Insulin

2. DIABETES MELLITUS:
 Metabolic disorder characterised by
hyperglycemia, glycosuria, hyperlipemia,
Negative nitrogen balance and some
time ketonemia
 Sign and Symptoms
 Increase in frequency of urination
(Polyuria)
 Excessive thirst (polydipsia)
 Excessive eating (Polyphagia)
 Fatigue
 Unexplained weight loss etc

3. Why diabetes should be controlled?
Uncontrolled leads to complications:
ACUTE
 Diabetic Ketoacidosis (DKA)
 Hyperglycemic hyperosmolar state
(HHS)
CHRONIC
 Retinopathy, Neuropathy,
Nephropathy- (microvascular)
 Coronary & peripheral vascular
disease and cerebrovascular
disease- (macrovascular)
 other

4. TYPES OF DIABETES MELLITUS:
Type 1 / Insulin Dependent
Diabetes Mellitus (IDDM)
Characterized by β-cell (pancreatic
islets) destruction leading to absolute
insulin deficiency
Type 2 / Non Insulin Dependent
Diabetes Mellitus (NIDDM)
Characterized by insulin resistance
and relative insulin deficiency

5. TYPE 1 DM TYPE 2 DM
Juvenile onset (<30 yrs) Maturity onset
β- cells are destroyed: NOT destroyed: relative
absolute deficiency deficiency
Autoimmune(type 1 a) mild or severe
Idiopathic (type 1 b)
Less common & less Very common & high
genetic predisposition Genetic
predisposition
Insulin is must Controlled by diet
change, exercise & oral
drugs: Insulin when
other fails

6. INSULIN:
 Discovered in 1921 by Banting
and best
 Banting and Macleod got nobel
prize in 1923
 Leonard Thompson: First
patient to receive insulin

12. Diabetes mellitus contd…….
Insulin is synthesised & secreted by Pancreas

13. PANCREAS
a) Exocrine Gland
b) Endocrine Gland
Exocrine Gland:
 secretes enzymes

14. ENDOCRINE
Islets of Langerhans contains:
 α cells : secrete glucagon.
 β cells : secrete insulin.
 δ cells : secrete gastrin &
somatostatin

15.  Insulin is polypeptide 51
aminoacid (MW 6000). Contains
two chains; chain-A 21 aa &
Chain-B 30
 These chains are held together
by two inter-disulfide bonds &
one intra disulfide bond
 Pork insulin differ by one aa
where as Beef by two aa differ

16. SYNTHESIS
 Synthesized as preproinsulin
(110 aa) in rough ER (single
chain)
 Preproinsulin → proinsulin (86 aa;
molecule fold )
 Transported to Golgi apparatus
 Converted to insulin & C-peptide
 Stored in the granules of β cells

17. C peptide
Proinsulin
A Chain
B Chain
PC2
(PC3)
PC3
Diabetes mellitus contd…….

18. Insulin contd…….
 Insulin is measured in IU
FACTORS CONTROLLING THE
SECRETION OF INSULIN
 Blood glucose concentration
 Hormonal control
 Neural control

19. Ca2+
Insulin granules
Na+
Na+
K+
K+
K+
K+
ATP
Na+
K+
-
K+
Glucose
GLUT2
Ca2+
Ca2+
Ca2+
Voltage-gated
Ca2+
channel
KIR
Vm
Pancreatic
ß cell IP3
cAMP
Glucokinase
Km= 7-9 mM
β cell integrates input from
various metabolites, hormones
and neurotransmitters
Diabetes mellitus contd…….

20. Glucose stimulated insulin secretion
β cells respond to blood glucose
concentration in 2 ways: Initial rapid phase &
delayed release phase

21. Neuronal control of insulin secretion
Parasympathetic nervous system:
~stimulates insulin secretion
Sympathetic nervous system:
~inhibits insulin secretion

22. EFFECTS OF INSULIN
ADIPOSE TISSUE
Increased glucose entry
Inhibits lipolysis & release of ffa
Increased triglyceride deposition
Increased K+
uptake
MUSCLE
Increased glucose entry
Increased glycogen synthesis
↑ed aa uptake & protein synthesis
Increased K+
uptake

23. LIVER
↑ed glucose uptake & glycogen
synthesis
Inhibits glycogenolysis &
glucose output
Inhibits gluconeogenesis
GENERAL
Increased cell growth

24. Cell-surface receptors:
α subunits contain
insulin binding sites
β subunits have tyrosine
kinase activity
plasma membraneplasma membrane
Diabetes mellitus contd…….

25.  MOA contd…
 Insulin binds to alpha subunit of receptor
tyrosine kinase (RTK) present in cell
membrane & activates tyrosine kinase
activity of beta subunit.
 There, it is phosphorylated by glucokinase,
which acts as a glucose sensor. The rise in
ATP levels causes a block of K+ channels,
leading to membrane depolarization and an
influx of Ca2+. The increase in intracellular
Ca2+ causes insulin release.

26. PHARMACOKINETICS
 NOT given orally, given s.c.
 Metabolised in liver, kidney & muscle
 Enzymatic degradation follows
receptor-mediated endocytosis
 t1/2 3-5 min

27. TYPES OF INSULIN
ACCORDING TO SOURCE
Conventional Insulin:
a)Bovine (More antigenic)
b)Porcine (Less antigenic)
Highly Purified Insulin Preparation
Human insulin:
Produced by rDNA technology
More water soluble & hydrophobic than
conventional insulin
More rapid s.c. absorption & shorter acting than
conventional insulin
Valuable in case of allergy to conventional,
insulin resistance, lipodystrophy, pregnancy

28. ACCORDING TO ONSET & DURATION
OF ACTION:
Rapid acting:
Insulin lispro, Insulin aspart, Insulin
glulisine
Short acting:
Regular (soluble) Insulin
Intermediate acting:
Insulin Zinc suspension (Lente)
Neutral protamine hagedorn (NPH) or
isophane insulin
Long acting:
Protamine zinc insulin (PZI)
Insulin glargine

29. Rapid acting: insulin lispro
lysine [B28], proline [B29]
Given immediately before or after meal
LYS
PROLYS
PRO
InsulinlisproInsulin

30. Insulin glargine
 Soluble in acidic pH of vial 4.0
 Precipitate in neutral pH & slowly enter into
circulation
 Delayed but peakless effect is obtained
ARG
ARG
ASNGLY
Insulinglargine

31.  Hypoglycemia
 Frequent & potentially more serious
 Common in DM patient receiving large dose
of insulin, missing meals and vigorous
exercise after insulin
 Symptoms: 1) Sympathetic stimulation
2) Neuroglucopenic symptoms
 Treatment: oral/ iv (severe case) Glucose or
Glucagon or Adrenaline treatment
 Local reactions: swelling, erythema ,
Lipodystropy (Common in conventional insulin)
 Allergy & resistance to insulin (esp. conventional)
 Insulin edema- transient on starting insulin
 Weight gain

32.  Type 1 DM:
 Dose is individualized: sliding scale
 2/3 of dose in morning & 1/3 in evening
 Special cases of Type 2 DM:
Failure of oral antidiabetic drugs
Underweight patient
During infection, trauma, surgery
Pregnancy (human insulin)
During complications of diabetes
mellitus
 Non diabetic use: Glucose + insulin to treat
hyperkalemia

33. Mix regimen 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)

34. 1. β blocker (nonspecific) are contracted in
Diabetic patient receiving insulin?
 Because β blockers mask the symptoms of
hypoglycemia and also
 Delays recovery-prolong hypoglycemic attack
2. Thiazide, furosemide, corticosteroids,
Oral contraceptives, Salbutamol – reduce
effectiveness
3. Acute ingestion of alcohol-
hypoglycemia