Insulin therapy in Diabetes Mellitus discusses various types of insulin, newer insulin analogs, and insulin regimens for managing type 1 diabetes mellitus. Rapid-acting insulin analogs have advantages over regular insulin such as quicker onset of action and less risk of hypoglycemia. Long-acting insulin analogs like glargine have advantages over NPH insulin such as a more consistent time action profile. The document discusses split-mix and basal-bolus insulin regimens and factors to consider when choosing a regimen. It also covers complications of insulin therapy, monitoring of blood glucose and HbA1c levels, and sick day management for patients with type 1 diabetes.

1. Insulin therapy in Diabetes Mellitus
Dr. Dilip Choudhary
Department of Pediatrics,
Mata Chanan Devi Hospital, New Delhi

2. • Insulin- types, action & drawback in
managing IDDM
• IDDM- complications, monitoring

3. Types of insulin
• Rapid acting- Lispro, Aspart, Glulisine
• Short acting- Regular or soluble
• Intermediate acting- Lente, NPH
• Long acting- Glargine, Determir

6. Newer insulin analogs
• Rapid-acting analogs:
Lispro, Glulisine and Aspart
• Long acting basal analogs:
Glargine and Detemir.

7. Rapid Acting Analogs Vs. Regular Insulin
Advantages over regular insulin
• Quicker onset of action- can be injected just before
eating, especially useful in young children who
cannot be relied upon to eat after the insulin shot, or
in those who have a short lunch break at school and
hence must inject and eat immediately.
• higher peak action achieved gives better post meal
glucose control.
• shorter “tail” effect the analogs are associated with
lesser risk of hypoglycemia especially at nights.
• Switching to analogs may help in resolution of
lipoatrophy when it occurs with regular insulin.

8. Drawbacks-
• Long term studies have shown little change in the
HbA1c with use of the analogs.
• Analogs are 3-4 times more expensive
• Rrequirement for basal insulin is higher when
analogs are used for pre-meal boluses, since the
“tail effect” of regular insulin provides some basal
effect.
“Therefore they should be offered only to families
who can easily afford them”.

9. LONG ACTING ANALOGS VS. NPH INSULIN
Advantages over NPH insulin-
• NPH has a distinct peak of action 6-10 hrs after
injection, necessitates ingestion of a snack to
prevent hypoglycemia in the daytime and also
increases the risk of night-time hypoglycemia. The
long acting analogs are relatively peakless hence
there is less need for snacks.

10. • NPH does not cover 24 hours hence 2-3 injections
a day are necessary when used as the basal
insulin. Glargine covers 24 hours in most children
and adolescents.
• NPH has a 25-50% variability of action from day to
day in the same individual. The long acting analogs
have a more consistent time action profile in a
given patient.

11. Drawbacks-
• The cost is 6-8 times more than that of NPH.
• Glargine, cannot be mixed in the same syringe
with other insulin, needs separate prick.
• Some children experience a burning sensation at
the injection site with glargine insulin.
• If accidentally injected intramuscularly, it’s time
action curve resembles that of regular insulin (can
cause night-time hypoglycemia)

12. Storing insulin
• Vials- in refrigerator at 2-8˚C, should never be
frozen; if frozen inadvertently, the vial would have
to be discarded.
• If no refrigerator- keep in a cool, dry place away
from sunlight and from other sources of heat (such
as the stove). It can be stored in an earthenware
pitcher or matka.
• Insulin pens- need not be refrigerated but should
be kept in a cool, dry place.

13. • Insulin should ideally be brought to room
temperature before injecting since cold insulin
may be painful.
• Potency-
At 4-8˚C- till the expiration date, however a vial in
use (after the seal has been punctured) should
not be used beyond 3 months if refrigerated.
At room temperature- full potency for only four
weeks.

15. Visual inspection of an insulin vial-
Normal appearance Abnormal appearance
Regular insulin,
Rapid acting analog
Glargine
Clear if appears cloudy or
has particulate matter, should
be discarded
NPH
Lente insulin
Cloudy if appears thick,
discoloured, or
has solid floating particles, or
solid residue at the bottom of
the vial, should be discarded.

16. Insulin Injection: Pen Or Syringe ?
• In India, insulin in vials available in two concentration (40 IU/mL
and 100 IU/mL).
• Extremely important to ensure that the insulin syringe has the same
number of subdivisions as the strength of insulin preparation in use.
Syringe and vial Pen and cartridge
Insulin in vials (for use with a syringe) is
cheaper
Expensive
preferred for those on split-mix regimens,
who need to mix two types of insulins,
suitable for those on a basal-bolus regimen.
• 30G-31G gauge needles are almost pain
free and can be reused (till the needle
becomes blunt.
• needle should never be cleaned with
spirit.
• Insulin Pens are an “attractive toy” .
• The needles are shorter, reducing the
chance of intramuscular injections.
• They are very convenient to use.
• No need of carrying insulin vials and filling
a syringe before each shot.
• near-painless
• 0.5 Unit dose also can be adjusted

17. Injection sites
• Subcutaneous injection (for this the skin must be
pinched up).
• Rate of absorption-
Abdomen>arm>thigh> buttocks
• Systematic site rotation
within the selected area
to prevent lipohypertrophy.
• The injection area should
remain the same for a given
time of the day.

18. • Within a given area not more than 2-3 doses
should be injected in a month at the same point.
• To achieve this, in each area 10-15 spots must be
marked in such a way that there is a distance of
two fingers width between any two spots.
• After injecting one should wait for 5-10 seconds
and then release the pinch before withdrawing the
needle; to prevent insulin leakage from the
injection site.
• Do not massage the injection site.

19. SEQUENCE FOR DRAWING TWO TYPES
OF INSULIN IN THE SYRINGE
• The vial of cloudy insulin should be gently
rotated between the palms (don’t shake the
vial).
• Short acting insulin is taken first followed by
the longer acting insulin ( ‘s’ before ‘l’ in
insulin).

20. Insulin regimens
• Short acting insulin alone is used alone only in
management of DKA and for supplements on “sick
days”.
• For day to day management:
- it must be injected Subcutaneously
- use rapid or short acting insulin together with
intermediate or long acting insulin.
• 2 regimens for giving insulin:
- Split-mix regimen
- Basal-bolus regimen

21. Physiological insulin secretion profile

22. Split-Mix Regimen
“one type of insulin covers one time period”:
-the pre-breakfast short acting covers the period
from breakfast to lunch while the intermediate
acting works between lunch and dinner;
-the evening short acting covers the period from
dinner to bedtime/midnight while the intermediate
acting covers the period from bedtime to pre-
breakfast.

23. Split Mix regime

24. 2 injection regimen:
-two injections, one pre-breakfast and the other pre
dinner. TDD (short/rapid +NPH)
2/3 BBF 1/3 BD
short/rapid and long1:3 1:1 or 1:2
3 injection regimen:
-If, on the 2 injection regimen, the BG at 2-3 am is in the
normal range with elevated fasting (pre-breakfast)
levels, In such cases it is common to split the evening
dose with the short acting being administered before
dinner and the intermediate acting at bedtime.

25. Basal-Bolus Regimen
• more physiological and if implemented correctly
(with frequent SBGM, corrective supplemental
doses of insulin and carbohydrate counting for
pre-meal bolus calculation) can give better control.
• Rapid or short acting insulin- cover meals and
• NPH or a basal analog- provide basal insulin (to
regulate hepatic glucose output in the fasting
state).

26. Regular insulin three times a day before each
major meal and NPH insulin only at bedtime or
preferably pre-breakfast plus bedtime.
Regular insulin three times a day before each
major meal and Glargine or Detemir once or twice
a day.

27. Basal Bolus regime

28. Choice of Insulin Regimen
depend on multiple factors:
• the age of the child
• stage of diabetes
• financial condition of the family
• school timings
• motivation of child and parents
• feasibility of giving multiple shots

29. The split-mix regimen Basal-bolus regimen
• Most commonly used in children as they
are simple and require fewer daily
injections.
• Appropriate for children who have a fairly
constant lifestyle (waking and sleeping
hours; school and play and meal timings).
• When good control cannot be achieved,
the patient should be switched to a basal-
bolus regimen.
• In patients who can afford the additional
cost
• Who are also motivated not only to take
multiple shots (including an afternoon
dose) but also to perform frequent SMBG
and act on the results.

31. Total daily dose (TDD) of insulin
Dose of insulin Comment
DKA management 0.1Unit/kg/hr
infusion of short
acting insulin
IV infusion
Recovering from DKA 2-3 U/kg/ day Initially high insulin requirement for first few
days, because of elevated levels of stress
hormone, increased appetite and to restore
depleted body stores of protein and glycogen
Honeymoon phase 0.5 U/kg/day or less -Increase in insulin production within several
weeks after initiating insulin therapy.
-some may virtually no insulin, but it is
preferable to continue with a very small dose.
- β cell destruction continues.
Maintenance 0.7-1 U/kg/day for
pre-pubertal
1-1.2U/kg/day for
pubertal
At puberty 1-1.5 U/kg/day Anti- insulin effect of growth hormone and
sex steroids

32. Honeymoon phase
• Partial remission phase defined as insulin
requirement of <0.5 U/kg/day and HbA1c <7%
• Increase in insulin production
• Commences within several weeks after initiating
insulin therapy and may last for weeks to yrs.
• some may virtually require no insulin, but it is
preferable to continue with a very small dose.
• β cell destruction continues.

33. Interesting facts
• Insulin sensitivity factor (ISF)-To know the drop in
BG (mg/dl) with 1 unit of regular insulin or rapid
acting analog.
 1800/TDD for rapid acting
 1500/TDD for regular
• Insulin:carbohydrate ratio- The grams of
carbohydrate for which 1 unit of rapid or short
acting insulin are needed.
500/TDD
Both ISF and Carb counting are very useful for
Basal Bolus regimen.

34. Example 1
• 5yrs old on a TDD of 20 Units insulin (aspart +
Glargine) wants to have a fruit cake (25 gm
CHO approx). How much extra insulin is
required?
• 500/20= 25 i.e, 1 unit insulin covers 25 gm
carbs, therefore 1 units extra aspart is
required before this snacks.

35. Example 2
• 18 yrs old on TDD of 50 units (NPH+ Regular)
has a premeal blood glucose of 200 mg/dl.
How much extra insulin is required?
• 1500/50= 30 i.e, 1 unit insulin lowers blood
glucose by 30mg/dl.
• Take a premeal target as 130 gm/dl, so 2 units
of extra regular insulin is required.

36. COMPLICATIONS OF INSULIN THERAPY
• Hypoglycemia- most common, so start with small
dose and adjust in small amount.
• Lipodystrophy-
-lipoatrophy: seen with older insulin, Rx- use newer
insulin and injecting in walls of the atrophic regions.
- lipohypertrophy: seen with use of any insulin, Rx- no
specific, except to inject in parts of body which are
usually covered.
• Edema- insulin has salt retaining properties
• Immunoresistance- impurities in the older insulin gave
rise to Ab which interfere with action. Minimal with
newer insulin.
• Allergy are very rare, unlike in the past.

37. Type 1 DM- complications & monitoring

38. Type 1 Diabetes Mellitus Complications
• Acute complications:
-Diabetic ketoacidosis
-Hypoglycemia
• Chronic complications:
-Nephropathy
-Hypertension
-Dyslipidemia
-Retinopathy

39. Monitoring of child with Type 1 DM
SMBG (Self Monitoring of Blood Glucose)-
• essential component of diabetes management.
• At least 4 times daily- BBF, BL, BD, Bedtime and
when insulin therapy is initiated and when
adjustment are made check at 12 AM and 3AM to
detect nocturnal hypoglycemia.
• Ideally BS should range from approx 80 mg/dl in
fasting state to 140 mg/dl after meals.

40. Insulin dose adjustment:
High fasting blood glucose Evening dose of long-acting
insulin is increased by 10-15%
and / or additional fast- acting
insulin coverage for bedtime
snack
High noon blood glucose Morning fast- acting insulin is
increased by 10-15%
High presupper glucose Noon dose of fast- acting
insulin in increased by 10-15%
High prebedtime glucose Presupper dose of fast acting
insulin is increased by 10-15%

41. Continuous glucose monitoring system (CGMS):
• Data obtained from a subcutaneous sensor every
5 min for 72 hrs
• Provides a continuous profile of tissue glucose
levels so doses can be fine tuned
• helpful in detecting asymptomatic nocturnal
hypoglycemia, to avoid hypoglycemia the glucose
sensor sounds an alarm.
• Studies are evaluating the fully automated closed
loop system of insulin delivery based on CGMS,
mistakenly k/as “artificial pancreas”.

42. Closed-loop system (artificial pancreas):

43. Glycosylated Hemoglobin monitoring-
• HbA1c should be obtained 3-4 times/yr.
<6%- non-diabetic
6-7.5%- good metabolic control
7.6- 9.9%- fair control
≥ 10%- poor control
• Target HbA1c Should be <7.5% regardless of
age.

44. Target Premeal blood glucose and HbA1c
Age group (yr) Target premeal BS (mg/dl) Target HbA1c (%)
<5 100-200 7.5- 9
5-11 80-150 6.5-8
12-15 80-130 6- 7.5
16-18 70-120 5.5- 7

45. Monitoring for long term complications
When to screen Frequency Preferred method of
screening
Retinopathy • After 5yr duration in prepubertal
• After 2 yr duration in pubertal
1-2 yrly Fundus examination
Nephropathy • After 5yr duration in prepubertal
• After 2 yr duration in pubertal
Annually -Spot urine sample for
albumine : creatinine
ratio.
- 24 hr urinary protein
Neuropathy Unclear in children; adults at diagnosis
in T2DM and at 5 yr after diagnosis in
T1DM
Unclear Physical examination
Macrovascular
disease
After age 2 yrs Every 5 yrs Lipids
Thyroid disease At diagnosis Every 2-3 yrs
or more
frequently
based on
symptoms
TSH

46. Sick day management

47. Infection can disrupt glucose control
+
counterregulatory hormones asso with stress blunt
insulin action
Hyperglycemia & ketosis
osmotic diuresis, dehydration emesis, anorexia
hypoglycemia
overall unpredictable effect

48. • Blood glucose and ketones must be checked
every 2-4 hours.
• Insulin should never be completely omitted even
if child refuses to eat.
• Insulin dose can be reduced only when BG is
below 80 mg/dL and the child cannot eat.
• In this case, the short or rapid acting insulin dose
is omitted while the intermediate or long acting
insulin is continued as usual.
• Goal- maintain hydration
control glucose level
avoid ketoacidosis

49. • Reduction in Usual Insulin Dose to Prevent
Hypoglycemia on “Sick Days”
• Insulin supplements on “sick days”- check ketones in every
other void
Blood glucose Urine ketones Action
<80 mg/dL Absent / trace Omit regular insulin or rapid acting analog
if oral intake is poor. Continue NPH / long
acting basal analog
<80 mg/dL > trace Also decrease NPH or long acting basal
analog by 20-30%
Urine ketones Blood glucose (mg/dl) Extra insulin (% of TDD)
Absent/ trace >180 5-10%
Small/ moderate 180-400 10-15%
>400 15-20%
Large >180 20%

50. Interesting facts
Q1. Somogyi phenomenon?
Ans- High morning BG, caused as rebound from
late night or early morning hypoglycemia, as
exaggerated conter regulatory response.

51. Q2. Dawn phenomenon?
Ans- caused by overnight GH secretion and
increased insulin clearance. It is a normal
physiologic process seen in most adolescent
without diabetes, who compensate with more
insulin output. Child with T1DM can’t
compensate.
It is usually recurrent and modestly elevates
most morning glucose levels.

52. Early morning hyperglycemia?
Decline in insulin level( most common)
Dawn phenomenon
Somogyi phenomenon( unlikely to be a common
cause).
So night time glucose monitoring may help clerify
ambiguously elevated morning glucose.

53. Reference
• Nelson Textbook of Pediatrics 20th edition
• ISPAD Clinical Practice Consensus Guidelines
• Essentials of medical pharmacology 7th edition

54. Thank you