Pharmacotherapy of

Diabetes Mellitus

Insulin
15 June 2010
 THE ENDOCRINE PANCREAS
1 million islets of Langerhans

4 hormone-producing cells

Cell type Hormone Function

Alpha [A] cells Glucagon Hyperglycemic factor

Beta [B] Cells Insulin, Pro insulin, Anabolic hormone

Amylin

Delta[D] Cells Somatostatin Universal inhibitor of

secretion

G Cells Gastrin Stim.Gastric secretion

F cell[PP cell] Panc.Polypeptide Digestion

 What is DM?

Diabetes mellitus

Elevated blood glucose

Associated with absent or inadequate pancreatic

insulin secretion

With or without concurrent impairment of

insulin action.
Expert Committee, 2003

Type 4 Type 3
 Diabetes mellitus -TYPES
TYPE 1 TYPE 2

• IDDM • NIDDM
• Loss of  beta • Due to insulin resistance
cells → deficiency • [or reduced insulin sensitivity]
• Combined with reduced insulin
of insulin secretion 
“Juvenile diabetes” • TYPE 3
majority cases • Drug induced or other causes
• TYPE 4
in children. • Gestational diabetes mellitus 
 INSULIN

Proinsulin

Two peptide chains

A & B of
21 and 30 amino acids
linked by disulfide
bridges
 Insulin Biosynthesis
[110AA] Preproinsulin (in RER)
↓
[110-24AA] Proinsulin (Golgi Apparatus)
↓
[51AA] Insulin + C Peptide[-35AA]
↓
Stored in granules of  cells

Basal rate: 1U/h,  during meals

 Control:Insulin Release
• Chemical • Neural
Glucose Adrenergic-a2↓
Incretins Adrenergic-b2↑
• Hormonal Muscarinic
GH [Vagal] ↑
Counter
regulatory Corticosteroids,
Thyroxine
Glucagon ↑
Somatostatin ↓
Insulin release from the pancreatic Beta cell
by Glucose

First phase- Within 2 minutes

Delayed phase
Role of ATP sensitive K+ channels (KATP)
Hyperglycemia
↓
 Intracellular ATP
↓
Blockade of KATP
↓
 Outflow of K+
↓
Depolarization of β cells
↓
Ca2+ influx
↓
Insulin Release
 Degradation of Insulin
• Endogenous:
– Liver – 60%, Kidney: 35-40%

• Exogenous:
– Liver – 40%, Kidney- 60%

•  Plasma half-life: 5-6 min.

 Insulin receptor
2 covalently linked heterodimers

The binding of an insulin molecule

Mutual phosphorylation of tyrosin recidues

Activated Tyrosin kinases

Further phosphorylates down stream proteins
[IRS]

•Translocation of glucose transporters (especially

GLUT 4) to the cell membrane with increase in
glucose uptake;
•Increased glycogen synthase activity and
increased glycogen formation;
Insulin •Multiple effects on protein synthesis, lipolysis,
receptor
substrate
and lipogenesis; and
•Activation of transcription factors that enhance
DNA synthesis and cell growth and division.
 Insulin receptors

• Glucocorticoids lower the affinity of

insulin receptors for insulin;
• Growth hormone in excess increases
this affinity slightly.
• Aberrant serine and threonine
phosphorylation of the insulin receptor
subunits or IRS molecules may result
in insulin resistance
Glucose transporters
[GLUT]
 Gluconeogenesis
IN LIVER
Absorption
Glycogenolysis

In
Insulin
[-] su
l in

[-]

Processes add glucose Blood

[Hyperglycemia]

in
ul
Processes utilize glucose
In In
s
[Hypoglycemia]
su [+]
lin

Insulin
[+]
[+] Peripheral
utilization

Lipogenesis
Protein Synth. In Muscles
Endocrine effects of Insulin
Endocrine effects of Insulin….
Endocrine effects of Insulin….
Over view of Insulin action
 Source and insulin preperations
Species A Chain B Chain
8th AA 10th AA 30th AA
Human THR ILEU THR
Pork THR ILEU ALA
Conventional prep.
Beef ALA VAL ALA •Impurities
•Antigenic
Analogs •Less expensive
1. Highly purified pork
Insulins •Replaced by
• Monocomponent insulins
1.Highly purified pork
Insulins
2.Human insulins
2. Human insulins 3.Insulin analogues
• Recombninant DNA
Technology[E.Coli, Yeast]

3. Insulin analogues
Changing or replacing AA sequences
1. Lispro
2. Aspart
3. Glulisine
4. Glargine 5. Detemir
 Genetic engineering
to produce human insulin
 Insulin preparations
*Long-acting insulins:
• Rapid acting insulins:
– Ultralente insulin
– Insulin lispro
Analogues
– Protamine Zinc Insulin (PZI)
– Insulin aspart
– Insulin Glargine
– Insulin glulisine Analogues
– Insulin detemir
• *Short acting insulins:
– Regular insulin
*Premixed insulins:
– 70% NPH + 30% Regular
• *Intermediate acting
– 50% NPH + 50% Regular
insulins:
– 75% NPH + 25% Lispro
– Lente insulin[Insulin Zinc
suspension *Animal or human
– NPH insulin [Isophane
Insulin suspension]
 Insulin preparations
Rapid acting
• More physiologic prandial insulin replacement - their
rapid onset and early peak action - closely mimic normal
endogenous prandial insulin secretion than does regular
insulin,
• Can be taken immediately before the meal without
sacrificing glucose control.
• Their duration of action is rarely more than 4–5 hours,
which decreases the risk of late postmeal hypoglycemia.
• Lowest variability of absorption [Monomers]
• Preferred insulins for use in continuous subcutaneous
insulin infusion [CSII] devices.
Insulin preparations
Rapid acting

Lispro
Insulin preparations
Rapid acting

Aspart
Insulin preparations
Rapid acting

Glulysine
 Insulin preparations
Short acting

• Recombinant DNA techniques, purified porcine

• Effect appears within 30 minutes - peaks between 2 and
3 hours after s.c injection -lasts 5–8 hours.
• Prandial hyperglycemia and risk of late hypoglycemia
[30-45 mts before meals]
• Only preperation for i.v.use.
 Insulin preparations Intermediate acting
Lente insulin[Insulin Zinc suspension]
NPH insulin [Isophane Insulin suspension]

–Onset-1-2 h
–Peak-6-12h
–Duration-18-24
–Dose related action profile
–Long acting analogs are preferred
 Long actingInsulin
preparations
–Onset-1-2 h Detemir
–Peak less
–Duration-18-24

THRThriiii

THR Myristic acid

Glargine
 Type Appearance Onset Peak Duration
Rapid/Short
Regular soluble Clear 0.5–0.7 1.5–4 5–8
Lispro Clear 0.25 0.5–1.5 2–5
Aspart Clear 0.25 0.6–0.8 3–5
Glulisine Clear --- 0.5–1.5 1–2.5
Intermediate 1–2
NPH (isophane) Cloudy 1–2 6–12 18–24
Lente Cloudy 6–12 18–24
Long
Ultralente Cloudy 4–6 16–18 20–36
Protamine zinc Clear 4–6 14–20 24–36
Glargine Clear 2–5 5–24 18–24
Detemir Clear 1–2 4–14 6–24
 Adverse Effects of Insulin:
Hypoglycemia
• Results from:
– Delay in taking a meal
– Inadequate carbohydrate intake
– Unusual physical exertion
– Too large insulin doses
Symptoms
• Autonomic hyperactivity
– Sympathetic
• Tachycardia, palpitations, sweating, tremulousness
– Parasympathetic:
• Nausea, hunger
– Convulsions / Coma
 Adverse Effects of Insulin:
Hypoglycemia
• Hypoglycemia unawareness

• Treatment:
– Glucose administration:
• Fruit juice / Glucose gel / Sugar containing
beverage/food to eat at first sign
• If severe: 50% dextrose i.v.

Carry identity card

 Adverse Effects of Insulin
Insulin Allergy:
• Noninsulin protein contaminants
• Less with purified insulin preparations
• ? Anaphylaxis
 Insulin Resistance
[Requirement of > 200U/day]
• Acute:
– Causes: Infections, trauma, surgery, stress (in stress
↑corticosteroids oppose insulin action)
– Treated by regular insulin
• Chronic:
– Common in type II
– Cause: Antibodies to contaminating proteins which also
bind insulin
– Treatment- change to human insulin
• Reversible
– Pregnancy
 Adverse Effects of Insulin
Insulin Lipodystrophy
• Older insulin preparations → Repeated injections at the
same site → Atrophy / Hypertrophy of subcutaneous fat
• Atrophy not seen with newer human insulin preparations,
hypertrophy still a problem
• ? Injection of newer insulin into atrophic area →
Restoration of normal contours
• Sites of injection: Abdomen best, Keep changing

Insulin Edema
• Na+ retention, Weight gain
 Unitage of Insulin
• 1 U = Amount required to reduce blood glucose by
45 mg% in a fasting rabbit

• 1mg=28units
 Insulin Delivery Systems
• Disposable needles and syringes: 27 G
• Portable Pen Injectors
• Jet injectors
• Continuous Subcutaneous Insulin Infusion: CSII
– Most physiologic insulin replacement
– Insulin reservoir/ Program chip/ Keypad/ Display screen
– Excellent glycemic control eg, pregnancy
• Inhaled Insulin
– Absorbed through alveolar walls
– Rapid onset of action / Short duration
– ? Pulmonary fibrosis/Pulmonary hypertension
• Oral insulin: Liposome encapsulated
 Clinical Uses of Insulin
• Type 1 diabetes mellitus
• Type 2 diabetes mellitus-
 Not controlled by oral agents
 Complications: Diabetic ketoacidosis, Gangrene,
 To tide over: Infection, Trauma
 Pregnancy [Gestational diabetes not controlled by
diet alone]
• Emergency treatment of hyperkalemia: Insulin + glucose
 Indications of Human Insulin
1. Insulin resistance

2. Allergy to conventional preparations

3. Injection site lipodystrophy

4. Short term use- surgery, trauma

5. During pregnancy
 Insulin regimens
• Intensive Insulin therapy-Based on formulae-
CSII
• Conventional- For type 2
• Spl circumstances
• Principle:
• Supply postprandial needs
• Provide basal control
Glargine + 3 Analogs
2Long acting+2 Rapid or Short acting
CSII
 Diabetic Ketoacidocis
[Diabetic coma]
• Precipitated by Treatment:
infection, trauma,
1.Regular insulin-I.V.
stress in insulin
dependent patients 2.Bolus followed by
• Serious infusion
3.i.v fluids.
• Hypotension, shock,
tachycardia, 4.Kcl ???
dehydration, 5.NaHco3
hyperventilation, 6.Phosphate
vomiting, coma 7.Antibiotics
 Drug interactions
• Beta blockers-
• Inhibit comp mechanisms
• Warning signs of hypoglycemia are masked
• Thiazides, Furosemide, Corticosteroids, OCPs,
reduce the effect of insulin
• Salicylates, Li, increase insulin secretion
 Insulin Delivery Systems

Disposable needles and syringes: 27 G Portable Pen Injectors

 Insulin Delivery Systems

Inhaled Insulin
 A device that uses high
pressure
instead of a needle to propel
insulin
through the skin and into the
body. 
 Insulin Delivery Systems

Continuous Subcutaneous Insulin Infusion:

CSII
 Insulin Delivery Systems

1 - Continuous
glucose sensor
monitors blood sugar
level
2 - Data transmitted
for the computer
program to work out
‘Artificial pancreas’ insulin dose
Sensor activated pump 3 - Insulin pump
delivers the dose