PRACTICE OF MEDICINE
Insulin Therapy : Practical Points
UC Kansra*, S Sircar**
Insulin is a polypeptide composed of two chains
of aminoacids : the A - chain has 21amino acids
and B - chain has 30 amino acids. The two chains
are linked with each other by two cysteine
disulphide bonds between CYS A 7 and CYS B7
and second bond between CYS A 20 and CYS
B19. There is an additional intra-chain disulphide
bond connecting cysteine between A 6 and A 11.
Insulin is essential for normal carbohydrate,
protein, and fat metabolism. Type 1 diabetics do
not produce enough insulin to sustain life, hence
are dependant upon exogenous insulin for
survival. On the other hand type 2 diabetics are
not dependent upon insulin for survival but many
patients will require supplemental insulin for
adequate control especially during times of stress
and illness.
In our country about 95% of patients have type
2 diabetes. At present there are about 25-30
million diabetic patients in India and this
number is projected to increase to 50 million
by 2010. Therefore the burden of type 2
diabetes is very large. It is estimated that 25-
30% of type 2 diabetes patients usually require
supplemental insulin after few years of OHA
(oral hypoglycaemic agents) therapy on regular
basis and most of them will require insulin at
one time or another in their lifetime either during

surgery or acute illness. Hence, the number of
type 2 patients on insulin outnumber the patients
of type 1 who are dependent upon insulin for
their survival. UKPDS study shows that diet alone
is ineffective in 90% of patients after one year
and by 6th year 50% of patients will need insulin
for proper control as 10-20% patients develop
secondary failure to OHA every year
1
.
Goals of insulin therapy
1. Elimination of prime glycosuric symptoms.
2. Prevention of ketoacidosis.
3. Restoration of lean bodymass.
4. Improvement in exercise and work
performance.
5. Reduction of frequent infections.
6. Decrease in foetal malformations, maternal
and foetal morbidity.
7. Delay, arrest, or prevention of micro and
macrovascular complications.
8. Improvement in the sense of well being.
Insulin preparations and characteristics
Insulin can be classified into different categories
based on parameters such as (a) Species; (b)
Purity; (c) Physical Characteristics; (d) Potency; and
(e) Time, Duration, and Effect.
A) Species: It is either derived from animal
pancreas or produced by genetic engineering
methods. Depending upon molecular

structure, insulin is classified as human,
porcine, or bovine. Porcine insulin differs from
human by one amino acid, whereas bovine
differs by three amino acids. Bovine insulin is
most immunogenic, whereas human is the
least. In India, either human or porcine insulins
are available whereas bovine preparations
have been recently withdrawn from the market.
Molecular structure
2
SPECIES A-CHAIN B-CHAIN Immunogenecity
A-8 A-10 B-30
HUMAN Threonine Isoleucine Threonine Least
PORCINE Threonine Isoleucine Alanine Intermediate
BOVINE Alanine Valine Alanine Most
B) Purity-measured in terms of proinsulin
content
Conventional < 3000 ppm – Not available
Highly purified < 10 ppm
* Senior Physician & Diabetologist,
Safdarjung Hospital,
New Delhi-110 029
** Consultant Physician & Diabetologist
D-656, CR Park, New Delhi-110 019.
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Monocomponent < 1 ppm – all human

insulins are monocomponent.
C) Physical characteristics: The solution can be
either clear or cloudy. All regular, soluble, or
crystalline insulins are clear solutions whereas
all long acting insulins like NPH, lente, or ultra-
lente are cloudy solutions. All insulins except
conventional bovine have neutral pH.
Conventional bovine insulin was acidic and is
not available for clinical use at present.
D) Potency: In India all types of insulins are
available as 40 units/ml in 10 ml vials. 100
units/ml vials as well as pen cartridges are also
available but care should be taken to use
appropriate or potency matching syringe. For
patients having insulin resistance even 500 -
5000 units/ml preparations are available.
E) Time Duration and effect
3
Insulin Type Synonyms Retardant Time of Effect Hours
Onset Peak Duration
Unmodified Soluble None 0.25-1 1.5-4 5-9
Regular H]
Short Acting P] same
B]
NPH Isophane Protamine 0-5-2 3-6 8-14
H]
P] same
B]
Lente Mixture of 30% Zinc H 1-2 3-8 7-14
Semilente (an P 1-2 3-8 7-16

amorphous precipitate B 1-5-3 5-10 10-24
of Insulin with Zinc
ions) with 70%
Ultralente Insulin Zinc H 2-3 4-8 8-14
Ultralente An Insoluble Crystal B 3-4 6-12 12-28
of Zinc and Insulin
Insulin Lispro None 5-15 1-2 4-5
Analogues Minutes
10/90
Premixed 25/75 Protamine 0.25-1.5 3-6 8-14
30/70 and 50/50
(H- Human, P- Porcine, B- Bovine)
Unmodified and lispro insulins do not have any
retardant hence have rapid onset of action, early
peak and short duration of action. NPH has
protamine or fishsperm as retardant, whereas
lente and ultralente have Zn as retardant. Lente is
a mixture of ultra and semilente in the ratio of
70:30. Only soluble or regular insulin is to be used
by intravenous route. NPH and lente are used in
once a day, basal, or twice a day regimen.
Ultralente is best for basal regimen. Lispro has
advantage over other insulins as it can be given
with meals because of rapid onset and short
duration of action. It is most suitable for old
persons and children as their eating habits are
often erratic. Normally, insulin is stored in vials as
hexamers and requires degradation to dimers and
monomers for absorption. Since in lispro insulin
there is interchange of proline and lysine at 28

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and 29, hence it remains in monomeric or
diameric form and is thus rapidly absorbed. Pre-
mixed insulins are usually available in a wide
range, but 25/75 & 30/70 are most popular. If
pre-mixed is with lente, then because of presence
of Zn almost 50% of crystalline insulin changes to
lente but this problem does not exist when regular
insulin is mixed with NPH. Almost all available
combinations are with NPH
4
.
Storage of insulin
All insulin preparations are required to be stored
in a cool and dark place; otherwise their potency
is lost, as it is temperature dependent. At 4 degree
C it loses only 2% potency over years. At 25 degree
C 2% loss occurs in 6 months. At 40 degree C 2%
loss occurs in one week and 5% in one month.
Therefore the extremes of temperature, that is, <2
and >30 degree C should be avoided
5
.
Therefore, keep insulin preparations away from
direct sunlight, in a cool and dark place. Do not
keep in a freezer compartment. The vial in current

use can be easily kept at room temperature in a
dark place without losing any potency, as most
patients will consume it within one month. If kept in
a freezer, then before injecting it should be taken
out and kept at room temperature for at least 1/2
an hour, otherwise injection will be painful if cold
insulin is injected. In rural areas or when refrigerator
is not available, it is advisable to put the vial in plastic
bag, tie a rubber band and keep it in wide mouth
bottle filled with water or in an earthen pitcher.
During travel
Ideally keep the insulin in a flask with ice, or in a
hand bag, or a proper container if outside
temperature is less than 30
°
C. Never keep insulin
in the glove compartment of a car.
Absorption of insulin
Except lispro, all insulins in vials are in hexamer
form and need to be changed to monomeric form
before absorption and it is the rate-limiting step
in absorption. Usually there is a lag period of at
least 10-15 minutes before insulin appears in
circulation. Insulin analogue is most rapidly
absorbed followed by human, porcine, and bovine
in descending order
6
.
Factors affecting absorption - can be
either physiological or structural

A) Capillaries at injection site
Higher density of capillaries enhances
absorption. Absorption is rapid from the
abdominal wall followed by upper arm and
thigh in descending order as abdominal wall
has high density of capillaries. It also depends
upon their functional status, that is, open or
closed capillaries at the site. Capillary density
and functional status decrease in lipo-
dystrophy and atrophy. Obesity and smoking
also cause a decrease in density and affect
functional status of capillaries
7
.
Exercise and massage, increased local
temperature, and better hydration result in
better absorption. Absorption is better with
intramuscular as compared to subcutaneous
route.
B) Insulin concentration and dose
40 u/ml is faster absorbed as compared to
100 u/ml insulin. Higher the dose, slower is
the absorption
8
.
Hence the onset and duration of action of same
type of insulin can vary depending upon the
physiological and structural factors at the
injection site.
Mixing insulins

Usually premixed solutions in a wide range are
available, but at times one has to mix short and
long acting insulins. Expect bovine insulin, all are at
neutral pH and can be easily mixed. Pre-mixed are
with NPH as lente is not suitable because presence
of Zn changes 50% of crystalline insulin to lente.
Technique
Wipe the top of vial with 70% isopropyl alcohol.
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Inspect the neutral soluble insulin vial for any
suspended particles and if present discard it. Roll
vial between palms and never shake it. First take
lente insulin vial and inject air equivalent to dose.
Withdraw the needle without draining the insulin.
Now take plain insulin vial, inject air equal to dose
and draw the required amount of insulin in syringe.
Now draw the lente insulin in the syringe. If lente
is drawn first and at the time of draining plain
insulin if some amount of lente enters plain vial it
will change plain to lente in the vial.
Injection site
For routine administration insulin is always given
subcutaneously. IV, IV infusion, or IM routes are
used only during ketoacidosis or stressful
conditions. It can be injected in anterior abdominal
wall, upper arm, thigh, and buttocks; the rate of

absorption also declines in above order. Same site
is used for at least one month and rotation is done
within the same site rather than rotating to different
sites with each injection (by an inch for each
injection). Using same site decreases variability in
day to day absorption. Rotation within the same
area prevents lipodystrophy. Avoid a site with open
wounds or blisters
9
.
Injection technique
If the injection site is clean, there is no need to
clean the site with alcohol or spirit as there are
bactericidal agents in insulin vial and as such
injection site infections are very rare. But if
antiseptic cleaning agent is used then let it
evaporate before injecting insulin
10
.
In thin or averagely built person, lift or grasp a
fold of skin between thumb and index finger and
inject at 45°or 90°. In obese person, full length
injection at 90° is recommended.
If there is pain or blood at injection site one must
review the injection technique.
Pain can be minimized by:
a) Injecting when insulin is at room temperature
b) Keep muscles at site relaxed.
c) Penetrate skin quickly while inserting or
withdrawing needle and do not change

direction.
d) Avoid air bubbles in the syringe
11
.
Syringes and other delivery devices
Insulin is available in two potencies, that is, 4O
u/ml and l00 u/mI, and always use compatible
syringe that is having 0-40 u/ml or 0-100 u/mI.
In disposable insulin syringes there is no dead
space hence insulin is not wasted. The needle used
is very fine, of 29 G or 30 G, having either 8 mm
or 12.7 mm length suitable for average and obese
patients respectively
12
.
Ideally, a syringe should not be reused but if reuse is
desired, then after injection recap it and store
properly at room temperature in appropriate box.
There is no need to sterilise or clean with alcohol or
spirit. The same syringe can be reused till the needle
becomes blunt. Reuse is not advisable if personal
hygiene is poor or open wounds are present
13
.
Among the other devices Insulin Pens have become
very popular. They are safe, accurate, convenient
and most suitable for elderly and handicapped
persons. They can be reused and only cartridges
need to be replaced. Each cartridge contain 300
u of insulin.

Other methods of administration are :
a) Jet injection
b) Insulin infusion pump
c) Nasal Insulin Infuser
d) Transdermal Insulin
e) Oral Insulin
Indications
A. Absolute
 Type 1 diabetic patients
 GDM (Gestational Diabetes Mellitus)
 Ketoacidosis
B. Relative
Type 2 diabetic patient with primary or
secondary failure to OHA
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 Surgery under general anaesthesia
 Type 2 diabetes with symptoms of glucose
toxicity
 Acute illness
 Acute infections, e.g., Pneumonia,
septicaemia, etc.
 Active pulmonary tuberculosis
 Acute MI, CVA
 Diabetic nephropathy
 Chronic liver disease, etc.
Choice of insulin

Soluble/Regular/Neutral
It is the only insulin suitable for IV use. Useful for
twice, basal-bolus, or CSII regimen for glycaemic
control. To be used in acute stressful conditions
and keto-acidosis.
Extended acting
Lente, NPH, ultralente, and premixed are suitable
for once, twice, or basal bolus regimen. Ultralente
is preferred for single bedtime injection and NPH
for single before breakfast (BBF) injection.
Lispro insulin - Best suited for post-prandial
hyperglycaemia but can be used in place of
regular in twice, basal bolus regimen, etc.
Premixed insulins
Premixed insulins are very popular and available
in wide range. Regular is mixed with NPH as it is
more stable. 30/70 and 25/75 are most popular
and used in twice a day regimen. 50/50 is
preferred for correction of post-prandial
hyperglycaemia.
Insulin regimens
A. Once daily regimen
It is most commonly used in type 2 diabetes
patients with secondary failure to OHA and
used in combination with OHA. Either lente,
ultralente, or NPH is used. NPH is preferred
before breakfast, whereas lente or ultralente
before dinner. The regimen is not suitable for
type 1 diabetes cases.
B. Twice daily regimen

It is the most commonly used regimen as it is
suitable for most type l, 2, and GDM patients.
It is very convenient as patient has to take only
BBF and before dinner (BD) dose and there is
no need to carry insulin to school or office.
Usually both short and long acting insulins are
used in combination, but in few cases only long
acting insulin can be used alone but not the
short acting. This regimen is not to be used in
acute medical emergencies. Usually, of the
total daily dose 2/3rd is given BBF and 1/3
before dinner; but depending upon eating
habits and glycaemic status, dose can vary and
even 50% can be given BBF and BD. Again,
the usual ratio of long acting to short acting is
2/3:1/3 or 70:30. But in premixed insulins
wide range is available from 10:90, 25:75 to
50:50. This regimen gives similar results as
compared to multiple injections or CSII by
pump.
C. Basal bolus regimen
In this regimen regular and intermediate
acting insulin is used. Basal requirement
is met by intermediate acting insulin given
twice a day before breakfast and dinner.
The regular insulin is given before each
meal thrice a day. Out of the total daily
requirement 50% is given as basal
(intermediate) and 50% as regular insulin.
The share of regular insulin (50%) is given

as 20% BBF, 10% BL and 20% BD. It gives
similar results as compared to twice a day
but the only disadvantage is that the
before lunch (BL) dose is to be taken at
school or office.
D. Continuous subcutaneous insulin infusion
Only short acting insulin is used and is
given by insulin pump which the patient
has to wear throughout the day. It is
neither practical, nor are the results better
than twice daily or bolus regimen.
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During surgery
All patients undergoing surgery, under general
anaesthesia, require changing over to insulin from
OHA and to regular insulin from intermediate
acting insulin. Surgery should be scheduled in the
morning. Omit BBF insulin. Do fasting blood sugar
and put patient on GIK (Glucose-Insulin-
Potassium) regimen according to blood sugar level
at least one hour before starting surgery. The GIK
regimen should continue at least one hour after
the patient has taken the first post operative meal
and patient is shifted to pre-surgery thrice a day
insulin regimen
14

.
During surgery do blood sugar at 1/2 hourly or
one hourly interval as per the status of patient.
Because of surgical stress, insulin requirements are
more with intra-abdominal or thoracic surgery.
CABG puts maximum surgical stress. The stress
caused by laparotomy is much more than the stress
caused by even whole body skin grafting.
Glucose-Insulin-Potassium (GIK) Regimen
Blood/Plasma Fluid Insulin Insulin KClmeq/100ml
Glucose mg.% 100 ml/hr. U/100ml U/500 ml
<100 10% Dextrose 1 5 2
100-200 10% Dextrose 2 10 2
200-300 10% Dextrose 3 15 2
300-400 10% Dextrose 4 20 2
>400 N/Saline 4 20 2
Insulin dose to be reduced to half if 5% Dextrose is used.
Insulin therapy for ketoacidosis
The use of low dose insulin regimen either
given by insulin infusion or intramuscularly
is now the accepted regimen for keto-
acidosis. The high dose regimen is no longer
used as with low dose regimen there is less
frequent hypokalaemia, hypoglycaemia, and
more predictable response.
Insulin is given as 6 u/hour by continuous IV
infusion. Only short acting insulin is used.
When the blood sugar falls to 250 mg% the
normal saline is replaced with 10% dextrose
and insulin infusion rate reduced to 4 u/hour.

But if significant drop in plasma glucose is
not observed after 2 hours of insulin infusion
and if fluid replacement, blood pressure, and
infusion lines are satisfactory, then double the
infusion rate.
Insulin can be given by IM route with dose of 6
u/hr but often a loading does of 20 u is
required. If after 2 hours the fall in sugar is not
satisfactory, either double the dose or start IV
infusion. The acidosis and ketosis resolve more
slowly than hyperglycaemia; hence, IV dextrose
preferably 10% dextrose with insulin should
continue till patient starts eating and shift to
thrice a day regimen by subcutaneous route. It
is advisable to increase the total daily dose by
20% of previous (before onset of ketoacidosis)
insulin dose and after recovery discharge on
previous or twice a day regimen.
Insulin regimen in special group of
patients
1. Elderly: Do not aim for strict glycaemic
control. Twice a day or once a day
regimen are most suitable.
2. Renal failure: There is considerable
reduction in insulin requirement and twice
daily or basal bolus regimens are suitable.
3. Recurrent hypoglycaemia: Insulin dose
distribution needs to be reviewed rather
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than the regimen. In some cases shifting
evening dose to bedtime can prevent
nocturnal hypoglycaemia.
4. Children: Same regimens are used as for
adults. Intermediate insulin may be ab-
sorbed faster. Twice a day is best suited
as it eliminates injection at school.
5. Secondary diabetes: Due to pancreatic
disease; usually have mild diabetes and
can be managed with twice a day
regimen.
6. Steroid and endocrine diabetes: They
have marked insulin insensitivity and
considerable endogenous insulin
secretions. It may require high dose of
insulin, but cessation of steroids often
allows patient to come off insulin again.
They are managed with twice daily
regimen. Endocrinopathies cause mild
diabetes which can be easily controlled
with twice a day insulin regimen.
7. Pregnancy: Insulin dose will increase as
pregnancy advances and balance of
insulin changing to greater daytime
requirement. There is sudden fall in insulin
requirement after delivery.
8. Cirrhosis of liver: Marked insulin

insensitivity during day but because of
impaired gluconeogenesis, no difficulty in
maintaining glucose concentration over
night. Hence require preprandial injection
regimen.
Adjustment of insulin dosage
For proper monitoring of control, the patient
should be encouraged to do SMBG (Self
monitoring of blood glucose). Ideally it
should be done by using glucometer and only
when glucometer is not available, gluco or
dextro sticks can be used. Urine sugar testing
is not reliable. Though expensive, HbA
1C is
good for monitoring the control. Ideally
plasma blood sugar should be done before
and after each main meal and at bed time.
Once good control is achieved the frequency
is reduced to once or twice a week.
Before attempting to readjust the insulin
dosage, a good number of blood glucose
readings should be available. If earlier
control was good within last 3 months and
there are no symptoms of hyperglyacemia or
reasons to suggest poor control, the blood
sugar should be repeated with same dosage
and also do HbA
1C before attempting any
change. The blood may also show 30-50%
variation at any one time of the day on

different days. Fasting and PP should be done
on same day for better assessment. The
guidelines for insulin dose adjustment are :
1. Do not change earlier than 2-3 days.
2. Change around 25% of any one
preparation at one time.
3. Do not change more than 10-20% of total
dose at one time.
4. Always modify the preceding dose.
5. Always review the dietary habits and
injection technique of the patient before
modification.
6. Reduce the dose by 15-20% at the time
of discharge.
Dose adjustment on changing from conventional
to human insulin
No dose adjustment is required if :
Requirement <1 u/kg body wt.
No lipodystrophy
Patient can do SMBG.
If patient is taking >1u/Kg body wt. then
reduce dose of human insulin by 15-20% at
the time of changing from conventional to
human insulin and readjust the dosage.
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Adjustment of Morning Dose

Before Lunch Before Dinner
a) Hyperglycaemia Increase short acting BBF Increase Intermediate (lente/NPH) BBF
b) Hypoglycaemia Decrease short acting BBF Decrease intermediate (lente/NPH) BBF
Adjustment to Evening Dose
Before Dinner Before Breakfast
a) Hyperglycaemia Increase Intermediate BBF Increase Intermediate before
OR Dinner
Add Short acting at Lunch
b) Hypoglycaemia Decrease Intermediate BBF Decrease intermediate before dinner
OR OR shift intermediate to bed time
Omit short acting at Lunch OR Decrease short acting before dinner
if dose is very high
Complications of Insulin Therapy
Hypoglycaemia
Identification card.
Carry 25-50 gm glucose while travelling even from home
to place of work.
Relatives and friends be taught to give Inj. glucagon.
Allergy (Localised/Generalised).
Lipoatrophy and Lipohypertrophy.
Insulin oedema.
Immunological insulin resistance.
Insulin antibodies.
Insulin resistance.
Obesity and weight gain.
Atherosclerosis, etc.
Summary
 Educate patient about the disease, need for
insulin, and problem of hypoglycaemia and
its management.

 Should keep 25 gm glucose at home, place
of work and carry while travelling.
 All new patients requiring insulin for short
period should be put on human insulin.
 If patient already well controlled on
conventional, no additional benefit with human
insulins.
 Always inspect vial before use.
 Explain storage and mixing.
 Teach and review injection technique yearly,
and earlier if local site complications are
present.
 Insist on self injecting of insulin.
 Set individual glycaemic goals.
 Tight control not desired in elderly, ESRD, and
patients with poor knowledge.
 Encourage SMBG.
 Only short acting can be given IV.
 Once daily not preferred.
 Twice daily/basal bolus/CSII/multiple injection
regimen have similar results.
 Adjust 15-20% of single preparation at one
time.
References
1. UK Prospective Diabetes Study Group: Intensive blood
glucose control with sulphonylurea or insulin compared
with conventional treatment and risk of complication in
patients with Type 2 diabetes (UKPDS33). Lancet 1998;
352: 837-53.
2. Yue DK, Turtle Jr. New form of insulin and their use in

treatment of diabetes. Diabetes 1977; 26: 341-7.
3. Homes PD, Alberti KGMM. Insulin Therapy Ed. Alberti
KGMM et al. In International text book of Diabetes
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Mellitus. England John Wiley & Sons 1992; 831-63.
4. Nolte MS, Poon V, Grodsky GM et al. Reduced solubility
of short acting insulin when mixed with longer acting
insulin. Diabetes 1983; 32: 1177-81.
5. Insulin Administration, American Diabetes Association.
Diabetes Care 1999; 22 (Suppl. 1): S83-S86.
6. Sherwin RS, Kramer KJ, Tobin JD et al. A model of kinetics
of insulin in man. J Clin Invest 1974; 53: 1481-92.
7. Hildebrandt P, Sejrsen P, Nielsen SL et al. Diffusion and
polymerisation determines the insulin absorption from
subcutaneous tissue in diabetic patients. Scand J Clin
Lab Invest 1985; 45: 685-90.
8. Rosenzweig JL. Principles of Insulin therapy. Ed Kahn CR,
Weir CC In Joslin’s Diabetes Mellitus. New Delhi. BI
Waverly Pvt Ltd 1996; 13: 460-88.
9. For references from 9-13, American Diabetes
Association. Continuous subcutaneous insulin infusion
(Position Statement). Diabetes care 1999; 22 (Suppl.1):
S87.
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