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]
of insulin Combined with reduced 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 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

Insulin
[-]
[-]

Processes add glucose Blood

[Hyperglycemia]

Processes utilize glucose

[Hypoglycemia]
[+]

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:
*Premixed insulins:
Regular insulin
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 45 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 58 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 0.50.7 1.54 58
Lispro Clear 0.25 0.51.5 25
Aspart Clear 0.25 0.60.8 35
Glulisine Clear --- 0.51.5 12.5
Intermediate 12
NPH (isophane) Cloudy 12 612 1824
Lente Cloudy 612 1824
Long
Ultralente Cloudy 46 1618 2036
Protamine zinc Clear 46 1420 2436
Glargine Clear 25 524 1824
Detemir Clear 12 414 624
 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