This document provides information about insulin, including: 1) It describes the structure of insulin as a 51 amino acid polypeptide made of an A-chain and B-chain, held together by disulfide bonds. 2) It explains that insulin secretion is regulated by both chemical and hormonal/neural mechanisms in response to glucose levels, including the roles of glucokinase and ATP-sensitive potassium channels. 3) It lists the different types of insulin preparations available, including regular insulin, NPH insulin, and rapid-acting insulin analogues like insulin lispro, aspart, and glulisine, as well as the long-acting insulin glargine and detemir.

1. Insulin
Dr. Pravin Prasad
MBBS, MD Clinical Pharmacology
Assistant Professor, Department of Clinical Pharmacology
Maharajgunj Medical Campus
29 June, 2020 (15 Asar 2077); Monday

2. By the end of this session, BDS 2nd
year students will be able to:
Describe the structure of insulin
Explain the regulation of insulin secretion
List the actions of insulin
Explain the mechanism of action of insulin
List the different insulin formulations available
List the different insulin analogues available
List the uses of insulin
List the different insulin regimens

3. Insulin: Introduction
• 51 amino acids (AA) polypeptide,
held together by 2 sulphide bonds
• A-chain 21 AA; B-chain 30 AA
• MolecularWeight: 6000
• Pork insulin more homologous
• β-cells: Preproinsulin (110 AA)
• Removal of 24 AA: proinsulin
• Both fragments are stored in
granules
• Secreted together in the blood
Human proinsulin

4. Regulation of Insulin Secretion
Basal condition ~1U/hr; larger quantity following meals
Regulated by following mechanisms:
Chemical
Hormonal
Neural

5. Chemical Regulation of Insulin
Secretion
Beta cells have glucose sensing mechanism activated by:
Entry of glucose into beta cells (aegis of glucose transporter
GLUT1)
Phosphorylation of glucose by glucokinase
Inhibits the ATP-sensitive K+ channels (K+ATP)
Partial depolarization of the β-cells
Increases Ca2+ availability
Exocytotic release of insulin from storing granules.
Response varies when nutrients are given orally and
parenterally

6. Hormonal and Neural Regulation of
Insulin Secretion
Hormonal Regulation
Intra-islet pancreatic
interaction
Growth Hormone,
Corticosteroids, Thyroxine
Neural Regulation
On stimulation
Insulin
Release
Adrenergic
alpha2
Decreases
Adrenergic beta2 Increases
Cholinergic (Ach
or vagal
mediated)
Increases
• Primary Central site of regulation of insulin secretion:
Hypothalamus
• Ventrolateral nuclei 

7. Insulin as an Anabolic Hormone:
Actions
Glucose transport across cell membrane
Expression of glucose transporters into the membrane
Intracellular utilization of glucose
Effects on gluconeogenesis
Effects on Lipid metabolism
Effect on Very Low Density lipoprotein and Chylomicrons
Effects on Protein Metabolism

8. Insulin: How it Acts

9. Insulin: How it acts
Binds to alpha subunit of receptor tyrosine kinase (RTK)
present in cell membrane
Activates tyrosine kinase activity of beta subunit
Activates a casacade of phosphorylation and
dephosphorylation reactions  Amplification of signals 
stimulation and inhibition of enzymes responsible for rapid
action of insulin
Translocation of glucose transporter GLUT4 to plasma
membrane and expression of genes directing synthesis of
GLUT4 is promoted
Long term effects exerted by generation of transcription
factors promoting proliferation and differentiation of specific
cells

10. Insulin: Its Fate
Distributed only extracellularly
Degraded if given orally
Injected insulin/insulin released from pancreas: metabolised in
liver (kidney and muscles also contributes)
Biotransformation results into reduction of disulphide bonds:
chains are separated.

11. Insulin: Its Preparations
Older commercial preparations:
Beef and pork insulin
~1% (10,000 ppm) other proteins (proinsulins, polypeptides,
pancreatic proteins, insulin derivatives)
Newer preparations:
Single peak and mono-component
Highly purified pork/beef insulin
Recombinant human insulin/insulin analogues, <10 ppm
proinsulin

12. Insulin: Its Preparations
Regular Insulin:
Soluble, buffered neutral pH of unmodified insulin stabilized
by a small amount of zinc
Given sub cutaenously, slow absorption, peak activity after 2-
3 hrs, lasts for 6-8 hrs
Needs to be injected ½ - 1 hr before meal: else risk of early
postprandial hyperglycaemia and late postprandial
hypoglycaemia
Cannot be mixed with insulin glargine/detemir

13. Insulin: Its preparations
Lente Insulin Neutral Protamine Hagedorn
(NPH) Insulin or Isophane
Insulin
Insulin-zinc preparation Insulin- Protamine preparation
Combination of Ultralente
and semilente
Protamine sufficient to complex all
insulin molecules
Ratio 7:3 Neutral pH
Combined with regular insulin in
the ratio 70:30 or 50:50
Injected twice daily s.c. before
breakfast and before dinner

14. Insulin Analouges
Insulin lispro:
Weak hexamers, dissociates rapidly
Quick and more defined peak
Injected immediately before or even after meal: better control
of meal-time glycaemia and lower incidence of post prandial
hypoglycaemia
Multiple injections, fewer incidence of hypoglycaemia
Insulin aspart:
Similar to insulin lispro
Insulin glulisine:
Used for continuous subcutaneous insulin infusion (CSII)

15. Insulin Analouges
Insulin glargine:
Remains soluble at pH4, precipitates at neutral pH
Delayed onset of action, maintained for up to 24hrs: “smooth
peakless effect”
Insulin detemir:
Binds to albumin and action is prolonged
Twice daily dose is required

16. Insulin: Unwanted Efects
Hypoglycaemia
Seen more in labile diabetes patients
Sympathetic symptoms and neuroglucopenic symptoms
Hypoglycaemic unawareness
Local Reactions
Swelling, stinging, erythema; Lipodystrophy
Allergy
Utricaria, angioedema, anaphylaxis
Edema

17. Uses of Insulin
Diabetes Milletus:
Mandatory in Type 1 DM (Insulin Dependent DM), post
pancreatectomy diabetes, gestational diabetes (0.4-0.8
u/Kg/day)
Some cases of Type 2 DM (Non Insulin dependent DM): not
controlled by diet/exercise, failure of OHA, under weight,
temporary situtations, during complications (0.2-1.6 U/kg/day)
Given as Split-mix regimen and Basal Bolus regimen
Diabetes Ketoacidosis
Regular insulin, 0.1-0.2 U/kg i.v. bolus followed by 0.1U/kg/hr
infusion- adjusted according to the fall in blood glucose levels
Hyperosmolar (non ketotic) Hyperglycaemic Coma

18. Insulin Regimens
Split-mixed Regimen Basal Bolus Regimen
Regular insulin with lente or isophane
(30:70 or 50:50)
Long acting insulin (Insulin glargine) and
short acting insulin (lispro/aspart) injected
separately
Injected Before Breakfast and Before
Dinner
Long acting insulin (glargine) injected daily
(before breakfast/ before bed time) with 2-3
meal time injections with rapid acting insulin
(lispro/aspart)
Only two daily injections required Better round the clock euglycaemia
• Post lunch glycaemia not
adequately controlled
• Late postprandial hypoglycaemia
may occur
• 3-4 daily injecctions
• More demanding and expensive
• Higher incidence of severe
hypoglycaemia
• Best avoided in young and children and
elderly

19. Inattentive students!!