INSULIN THERAPY

Dr. Salha Gliwan

CONTENTS
oHistory of insulin.

oTypes of insulin .

oAdvantages and disadvantages.

oNew insulins.

oInsulin regimen.
INSULIN HISTORY
In 1921
oInsulin extracted by dr Banting & Best.
oInsulin preparations from beef/pork pancreas.
In 1922
othe first medical administration of insulin.
In 1978
obiotechnology company named genentech produced the 1st
synthetically engineered human insulin by DNA recomponent
technology.
INSULIN HISTORY
oThe gene for insulin was inserted into bacterial DNA the result was
human insulin, called recombinant DNA insulin.
In 1996
oInsulin analoges.
oThe vast majority of insulin currently used worldwide now is recombinant
human insulin or its analogs.
Insulin analoges
In insulin analoges, different a mino acids are added or substituted at certain
positions a long the A and B chains, these changes in the properties of insulin ,its
solubility and time of action e g Aspart ,replacing the proline at B28 by Aspartic
acid results in the formation of an insulin analoges that rapidly changed to a
monomers.
NORMAL PHYSIOLOGICAL PROFILE OF SERUM INSULIN
CONCENTRATION

Kruszynska. Diabetologia 1987;30:16

COMPONENTS OF INSULIN THERAPY
oBackground or basal insulin :
✓ Provides a low ,continuous level of insulin.
✓ The action of basal insulin secretion is fundamental to stop
ketogenesis and hepatic glucose output.
✓ Once or twice injection.
✓ Represents about 50% of daily insulin requirement.

oPrandial insulin:
✓Rapid onset, short duration.
INTERMEDIATE ACTING INSULINS
oTwo principal preparations exist:
✓ NPH (neutral protamine Hagedorn) ,isophane insulins.
✓Crystalline zinc acetate insulin (insulin zinc suspensions, IZS or Lente
insulins).
✓NPH is insulin treated with protamine and zinc@ neutral pH(7.2)
,protamine complexes with insulin and zinc to yield particles that
slowly dissolve in body fluids forms a fine precipitate of protamine
zinc insulin( insoluble).
✓Isophan insulin suffer from variable absorption profiles because of
differences in particle size.
oThe action profiles of these insulin onset of action 2-4hrs,peak 4-12hr,
duration 12-24hr, make them suitable for twice daily regimens .

oIsophane insulins is suitable for mixing with regular insulin in the same
cartridge.
 INTERMEDIATE ACTING INSULINS
What are the limitations?
oIt has peak, risk of hypoglycemia( nocturnal hypos).
oDuration of action not long.
oAction profile depends on dose in that smaller dose has a shorter
duration of effect and earlier peak..
oVariability of absorption with site/exercise.
 GLARGINE
oIs often given once a day, but many children may need to be injected
twice.
oOnset of action 2-4hrs, Peak 8-12hrs, duration 22-24hrs.
oCan be given before breakfast or before dinner, or at bed time with equal
effect.
oTransferring to glargine, the total dose of basal insulin needs to be
reduced by approximately 20%.
oPredictable absorption independent of dose or site of injection.
 DETEMIR
oInsulin detemir has the amino acid threonine at B30 omitted and a 14-carbon
fatty acid covalently attached to the lysine at B29. The fatty acyl side chain
stabilizes the hexamers and prolongs the persistence of insulin detemir at the
injection site by slowing hexameric dissociation and subsequent monomeric
absorption. In addition, the fatty acyl chain enables binding to serum albumin
and reduces the amount of free insulin available for engagement with insulin
receptors. Subsequently, the disposition of detemir to peripheral tissues and its
clearance from the body are slow
oAction profile, onset of action 1-2hrs, peak 4-7hrs,duration 20-24hrs.
oUsed once or twice,In pediatric study,70% of patient used detemir
twice daily.
oIn adults studies with detemir have shown less weight gain, which has
been observed also in children and adolescents, . Although the precise
mechanism remains unclear, it is likely that the weight sparing effect of
insulin detemir can be explained by a combination of mechanisms.
Human studies have shown changes in cerebral mechanisms leading to
decreased appetite with detemir infusion as well as preferential liver
utilization over peripheral tissue resulting in less lipogesis.
oWhen transferring to detemir from NPH ,the same doses, can be used
to start with.
Degludec:
Insulin degludec,a novel ultra long acting basal insulin, is a
almost identical to human insulin in structure except for the
last a mino acid deleted from the B chain and a addition of a
glutamyl link from lys B29 to hexa decandioic fatty ac
 DEGLUDEC (TRESIBA)
oIs ultra long acting analog provides a duration of action
beyond 42 hrs.
oFlat and stable glucose lowering effect.
oBecause Half life is 25hrs , dose adjustments are made every
3–4 days.
oFlexibility in day to day dosing time with a minimum of 8hrs
between injection.
oStarting dose: if patient not on insulin
oIn type 1dm one third to one half of the total daily insulin or
0.2-0.4 u/kg
oType 2 DM 10 units SC once daily.
oIf patient already on insulin (type1 & type2) use the same dose
of basal insulin.
oLower risk of over all, nocturnal and sever hypoglycemia.
oDegludec is approved to be used in pediatric age above 1 yr.
TRESIBA® SHOWS LOWER RATE OF HYPOGLYCAEMIA THAN
INSULIN GLARGINE U100 IN SWITCH 1 TRIAL

SWITCH 1 TRIAL DESIGN HEADLINE RESULTS

1 20% insulin dose reduction when initiating titration

Note: Daily injections of both Tresiba® and insulin glargine evenly split between morning and evening
IGlar: insulin glargine U100; IAsp: insulin aspart
* p < 0.001; BG: blood glucose;
 GLARGIN300
U-300 glargine displays a more even and prolonged PK/PD profile compared with U-100
glargine, offering blood glucose control beyond 24 hours

LLOQ = lower limit of quantification; GIR = glucose infusion rate.

Becker RH, et al. Diabetes Care. 2015;38(4):637-643.
The full glucose lowering effect may not be apparent for at least 3 to 5
days of use. The EDITION 4 trial, which was a randomized study in
adults with T1D, and the EDITION JUNIOR trial, focusing on persons 6–
17 years old with T1D, showed non-inferiority of glargine U300 to
glargine U100 with similar rates of hypoglycemia and similar glycemic
control. However, some studies have shown that glargine U300 has
reduced nocturnal hypoglycemia and improved glycemic stability
compared to glargine in adults with T1D.
U300 is EMA and FDA approved for children ≥6 years.
Prandial insulins
 Regular insulin(short acting):
Usually identical to human insulin.
Is still used as an essential component of most daily
replacement regimen.
➢Should be given 20-30 min premeal.
Action profile of regular insulin(short acting):
LIMITATION OF REGULAR INSULIN

oDelayed onset of action lead to post prandial hyperglycemia.

oProlonged peak action(2-4hr)&duration of action, late post prandial
hypos.
oDose should be given 30min before meal, so the dose can not be
adjusted according to meal.
oAbsorption varies with injection site(variability of absorption as much as
25%).
oAction profile is dose dependent( smaller dose has a shorter duration&
earlier peak)
Rapid acting analoges:
oInsulin Lispro.(indicated in all persons regardless of age)
oInsulin Aspart. (≥1 year age)
oInsulin glulisine. (≥6 years age).
 (1) mimic physiologic prandial insulin secretion by accelerating insulin
absorption into the bloodstream for a rapid onset of action relative to
human regular insulin.
(2) shorter duration of action that provides enough time to control
postprandial BGLs while preventing late hypoglycemia.
RAIs have a more rapid onset of action and a shorter duration of
activity compared to regular human insulin when administered
subcutaneously. This glucose lowering action profile of RAI allows for
insulin injection closer to meal onset, allowing postprandial glycemic
control with greater flexibility in daily life
MEAL INSULIN: RAPID-ACTING ANALOGS (LISPRO,
ASPART, GLULISINE) VS REGULAR

RHI = regular human insulin

Adapted with permission from HoweyDC et al. Diabetes. 1994;43:396-402
RAPID ACTING ANALOGUE VS REGULAR
o RAI should be given ideally 10–15 min before meals or immediately
before meals given the strong evidence that the rapid action not only
reduces postprandial hyperglycemia, or after meal (in exceptional
cases)which is very suitable for children who are unpredictable eaters.
oHas a rapid action and short duration.
oBetter post prandial glycemic control.
oLess post prandial hypoglycemia.
oOnset of action/duration independent of dose and site of injection.
oGive a quicker effect than regular insulin when treating hyperglycemia.
oParticularly useful for pumps.
WHICH IS THE BEST RAPID ACTING INSULIN?

oInsulin Aspart
oInsulin Lispro
oInsulin glulisine.
oSome studies conclude that different rapid acting analogs have different
chemical properties, but no significant clinical difference in time of action
and duration.
2011 COMPARISON BETWEEN INSULIN ASPART . LISPRO AND GLULISIN
IN PUMP USERS-DURATION 39WEEKS
o1st group 13 wks Aspart, 13 wks Lispro and 13 wks Glulisin
o2nd group 13 wks Glulisin, 13 wks Lispro and 13 wks Aspart
o3rd group 13 wks Lispro, 13 wks Aspart and 13 wks Glulisin

RESULTS (No Statistically Significant Difference In)

oGlycemic control.
oHypoglycemia.
oEpisodes of DKA.
oCatheter set occlusion.
 PRE-MIXED INSULIN PREPARATIONS
o Pre-mixed insulins (fixed ratio mixtures of pre-meal and basal
insulins) are popular in some countries particularly for prepubertal
children on twice daily regimens.
o Regular(or rapid acting):NPH in different ratios e.g 10:90,15:85,
20:80 , 25:75,30:70,40:60, 50:50 are available in various countries
from different manufacturers.
oAlthough they reduce potential errors in drawing up insulin, they
remove the flexibility offered by separate adjustment of the two types.
o Premixed insulins may be useful to reduce the number of injections
when compliance (or adherence) to the regimen is a problem.
NEW INSULINS
 ULTRA RAPID ACTING INSULIN
oFiasp is brand name for fast acting insulin aspart containing niacinamide
and L arginine to speed up the monomer formation.
oAction profile, onset 5-10 min,peak 1-3hrs,duration 3-5hrs.
oFiasp approved by FDA in 2017 for adult, approvals for (children ≥1 year
old)
ULTRA-RAPID-ACTING INSULINS WHICH REPLICATE “NORMAL” INSULIN RESPONSE
MAY REPRESENT A STEP CHANGE IN INSULIN THERAPY
Ultra-rapid-acting lispro is approved for adults with diabetes. The
pharmacodynamic and pharmacokinetic action of ultra-rapid-acting
lispro has been investigated in a small-scale meal study in children
(6– 18 years old); however, it is not yet approved for young people
with diabetes.
 INHALED INSULIN
oThis new form of insulin therapy has been investigated in children above
12yrs of age as part of study in adults.
oAfreeza is an ultra rapid acting meal time insulin therapy being developed
for type1&2 DM, rapidly absorbed.
oIt is a drug device combination product consisting of insulin inhalation
powder and inhaler. June 2014, FDA approved Afrezza for both type1 and
type2 adult diabetics, with restriction for patients having disease or COPD
 Icodec
Once weekly basal analogs. There is ongoing research to develop novel
basal insulin analogs intended for once-weekly administration.
The Icodec: ultra-long acting, weekly basal insulin analog includes
three amino acid substitutions (A14Glu, B16His, B25His) that increase
molecular stability, reduce enzymatic degradation and insulin receptor-
mediated clearance. 20-carbo icosane fatty acid attached to the insulin
amino acid chain via a hydrophilic linker to insulin leads to durable
binding to circulating albumin and very protracted release
These modifications extend Icodec insulin's half-life to about 8 days with a flat
and stable pharmacokinetic profile, low peak-to-trough variations, and evenly
distributed glucose lowering efficacy with a weekly dosing interval
 SMART INSULIN
Glucose responsive insulin.
Is designed to circulate in the body and turn on when its needed and off
when it is not.
Perfect glycemic control.
Decrease the need to monitoring of BS.
Decrease the risk of short and long term complication.
 SMART INSULIN
oThis insulin would be administrated once a day or
week and then just automatically work according to the
glucose found in the blood stream.
oOne day smart insulin may be able to keep blood sugar
level stable without the constant need to check and
then inject.
oUnfortunately this researches is in very early stages.
 Biosimilar insulins
Biosimilar insulins demonstrate similarity to existing insulins. In
contrast to generic drugs, which are believed to be chemically identical
to their reference product, biologics such as insulin demonstrate slight
differences in their available counterparts given the use of different
manufacturing techniques and materials (e.g., host cells, tissues). The
FDA regulatory transition of insulins in March 2020 opened a regulatory
pathway for biosimilar insulin products in the United States and led to
the approval of three glargine biosimilars (Basaglar: FDA approved for
children ≥4 years old, Semglee, Rezvoglar . and a lispro biosimilar
insulin for adults and children.
Insulin regimen
 Insulin regimens
The choice of insulin regimen will depend on
many factors including: age, duration of diabetes, lifestyle (dietary
patterns, exercise schedules, school, work commitments etc.), targets of
metabolic control and particularly individual patient/family preferences.

✓ The basal-bolus concept has the best possibility of imitating the

physiological insulin profile.
Blood Glucose (mmols

10- Four injections/day

8-

6-

4-

2-
R or H at every meal N or G once or twice/day
0
8am noon 6pm 2am 4am 8am

Time
 Intensive insulin therapy:
➢Multiple daily injection: glucose and meal adjusted injection
regimen:
Basal 50%.
Prandial insulin before each meal adjusted the
dose according to meal content, level of
glucose, daily activity.
Insulin pump regimen with variable Basal rate and adjusted
bolus doses with meals.

Continuous Infusion

8am noon 6pm 2am 4am 8am

Time
 Less intensive regimen
Two injections/day

R + N in AM R + N at Supper

8am noon 6pm 2am 4am 8am

Time
ADA recommendation for management of type1DM

Most people with type 1 diabetes:

▪Should be treated with MDI injections,
(3–4 injections per day) or
continuous subcutaneous insulin infusion (CSII).
▪Should be educated in how to match prandial insulin dose to carbohydrate
intake, pre meal blood glucose, and anticipated activity.
 Doses of insulin:
oDosage depends on many factors such as:
oAge.
oWeight.
oStage of puberty.
oDuration and phase of diabetes.
oNutritional intake.
oUndercurrent illness.
oExercise patterns.
So the correct dose of insulin is that achieves the best attainable
glycemic control for an individual child or adolescent without causing
obvious hypoglycemia and the harmonious growth according to weight
and height in children charts.
oDuring the partial remission phase, the total daily insulin dose is often
<0.5 IU/Kg/day.
oPrepubertal children (out side the partial remission phase) usually
require 0.7- 1 IU/Kg/day.
oDuring pubertal requirements may rise substantially above 1.2
IU/Kg/day and even up to 2 IU /Kg/day.
 summery
oThe goal of insulin therapy is to mimic normal insulin
physiology.
oRegular/NPH are still used as an essential component of most
daily replacement regimens in many parts of the word.
oUse of newer insulin formulations results in proper insulin
action times and less hypoglycemia.