InsulinInsulin Site of Secretion:Site of Secretion:

Pancreas contains:Pancreas contains: -cells Glucagons-cells Glucagons -cells Insulin-cells Insulin -cells Somatostatin-cells Somatostatin F-cells (PP cells) F-cells (PP cells) Pancreastic polypeptides.Pancreastic polypeptides.

StructurStructure:e: Peptide hormone composed of two chains of amino acids.Peptide hormone composed of two chains of amino acids.

Chain A composed of 21 amino acid residues.Chain A composed of 21 amino acid residues. Chain b composed of 30 amino acid residues.Chain b composed of 30 amino acid residues. The two chain are connected by two disulfide bonds.The two chain are connected by two disulfide bonds. Insulin is stored as proinsulin.Insulin is stored as proinsulin.

Animals Animals Insulin:Insulin:

Procine Insulin:Procine Insulin: Differ from human Insulin in the terminal Differ from human Insulin in the terminal

amino acid of chain B.amino acid of chain B. Less side effects.Less side effects.

Bovine Insulin:Bovine Insulin: Differ from human Insulin in the terminal Differ from human Insulin in the terminal

amino acid of chain B (B 30). In addition to amino acid of chain B (B 30). In addition to A8, A10 in chain A.A8, A10 in chain A.

Regulation:Regulation: Stimulated by:Stimulated by:

Glucose, Amino acids, Fatty acids and ketone Glucose, Amino acids, Fatty acids and ketone bodies.bodies.

Vagal nerve and Vagal nerve and 22-adrenergic receptors -adrenergic receptors stimulation.stimulation.

Inhibited by:Inhibited by: 22-adrenergic receptors stimulation.-adrenergic receptors stimulation.

Actions of Insulin:Actions of Insulin: Immediate (Rapid) Effect:Immediate (Rapid) Effect:

Starts within seconds.Starts within seconds. Enhanse transport of glucose into muscle Enhanse transport of glucose into muscle

cells and adipose tissues.cells and adipose tissues. Intermediate Effect:Intermediate Effect:

3- 6 hours after administration.3- 6 hours after administration. Enhances all cellular enzymes.Enhances all cellular enzymes.

Long-term Effect:Long-term Effect: Several hours to days.Several hours to days. Stimulate cell division and cell Stimulate cell division and cell

differentiation. differentiation.

GlucagonsGlucagons

Site of Secretion:Site of Secretion: -cells of the pancreas.-cells of the pancreas.

Structure:Structure: Polypeptide composed of 29 amino acid Polypeptide composed of 29 amino acid residues.residues.

Action:Action: Enhances Glycogenolysis and Enhances Glycogenolysis and Gluconeogenesis. It prevents hypoglycemia.Gluconeogenesis. It prevents hypoglycemia.

Antagonists:Antagonists: Used to treat type two Diabetes. Used to treat type two Diabetes.

SomatostatinSomatostatin

Site of Secretion:Site of Secretion: -cells of the pancreas.-cells of the pancreas.

Structure:Structure: Polypeptide.Polypeptide. Action:Action:

Inhibits both Insulin and Glucagons secretion.Inhibits both Insulin and Glucagons secretion. Improve plasma glucose level in Diabetics.Improve plasma glucose level in Diabetics. Reduce Insulin dose required for treatment of Reduce Insulin dose required for treatment of

type 1 diabetic patients.type 1 diabetic patients. Less hyperglycemia in type 1 diabetic patients Less hyperglycemia in type 1 diabetic patients

deprived from Insulin.deprived from Insulin.

Diabetes MellitusDiabetes Mellitus(Carbohydrates Intolerance)(Carbohydrates Intolerance)

Types of Diabetes:Types of Diabetes: Type 1 (Insulin-Dependent Diabetes) Type 1 (Insulin-Dependent Diabetes)

(IDDM):(IDDM): Autoimmune disease resulted in destruction of Autoimmune disease resulted in destruction of

the the -cells.-cells. Treated by Insulin only.Treated by Insulin only.

Type 2 (Noninsulin-Dependent Diabetes)Type 2 (Noninsulin-Dependent Diabetes)(INDDM):(INDDM):

Occures in adults and usually associated with Occures in adults and usually associated with obesity.obesity.

Insulin level is high but there is resistance to its Insulin level is high but there is resistance to its effects.effects.

Treatment by oral hypoglycemic drugs.Treatment by oral hypoglycemic drugs.

Symptoms of Diabetes:Symptoms of Diabetes: Type 1:Type 1:

Occurs in acute manner.Occurs in acute manner. PolyphagiaPolyphagia PolydypsiaPolydypsia PolyuriaPolyuria Weight lossWeight loss

Type 2:Type 2: Often asymptomatic.Often asymptomatic.

Diagnoses of Diabetes:Diagnoses of Diabetes: Serum Glucose level:Serum Glucose level:

Fasting Plasma Glucose (FPG) over 126 Fasting Plasma Glucose (FPG) over 126 mg/dL.mg/dL.

Casual Plasma Glucose level over 200 mg/dL.Casual Plasma Glucose level over 200 mg/dL. FPG between 110- 126 mg/dL is called FPG between 110- 126 mg/dL is called

Impared fasting Glucose (IFG) disorder Impared fasting Glucose (IFG) disorder (Precursor condition to Diabetes).(Precursor condition to Diabetes).

Hemoglobin HbAHemoglobin HbA1c1c:: Glycosylated hemoglobin formed in excess when Glycosylated hemoglobin formed in excess when

glucose level increase (spiking).glucose level increase (spiking). Half life in blood is 120 days.Half life in blood is 120 days. Normal level 5- 8%.Normal level 5- 8%. 10% or more is diagnostic for Diabetes.10% or more is diagnostic for Diabetes.

Complications of Diabetes:Complications of Diabetes:

Blood Capillaries:Blood Capillaries: Eyes: Retinopathy.Eyes: Retinopathy. Kidney: Nephropathy.Kidney: Nephropathy.

Blood vessels:Blood vessels: Atherosclerosis and vascular complications.Atherosclerosis and vascular complications.

Nerve cells:Nerve cells: Neuropathy.Neuropathy.

Sorbitol increase osmotic pressure in the Sorbitol increase osmotic pressure in the eyes leading to over hydration and cataract.eyes leading to over hydration and cataract.

Spiking (Increase Glucose level)

Glucose

Cells

SorbitolAldose reductase enzyme

cells swell and rupture

Stability of Insulin:Stability of Insulin: Must be in the monomeric form to be active.Must be in the monomeric form to be active. In Concentration more than 0.6 mM Insulin polymerizes.In Concentration more than 0.6 mM Insulin polymerizes. At neutral pH in the presence of Zn Insulin form At neutral pH in the presence of Zn Insulin form

hexamer.hexamer. Zn Stabilizes Insulin:Zn Stabilizes Insulin:

Protamine Zn Insulin: Long acting Insulin suspension.Protamine Zn Insulin: Long acting Insulin suspension. Neutral Protein Hagedorn (NPH): Short acting Insulin containing Neutral Protein Hagedorn (NPH): Short acting Insulin containing

equal amount of Protamine and reserved with m-Cresol.equal amount of Protamine and reserved with m-Cresol. Addition of extra Zn to Hexameric-2-Zn Insulin in neutral Addition of extra Zn to Hexameric-2-Zn Insulin in neutral

medium resulted in different crystal form with different medium resulted in different crystal form with different dissolution rates.dissolution rates.

Unfolding of monomeric Insulin form viscous gel or Unfolding of monomeric Insulin form viscous gel or insoluble particles “Fibrils”. This process is irreversible insoluble particles “Fibrils”. This process is irreversible and activity is lost.and activity is lost.

Insulin may be adsorbed on tubing or other surfaces. Insulin may be adsorbed on tubing or other surfaces. The problem is solved by addition of albumin.The problem is solved by addition of albumin.

Stability of Insulin:Stability of Insulin:

Short acting Insulin Zn solutions at pH 2- 3 Short acting Insulin Zn solutions at pH 2- 3 and 4 and 4 00C undergo deamination of A21 C undergo deamination of A21 aspargine at rate of 1- 2%/month. At 25 aspargine at rate of 1- 2%/month. At 25 00C C 90% will undergo deamination in 6 months. 90% will undergo deamination in 6 months.

Insulin Zn solutions at neutral pH undergo Insulin Zn solutions at neutral pH undergo deamination of B3 aspargine in a slow rate. deamination of B3 aspargine in a slow rate. Resulted compound retain the activity.Resulted compound retain the activity.

Cleavage of A8 Threonine-A9 Serine bond and Cleavage of A8 Threonine-A9 Serine bond and cross linking of the resulted fragments with cross linking of the resulted fragments with other Insulin or Protamine resulted in a new other Insulin or Protamine resulted in a new proteins cause hypersensitivity reactions.proteins cause hypersensitivity reactions.

Sources of Sources of Insulin:Insulin:

Natural Procine or Bovine Insulin Natural Procine or Bovine Insulin contaminated with Glucagons and contaminated with Glucagons and Proinsulin.Proinsulin.

In 1980’s natural Insulin was more pure.In 1980’s natural Insulin was more pure. Chemical modification of Procine Insulin Chemical modification of Procine Insulin

to convert to human Insulin [B30 Alanine to convert to human Insulin [B30 Alanine is replaced by Threonine (Thr)].is replaced by Threonine (Thr)].

Recombinant DNA technology to produce Recombinant DNA technology to produce human Insulin from Bacterial cell human Insulin from Bacterial cell cultures. cultures.

Insulin Insulin Analogs:Analogs:

Actrapid HM:Actrapid HM: Replace B9 Serine (Ser) by Aspargine (Asp).Replace B9 Serine (Ser) by Aspargine (Asp). Replace B27 Threonine (Thr) by Glutamine Replace B27 Threonine (Thr) by Glutamine

(Glu).(Glu). Lispro Insulin: Lispro Insulin:

Reversing B28 Proline (Pro) and B29 Lysine Reversing B28 Proline (Pro) and B29 Lysine (Lys).(Lys).

Lispro Insulin is potent short acting.Lispro Insulin is potent short acting.

Oral Hypoglycemic Oral Hypoglycemic agents:agents:

Sulfonylurea:Sulfonylurea: Increase the release of Insulin from Increase the release of Insulin from the the -cells.-cells.

Sulfonamides:Sulfonamides: Increase the release of Insulin from Increase the release of Insulin from the the -cells.-cells.

BiguanidesBiguanides (Antihyperglycemic agents)(Antihyperglycemic agents):: Action not related to Insulin or Action not related to Insulin or -cells.-cells. Never produce hypoglycemia at any dose.Never produce hypoglycemia at any dose. Increase glucose utility by cells.Increase glucose utility by cells. E.g. Metformin.E.g. Metformin.

Thiazolidinediones:Thiazolidinediones: Enhance Insulin action in liver, muscles and fat tissues.Enhance Insulin action in liver, muscles and fat tissues. Useful for type 2 Diabetes.Useful for type 2 Diabetes.

-Glucosidase Inhibitors:-Glucosidase Inhibitors: Inhibit the release of glucose from disaccharides and Inhibit the release of glucose from disaccharides and

polysaccharides. polysaccharides.