin on various tissues
Liver
Decreased ketogenesis
Increased protein synthesis
Increased lipid synthesis
Decreased gluconeogenesis
Increased glycogen synthesis
General
Increased cell growth

33. 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

34. Mechanisms of Insulin Secretion

36. 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

37. Biphasic insulin response to Glucose,
1st rapid phase – preformed, 2nd slow rise phase - new

38. Glucagon
Growth Hormone
Insulin Vs Cortisol
Epinephrine
Thyroid hormone

39. Thank You…