Insulin 😍

Insulin Structure

MODY → Applied aspect

• Mutation in HNF (Hepatocyte Nuclear Factor) → Maturity Onset Diabetes of the Young (MODY).

Disulfide Bonds → Between Cysteine amino acids

• Interchain
• between A and B chains
• 7A → 7B
• 20A → 19B

• Intrachain
• within A-chain
• 6A → 11A

Insulin Modifications for Analogs

• Composed of two polypeptide chains:
• A-chain: 21 amino acids
• B-chain: 30 amino acids
• First protein:
• Completely sequenced (By Sanger).
• Produced by recombinant DNA technology.
• Zinc stabilizes insulin structure.
• Prolong insulin action

Insulin Analog	Modification
Lispro	Proline (28) ↔ Lysine (29) in B-chain are interchanged
Aspart	Proline (28) in B-chain → Aspartic acid
Glulisine	Asparagine at B3 and Lysine at B29 → Lysine and Glutamic acid
Glargine	Asparagine (A21) → Glycine; 2 extra Arg residues added at B-chain (positions 31, 32)
Detemir	Threonine (B30) removed; C 14 fatty acid added at position B29

 

Somogyi Effect

• So much insulin at Night

• 4 AM: Sugar falls
• Early morning hypoglycemia
• d/t excess insulin at bedtime/less food

• Release of counter-regulatory hormone (Glucagon)

• Pre-breakfast hyperglycemia

• Red: Insulin levels in Somogyi effect

• Green: Insulin in Dawn phenomenon

Dawn Phenomenon

• Insulin sensitivity down in middle of night

• Decreased insulin receptor sensitivity (4–7 AM)

• 4 AM: Blood sugar rises (↓ GLUT-4 in T2DM)

• 7 AM: Pre-breakfast hyperglycemia

Insulin and Protein Synthesis

• Insulin is an anabolic hormone that activates protein synthesis.

• It functions through phosphorylation of translation initiation factors:
• eIF4G
• eIF4E-binding proteins (4E-BPs)

Mechanism

1. Insulin binds to its receptor and activates the PI3K (Phosphatidylinositol 3-kinase) pathway.

2. This leads to activation of mTOR kinase (mammalian target of rapamycin).

3. mTOR phosphorylates 4G and 4E-BPs.

4. Phosphorylation of 4E-BPs causes them to dissociate from eIF4E.

5. This frees eIF4E to bind eIF4G, leading to formation of the eIF4F complex.

6. eIF4F complex initiates mRNA translation, thus boosting protein synthesis.

Insulin Release Mechanism (Pancreatic β cell)

NOTE: Different Fanconis

ㅤ	ㅤ
Fanconi disease/syndrome	• Proximal tubular reabsorption problem → Type 2 RTA • Glycosuria, aminoaciduria
Fanconi anemia (Not syndrome)	• Pancytopenia + radial ray
Fanconi Bickel syndrome	• Mutation in GLUT-2   • Bickel → Bi → 2 (GLUT 2) Defect in glucose sensing → ↓ insulin release • Postprandial Hyperglycemia. • Fasting Hypoglycemia • Glycogen accumulation disorder

Stranger things characters

• Dustin (Cleido cranial dysplasia)

• Robin (Cock robin position)

• Ray (Radial Ray) Hopper (Holt Oram ASD)

Transport

• Sites (insulin dependent areas): muscle, adipose tissue, heart.

• Process: Facilitated diffusion.

• Transport protein: GLUT-4.

• Special case: During exercise, glucose enters skeletal muscle independent of insulin.
• Exercise → Activates AMP → Insertion of GLUT-4 in skeletal muscle.
• This is AMP-activated Kinase pathway.

• Significance: Exercise is important in Rx of DM.

Insulin Receptor

• Located on cell membrane.

• Composed of α and β subunits.

• Contains Tyrosine kinase activity.

• Activates two main pathways via Insulin-receptor substrates (IRS):
• Phosphatidylinositol-3'-kinase (PI-3-kinase) pathway:
• Mediates GLUT 4 insertion.
• Mediates metabolic actions.
• Mitogen Activated Protein Kinase (MAPK) pathway:
• Mediates Promotion of growth.

Actions

• Time dependent actions:
• Rapid actions (Within seconds):
• ↓ Blood glucose (Via GLUT-4).
• ↓ K+ levels.
• Clinical correlation: Used in Rx of hyperkalemia (Insulin + dextrose).
• Long term actions (In days):
• Major anabolic hormone leading to Storage.

• Pathways mediated:
• Pathways stimulated:
• Glycogenesis
• Lipogenesis
• Glycolysis
• Pathways inhibited:
• Glycogenolysis
• Neoglucogenesis
• Lipolysis
• Ketogenesis

Factors Affecting Insulin Secretion

↑ Insulin Secretion:

• High blood glucose.

• α cells: Glucagon.

• Amino acids: Arginine, Leucine.

• Autonomic nervous system:
• Parasympathetic: Vagal stimulation, acetylcholine.
• Sympathetic: Only β receptor stimulation.

• Gastrin, CCK, Secretin.

• Incretins.

• Protein rich meal: Also ↑ glucagon to prevent hypoglycemia.

• Mnemonic: Diabetic people should run (Sympathetic) shouting beta beta (Beta)

↓ Insulin Secretion:

• Somatostatin.

• Streptozocin, Alloxan: Destroy β cells (Used only for research experiments).

• Sympathetic: α action (Dominant action).

Applied Aspect of Incretins

• Incretins include Glucagon like Peptide 1 (GLP-1) and Glucose dependent insulinotropic peptide (GIP).

• Degraded by Dipeptidyl peptidase 4 (DPP-4).

• Incretin effect: Oral glucose → Stimulate incretins (GIT hormones) → ↑ insulin release compared to IV glucose.

• Management of diabetes:
• GLP-1 analogues: Eg: Exenatide.
• Dipeptidyl peptidase 4 (DPP-4) blockers: Eg: Gliptins (sitagliptin).
• These drugs ↓ DPP-4 degradation → Prolonged action of GLP-1.

Glucose Homeostasis

• Decrease in blood glucose (Hypoglycemic hormone): Insulin.
• Blood glucose < 30 mg/dl → Coma.

• Increase in blood glucose (Counter regulatory hyperglycemic hormones):
• Growth hormone.
• Dawn phenomenon: Early morning ↑ in glucose.
• Glucagon.
• T3.
• Cortisol.
• Epinephrine.

Insulin

• Indications:
• All patients with type 1 DM.
• Uncontrolled patients with type 2 DM.
• Diabetes in pregnancy.
• Diabetic Ketoacidosis.
• Hyperkalemia

• Routes of Administration:
• Subcutaneous (MC route):
• Self-administration possible.
• All insulin preparations can be given.
• Site of administration:
• Entire abdomen (except around umbilicus).
• Anterior thigh.
• Lateral thigh.
• Arm.
• Intravenous:
• Only regular insulin can be given.
• Insulin of choice in diabetic Ketoacidosis → Regular insulin.
• Inhalational:
• Afreeza → Short acting insulin → Given before every meal.

Methods of Insulin Delivery

• CSII (Continuous subcutaneous insulin infusion) / Insulin Pump
• most preferred

• Insulin pen (dose adjustable)

• Multi-dose vial

• Pre-filled syringes

Sites of Injection

• Upper outer arms

• Abdomen

• Buttock

• Upper outer thighs

Insulin pump (Best)

• Mimics artificial pancreas
1. Basal insulin → continuous secretion
2. Bolus insulin → mealtime, proportionate to carbohydrate intake

Insulin injection at same site

• lipoatrophy

Insulin Analogues:

• Rapid/Ultra short acting:
• LISPRO
• ASPART
• GLULISINE

• Ultra-Long/Long Acting:
• GLARGINE
• DETEMIR
• DEGLUDEC (Longest Acting)
• These are peakless insulins.
• Have low risk of hypoglycemia.

• Side Effects:
• Hypoglycemia
• Hypokalemia

Important

• Most preferred site:
• Anterior abdominal wall (2cm from umbilicus)

• Most preferred route:
• CSII

• MC side effect:
• Hypoglycemia

• β-blockers contraindicated
• they mask hypoglycemia

Types of Insulin

Type of Insulin	Duration	Examples	ㅤ
Inhaled	2–3 hours	Afrezza	Postprandial hyperglycemia C/I → COPD, Asthma
Rapid acting	3–4 hours Onset: 10-15 min	Aspart (NovoRapid) Glulisine (Apidra) Lispro (Humalog)	ㅤ
Short acting	6–8 hours	Regular	Inject at 15-30 min before meal IV in emergencies like • DKA • hyperosmolar coma • dangerous hyperkalemia
Intermediate acting	10–16 hours	NPH, Lente Isophane/zinc	NPH → Cloudy ↳ Humulin-N ↳ Novolin-NPH Used between meals. Can combine with short-acting
Long acting	12–24 hours	Detemir (Levemir) Glargine(Lantus, 24 hrs)	Bedtime, "Peakless," [taken once daily]
Ultra-long acting	42 hours	Degludec	ㅤ