Insulin - A hormone from Pancreas
Lecture NO : 02nd MBBS
Dr Muhammad Ramzan
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
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
Endocrine Pancreas
• Pancreas is made up of 2 functionally different organs
• An endocrine Pancreas - the source of Insulin; Glucagon
Somatostatin and pancreatic polypeptide
1
• The exocrine Pancreas is the major digestive gland. 2
Pancreas – Endo and Exocrine parts
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
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
Structure of Insulin
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
3
• 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
Biosynthesis of Insulin – the pathway
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
Insulin Exocytosis
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 8 -12 vs. 4-6 minutes
2
• It allows discrimination B/w endogenous and exogenous
sources of insulin in the evaluation of hypoglycemia
3
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 4 - 6 minutes
• C- peptide is cleared later than insulin
Insulin clearance/degradation
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
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
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
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)
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
Insulin receptor – the mechanism
Insulin - mechanism of action
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
Metabolic effects of Insulin
• These include effects on :
• Carbohydrate (CHO)metabolism
• Lipid metabolism and
• Protein metabolism
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)
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
1
2
• Production of ATP from aerobic metabolism of glucose
Conversion of excess glucose to Glycogen
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
Insulin - Effects on lipid metabolism
promotes Lipogenesis
• It increases triglyceride (TG) synthesis from the FAs and
• storage in fatty tissue (FAs from excess glucose)
1
• It reduces breakdown of fats in adipose tissue- Lipolysis
by inhibiting intracellular lipase to hydrolyze TG
2
Insulin – metabolic effects on CHO and lipids
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
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
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
Excess of Insulin – the Clinical Significance
• Insulin excess causes the development of :
• Hyperinsulinemia, Insulin resistance, obesity and
• Metabolic syndrome
• Dyslipidemia
• Cardiovascular disease