1. Insulin - A hormone from Pancreas Lecture NO : 02nd MBBS
Dr Muhammad Ramzan

2. Insulin – the definition
Insulin is a protein hormone(51AAs) secreted by the β cells of the Islets of Pancreas
Insulin is a major hypoglycemic agent

3. Insulin - the background
Major action of the Insulin is to regulate metabolism of CHO (glucose) and lipids
↑ glucose uptake by the liver, muscles and adipose
Reduces hyperglycemia
It facilitates Glycogen storage in the Liver and muscles
Insulin Deficiency produces Diabetes mellitus and
Excess Hyper insulinemia, Insulin resistance and obesity

4. Endocrine Pancreas
Pancreas is made up of 2 functionally different organs
An endocrine Pancreas - the source of Insulin; Glucagon Somatostatin and pancreatic polypeptide
The exocrine Pancreas is the major digestive gland. 2

5. Pancreas – Endo and Exocrine parts

6. Islets of Langerhans – the composition
Endocrine Pancreas consist of .7-1million endocrine glands - Islets of Langerhans – Wt 1- 2 G in adults 4 types of cells are present in Islets:
A/α cells = Glucagon's
B/ β cells = Insulin – 60% of Islets cells
D/ delta cells = Somatostatin
F cells = Pancreatic polypeptide

7. Structure of insulin - 2 peptide chains and C- peptide
Insulin has of 51 Amino acids, arranged in 2 peptide chains designated as A and B
Chain A = 21 AAs - Chain B = 30 AA
Both are linked together by 2 disulfide bridges
Insulin molecule is secreted always with equal amount of C – peptide with 31 AAs

8. Structure of Insulin

9. Biosynthesis of Insulin - the pathway secreted as Pre Prohormone 86 AAs
It is produced as Prepro– insulin (111AA) in the RER of β cells
Has Signal sequence; A+ B chain and C- peptide - 4
Cleaved to Proinsulin (86AA) by the Microsomal enzymes after losing Signal Sequence in RER
C-peptide (35AA) is excised from the Proinsulin by the Endo - peptidase in the RER, Generating the mature form of Insulin
Regulation of Insulin synthesis Current Diabetes Rev; 2014

10. Biosynthesis of Insulin – the pathway

11. Insulin secretion as vesicles - Exocytosis in response to CHO ingestion
Insulin and free C - peptide is packed in Golgi and stored as secretary vesicles into the β cell cytoplasm
C - peptide is also released into circulation in equal amounts along with Insulin
Secretary vesicles are released from β cells by Exocytosis and diffuse into Islet capillary blood after :
Receiving stimulus from the body like CHO ingestion

12. Insulin Exocytosis

13. Significance of C- peptide 35 to 31AAs by cleavage
C- peptide (31AA) is produced during Insulin synthesis and is released in the equal amounts with insulin
Has no biological Activity but is essential for Insulin folding 1
Good indicator for insulin secretion for having long half life than insulin vs. 4-6 minutes
It allows discrimination B/w endogenous and exogenous sources of insulin in the evaluation of hypoglycemia 3

14. Insulin - the degradation and clearance
It is degraded by the Insulinase in the GIT that is why it is given parentally only
Is cleared by the kidney and liver
Half life of insulin is minutes
C- peptide is cleared later than insulin

15. Insulin clearance/degradation

16. Insulin secretion – the regulation 2 pathways direct and indirect
Insulin secretion is regulated through 2 pathways :
Direct regulation: through hyperglycemia sensed by β cells – the major one and :
indirect regulation : Through physiological stimuli, diet and hormones

17. Direct regulation of Insulin secretion hyperglycemia is the major stimulus
Primarily insulin is secreted in response to plasma glucose level and hyperglycemia is sensed by the β cells
It stimulate the release of Insulin from the secretary vesicles
stored in the cytoplasm of β cells
C- peptide is also released along with Insulin

18. Indirect regulation of Insulin secretion the stimulators
Insulin secretion is also regulated through :
physiological stimuli : smell, sight and taste of food
Diet containing CHOs (glucose) , proteins (AA ). Leucine
Hormones: GH; Prolactin, Catecholamines
Enteric hormones: Gastrin and Cholicystokinin

19. Insulin – the mechanism of action like peptide hormones
Insulin is a polypeptide and it acts through extra cellular receptors - Tyrosine Kinas (Tetramer, α and β subunits. 4 units)
Tyrosine Kinas also functions as an enzyme that transfers phosphate group from ATP to the :
Tyrosine residues in the intracellular target proteins
Binding of Insulin to α subunit causes the β subunit to phosphorylate itself - (Auto Phosphorylation)

20. Insulin – Phosphorylation of proteins an activator of receptor
It, thus activates the catalytic activity of the receptor
The activated receptor, Phosphorylates a no of intracellular proteins which alter their activity and :
generates biological effects
Several of these proteins act as Insulin Receptor Substrate like Insulin Receptor Substrate 1 or IRS -1 (Skeletal muscles)
IRS activate Glucose transporters (GLUT) to ↑ entry of Glucose

21. Insulin receptor – the mechanism

22. Insulin - mechanism of action

23. Phospho and dephosphorylation of Proteins/enzymes
When these Receptor Substrates are Phosphorylated
they phosphorylate other proteins/enzymes to :
mediate insulin effects
Action of insulin is terminated by Dephosphorylation of Receptor and IRS - 1 or degradation by Insulinase

24. Metabolic effects of Insulin
These include effects on :
Carbohydrate (CHO)metabolism
Lipid metabolism and
Protein metabolism

25. Insulin effects on CHO metabolism produces hypoglycemia
Major effect of Insulin is to increase the Glucose uptake by the Liver, muscles and Adipose tissue
the Insulin sensitive tissues
This decreases the blood glucose level especially after
dietary intake to prevent hyperglycemia after :
GIT absorption (Post parandial hyperglycemia)

26. CHO metabolism – Excess of glucose Glycogen in liver
Insulin increases Synthesis and Storage of glycogen in liver and muscles - ↑Glycogenesis
↓es breakdown of glycogen – Glycogenolysis
Production of ATP from aerobic metabolism of glucose

27. Conversion of excess glucose to Glycogen

28. Insulin -– further excess of Glucose TG and Lipoprotein Synthesis
Further excess is used for FA synthesis in liver and Glycerol in Adipose tissues
FAs and glycerol are used by the liver to synthesize TG and lipoproteins (VLDL – C)
TG and lipoproteins are exported to the peripheral tissues for energy production and consumption - ATP

29. Insulin - Effects on lipid metabolism promotes Lipogenesis
It increases triglyceride (TG) synthesis from the FAs and
storage in fatty tissue (FAs from excess glucose)
It reduces breakdown of fats in adipose tissue- Lipolysis by inhibiting intracellular lipase to hydrolyze TG

30. Insulin – metabolic effects on CHO and lipids

31. Insulin effects on lipid metabolism – the benefits prevents fats consumption for energy
Insulin prevents the use of fats as an energy source by inhibiting the release of Glucagon
It prevents FA oxidation and Ketogenesis
Instead, Insulin facilitates the breakdown of glycogen in liver and muscles As insulin is always present in the body

32. Insulin - Effects on Protein metabolism Increases protein synthesis
Insulin is an anabolic hormone and stimulates the entry of AAs in the cell to increase protein synthesis
It ↑ genetic expression by Replication of DNA leading to (transcription) mRNA synthesis and leads to :
Translation for protein synthesis and enzymes
↑ growth by cell proliferation in Liver land embryo

33. Insulin – secretion abnormalities the deficiency
Insulin may be secreted in excess or there can be deficiency of Insulin
Both conditions lead to the development of significant clinical conditions
Insulin deficiency leads to the development of Diabetes Mellitus – A hyperglycemic state
It is the inability of the body tissues to utilize Glucose

34. Excess of Insulin – the Clinical Significance
Insulin excess causes the development of :
Hyperinsulinemia, Insulin resistance, obesity and
Metabolic syndrome
Dyslipidemia
Cardiovascular disease