Insulin Therapy in Type 1

Diabetes Mellitus

Prof. Dr. MONA EL SAMAHY

Professor of Pediatrics,
Head of Diabetes Unit
Ain Shams University, Cairo, Egypt.
Why are We Concerned about Diabetes?
Egypt will be the 10th. World wide

2000 2030
People with People with
Ranking Country Country
diabetes (millions) diabetes(millions)

1 India 31.7 India 79.4

2 China 20.8 China 42.3
3 USA 17.7 USA 30.3
4 Indonesia 8.4 Indonesia 21.3
5 Japan 6.8 Pakistan 13.9
6 Pakistan 5.2 Brazil 11.3
7 Russian Fed. 4.6 Bangladesh 11.1
8 Brazil 4.6 Japan 8.9
9 Italy 4.3 Philippines 7.8
10 Bangladesh 3.2 Egypt 6.7

The worldwide diabetes market is experiencing exponential growth, especially

with respect to type 2 diabetes, which has been described as a global epidemicv

Wild S et al. Diabetes Care 2004;27:1047–53

Lowering HbA1c reduces the risk of complications

Deaths related to
21%
diabetes

HbA
1c 37%
Microvascular
complications
1%

Myocardial
14%
infarction

Stratton IM, et al. BMJ 2000; 321:405–412.

Treat To Target Guidelines
Need For Progressive Treatment Strategy

Glucose control Healthy ADA1 AACE2 IDF3

HbA1c (%) <6 <7 6.5 6.5

Mean FPG <5.6 57.2 <6 <6

mmol/l (mg/dl) (<100) (90130) (<110) (<110)

Mean postprandial PG <7.8 <10* <7.8** <7.5**

mmol/l (mg/dl) (<140) (<180) (<140) (<135)

*12 hours postprandial; **2 hours postprandial.

PG=plasma glucose.
1.American Diabetes Association. Diabetes Care 2005;28(suppl 1):S14—36.
2.American Association of Clinical Endocrinologists. Endocr Pract 2002;8(suppl 1):43—84.
International Diabetes Federation. Diabet Med 1999;16:716—30.
3.
 Treatment

Ideal therapy
Should include the following:
* Insulin.
* Diet.
* Exercise.
* Psychological management.
* Health education.
* Home glucose monitoring.
 Before Insulin….What‟s After?

• Before insulin was

discovered in 1921,
everyone with type 1
diabetes died within
weeks to years of its onset

JL on 12/15/22 and 2 mos later

Insulin Therapy in Type 1 Diabetes
is a must………
 Insulin
is the 1ry mode of therapy in type 1
diabetes

 Insulin
treatment must be started as soon
as possible after diagnosis to prevent
metabolic decompensation and diabetic
ketoacidosis
 Most children are prescribed human insulin
because of their availability through modern
manufacturing techniques using recombinant
DNA technology and because of their low
immunogenicity
Porcine or bovine preparations may be cheaper
and more readily available in some parts of the
world. They are not inferior in clinical efficacy to
human insulin. They may have greater
immunogenicity and high titer antibodies may
alter pharmacodynamics by acting as insulin
binding proteins
 Insulin concentrations:
The most widely available insulin concentration is 100
IU/ml. It must be given by insulin syringes calibrated to
the concentration of insulin being used
 Injection sites:
1- Front of the thigh/ lateral thigh
2- Abdomen
3- Buttocks
4- Lateral aspect of arm
 Storage of insulin :

. Insulin must never be frozen

. Unused insulin should be stored
in a refrigerator (2-8C)
. Direct sunlight damages insulin
. After opening, an insulin vial
should be discarded after 3
months if kept at (2-8C)
 Problems with injections

1- Local hypersensitivity reactions

2- Lipohypertrophy
3- Lipoatrophy
4- Painful injections
5- Leakage of insulin
6- Bruising and bleeding
7- Bubbles in insulin
 Insulin Preparations

 Short Acting Insulin (Regular)

 Rapid - Acting Analogues
 Intermediate - Acting (NPH) Insulin
 Premixed Insulin
 Long - Acting Insulin
 Long Acting Analogues
Premixed insulins are popular in some
countries particularly for prepubertal
children on twice daily regimen.
Although they reduce potential errors
in drawing up insulin they remove the
flexibility offered by separate
adjustment of the two types
 Pharmacokinetics of Current Insulin
Preparations Compared With Insulin Glargine

Effective
Onset Peak Duration

Insulin lispro <15 min 1 hr 3 hr

Regular 0.5-1 hr 2-3 hr 3-6 hr
NPH/Lente 2-4 hr 7-8 hr 10-12 hr
Ultralente 4 hr Varies 18-20 hr
Insulin glargine 1-2 hr Flat/Predictable 24 hr

Barnett AH, Owens DR. Lancet. 1997;349:97-51. White JR, et al. Postgrad Med. 1997;101:58-70.
Kahn CR, Schechter Y. In: Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 1990:1463-1495.
Coates PA, et al. Diabetes. 1995;44(Suppl 1):130A.
 Principles of insulin therapy

 To
provide sufficient insulin throughout the 24
hours to cover basal requirements.

 To
deliver higher bolus of insulin in an attempt to
match the glycemic effect of meals.
 Insulin regimens

 Two injections daily of a mixture of short and

intermediate acting insulin (before breakfast and
the main evening meal)
 Threeinjections daily using a mixture of short and
intermediate acting insulin before breakfast,
short acting insulin alone before an afternoon
snack or main evening meal, intermediate acting
insulin before bed
 Basal-bolus regimen of short acting insulin 20-30
min before main meals, intermediate or long
acting insulin at bed time
 Basal-bolusregimen of rapid acting insulin
analogue immediately before main meals,
intermediate or long acting insulin at bed time,
probably before breakfast and occasionally at
lunch time
Treatment
 Ideal Insulin Regimens Type 1 DM

The challenge is to
• Come as close as possible to normoglycemia and reduce hypoglycemia.

Minimizes nocturnal
hypos Optimize
FBS

Minimizes late morning and

afternoon hypos
Basal-Bolus Regimen
Intensive Insulin Therapy
Intensive glycemic control is the therapeutic
approach

• That aims to achieve near normal glycemia.

• Reduce the risk of microvascular complications

with intensive insulin therapy is associated
with increase risk of hypoglycemia [specially
nocturnal 55%].
 Daily insulin dosage

 Dosage depend on many factors such as: age,

wt, stage of puberty, exercise, nutritional in take,
results of blood glucose monitoring, etc…
 Inthe partial remission phase the daily insulin
dose is <0.5 IU/kg/day.
 Prepubertal children 0.7-1 IU/kg/day
 During puberty >1 IU/kg/day
 Insulin Therapy in Type 1 Diabetes

• Physiologic insulin delivery:

– About half of insulin dose is “basal,” unrelated to meals
– About half of insulin dose is required to utilize ingested
carbohydrate, distributed approximately in proportion to
carbohydrates in meals or snacks
– Total dose in adults ~ 0.7- 0.9 U/kg/day, in adolescents up to
1.5 U/kg/day
• Distinguish between “revising the regimen” and
“adjusting individual doses”:
• Revising the regimen means changing the usual dose on a
recurring basis
• Adjusting individual dose means one time only
 Insulin Therapy in Type 1 Diabetes

Revising the regimen:

• Change basal dose according to overnight BG profile (e.g. if BG
rises, increase dose)
• Change usual meal dose according to BG profile between meals
or post-prandial BG
• With practice, many patients can learn to revise the regimen
Adjusting individual doses:
• Each meal dose should be adjusted for current BG level (e.g. +1
unit/50 mg/dl)
• Each meal dose may be adjusted for expected or planned
carbohydrate intake (e.g. +/- 1 unit/15 gm carbohydrate)
• Give written individual dose change schedules as a sliding scale
or algorithm
Indications for Revising Insulin Regimen

• HbA1c > 7%
• SMBG results erratic, or outside target range
• Frequent hypoglycemia
• Severe hypoglycemia without warning
• Recurrent severe hypoglycemia
• Symptoms of hyperglycemia
 NEW INSULINS

 1) Insulin analogues
– Rapid-acting analogues.
– Long-acting analogues.
 2) Oral insulin.
 3) Inhaled insulin.
Rapid Acting Analogues
 Limitations of Regular Human Insulin (RHI)

 Properties of RHI:
– SC injection does not appropriately match the postprandial hyperglycaemic peak.

– Slow onset of action with subcutaneous (SC) injection which lead to:

– Late postprandial hypoglycaemia, if the meal is delayed.

– Nocturnal hypoglycaemia.
– Requires administration 30–45 minutes before any meal.

Wittlin SD, et al. In: Leahy JL, Cefalu WT, eds. Insulin Therapy:2002:73–85
 Ideal Rapid - Acting Analogue

 Similar physiological properties to human insulin, with faster absorption & onset
of action
 Faster absorption & higher concentration after SC. Injection compared to
conventional insulin , thus more physiological action reduce post prandial
glucose to greater extent.
 Give peak plasma concentration within 30 – 60 min.
 Rapid return to basal level by 180 min ( no delayed peak concentration)means
less incidence of hypoglycemia
 Reduced tendency for self association or rapid dissociation.
 Improve patient convenience (pre & post meal).
 Achieve the best glycemic control (post – prandial control). Diabetes care
1990 – 1991 & The Lancet 1997
 Rapid Acting Analogues

Appearance: CLEAR
 Onset: 15 minutes
 Peak: one hour
 Duration: 2-4 hours
 Examples:
– Lispro (Humalog: Insulin analog)
– Insulin Aspart (Novolog)
 Administration: subcutaneous
 Usually given 5 minutes before the meal:
– Peak coincides with postprandial rise in BS
Structure of insulin Lispro (LysB28, ProB29)

A-chain

1 6 7 11

19
1

21

7 20

B-chain
30 29 28
B29B28
Pro Lys
 Novo-Rapid
Pro
Asp Phe Gly
Phe Arg
Tyr
Glu
Thr Gly
Asp
B28 Cys
Lys
B30
Thr A21 Asn Cys Val
Tyr
Leu
Gly
Asn
Tyr
Ile
Glu
Leu
Val
Leu
Glu Ala
Gln
Gln Glu
Tyr
Val
Cys Leu
Cys Thr Ser Ser
Ile Cys Leu

His
Ser
Gly
Cys
Leu
B1 Phe Val Asn Gln His
 Rapid – Acting
INSULIN ANALOGUES
„monomeric‟

B9 ASP, B27ASP
X
B10 ASP

B28 LYS B29 PRO Insulin lispro

B28ASP Insulin Aspart

B3Lys, B29Glu : HMR 1964

Insulin glulisine (Apidra)
 Structure Difference
How Insulin Glulisine is different?
 Rapid-acting Insulin Glulisine ―Apidra‖

Insulin Glulisine:
Replacement of Asparagine B3 with
A chain lysine and lysine B29 with glutamic
Gly
acid
S
1 S
Ala
Gln Cys

Lys Glu
5 20
Phe Thr
Gln
S Ile S Lys
1 Asn Pro 30
10 15
His
S Phe
B chain S
5 25
Gly
His

Leu 20
10
15

= Substitution
Modified Human Insulin

Apidra (insulin glulisine [rDNA origin] injection) USPI. Sanofi Aventis 2004; EU SPC. Sanofi Aventis.
 Insulin glulisine APIDRA®
The Only Rapid Insulin Analogue …

Without Zinc

Zinc free reduce the formation of stable hexamers and obtain the fast
acting properties (quick onset of action).
An alternative stabilizer than zinc was needed.

With Polysorbate 20 Stabilizer

•Improved physical stability in solution.

•Inhibits the denaturation resulting from thermal &
mechanical stress.
•Improved in-use stability.
•No influence on the time-action profile of insulin glulisine.
 APIDRA® (insulin glulisine)
Rapid Onset of action

The two substitutions favour

monomer formation and facilitate
rapid absorption from the tissue
following subcutaneous injection.

Hollemen F, et al. N Engl J Med 1997;337:176–83 (adapted from Brange 1988)

 Insulin Glulisine “Apidra”
Provides Rapid Onset & Short duration of action
Insulin glulisine
Insulin lispro
RHI

14

12

10

6
Glucose infusion rate

2
(mg/kg/min)

–60 0 60 120 180 240 300 360 420 480 540

Dosage=0.3 U/kg
Time (minutes)

Drugs of Today 2005, 41 (7): 433-440

Becker RHA, et al. Diabetes 2003;52:471-P
 Rapid-Acting Analogs and RHI in Obese
Subjects

6
* Glulisine
Lispro
5
*
Regular human insulin
GIR, mg.kg-1.min-1

4
N=18
BMI=30 kg/m2 to 40 kg/m2
3

0
0 60 120 240 360 480 600

Time, min

* p< .05 GIR-t vs RHI and Lispro

Dosage=0.3 U/kg GIR=Glucose Infusion Rate 20%

Frick AD et al. ADA 64th Scientific Sessions, 2004. Abstract 526.

Long acting analogues
The need for a 24 hour basal insulin

• To achieve near normal glycemia exogenous insulin

must be delivered in a way that closely mimic normal
physiologic insulin secretion:
a) Continuous low level [basal insulin sec.]
b) Stimulated sec. after meals [prandial insulin]

• Reduce hepatic glucose production (more effective

approach for glycemic control)
• Maintain glucose level for brain and other vital organs
dependent on proper glucose utilization
 Which type Of Basal Insulin?
Attributes of an ideal basal insulin

 Basal insulin should be characterised by:

– Peakless
1
– 24-hour profile enabling once-daily dosing
– Good glycaemic control
2
– Less incidence of hypoglycaemia with proven long-term safety
3
– Ability to easily titrate to targets
– Minimal weight change
– Improved quality of life and treatment satisfaction

International Diabetes Federation. Diabet Med 1999;16:716–730

Treat-to-target study. Riddle M, et al. Diabetes Care 2003;26:3080–3086
 The Challenge is, The way the pancreas does it
Novel Basal Insulin
24-hour peakless profile of insulin glargine
allows once-daily administration

1. Lantus® (insulin glargine) Approved Product Information

2. McKeage K et al. Drugs. 2001;61:1599-1624.
3. Kramer W. Exp Clin Endocrinol Diabetes. 1999;107(suppl 2):S52-S61.
 Structure of Insulin Glargine

Gly

1 5 10 15 20 Asn Substitution

1 5 10 15 20 25 30

Extension
Arg Arg

• Modifications to human insulin chain

– Substitution of glycine at position A21
– Addition of two arginines at position B30
– Unique release pattern from injection site
 Absorption of Insulin Glargine
Sc Injection of Insulin
Glargine

Clear Solution pH 7.4

PH 4.0 Microprecipitates
at neutral PH 7.4

Precipitation
“depot” of
Dissolution Insulin Glargine
Hexamers Dimers Monomers
10-3 M 10-5M 10-8 M
Slow dissolution of free
Glargine Hexamers
Capillary Membrane
Continuously released
Insulin in Blood over 24 hours
Once daily dose
Insulin Glargine as an ideal basal insulin

• Reliable, constant basal insulin concentration to control basal

metabolism.
 Prolonged duration of action (24 hours) compared with NPH
human insulin (14.5 hours).
 Once-daily dosing
 Safety Smooth peakless time-action profile
 Lower risk of clinically hypoglycemic events
 Clear Soluble with less interpersonal variation.
 Consistent absorption from arm, leg and abdomen unlike
other insulin formulations
 Basal Insulin Profiles
Glucose Infusion Rates

4 Ultralente
NPH
Glucose infusion
(mg/kg/min)

1
Glargine
0
0 4 8 12 16 20 24
Hours
Lepore et al. Diabetes 49: 2142-2148, 2000
 Which type Of Basal Insulin?
Look at all available basal insulins

Glucose infusion Glucose infusion Glucose infusion Glucose infusion

rate (mg/kg/min) rate (µmol/kg/min) rate (mg/kg/min) rate (µmol/kg/min)
8
4 NPH 24 sc 40
injection
Ultralente 20 6
3
30
16

2 CSII 12 4
20
8 Insulin detemir
1 2
Insulin 0.4 IU/kg 10
4
glargine NPH
0 0 0 0.3 IU/kg 0

0 4 8 12 16 20 24 0 4 8 12 16 20 24
Time (hours) Time (hours)
sc injection
0.3 IU/kg or CSII 0.3 IU/kg/24/h

Lepore M, et al. Diabetes 2000;49:21428. Plank et al 2005 (n=12)

Adapted from Plank J, et al. Diabetes Care 2005;28:1107–12.
 RESULTS
216 12

180 s.c. insulin PLASMA GLUCOSE 10

0.35 U/Kg

mmol/l
mg/dl

144 8

108 6

Glargine (N=24)
72 4
Detemir Mean±SD
24 100

Subjects (%)
20 84
Subjects (N)

16 (Subjects with plasma glucose > 150 mg/dl)

67
12 by time of study 50
8 33
4 17
0 0
0 2 4 6 8 10 12 14 16 18 20 22 24
Time (hours)
Porcellati F et al., Diabetes 55 (Suppl.1): A130, 2006
 Ideal Insulin Regimens Type 1 DM

The challenge is to
• Come as close as possible to normoglycemia and reduce hypoglycemia.

Minimizes nocturnal
hypos Optimize
FBS

Minimizes late morning and

afternoon hypos
Basal-Bolus Regimen
 Delivery System

 Disadvantages of conventional subcutaneous injection:

– Discomfort
– Inconvenience
– Systemic delivery
– Inconsistent pharmacokinetics
– Irreversible after injection

 Insulin pumps

 Insulin pen

 Systems in clinical testing:

– Inhaled formulation
Insulin Pen Development
 Development for reusable pens

Alpha disposable pen

OptiSet disposable pen

Omega Lite electronic

reusable pen
Easy to teach
Simple and quick
Easy to use
Just dial and dose
Easy to inject 1,2
Easy-to-push, soft
and gentle injection1

1. Clarke A, Spollett G. Expert Opin. Drug Deliv 2007; 4(2):165-174.

2. Haak T, et al. Clin Ther (2007) 29: (4) 2007.
Easy Accurate Efficacy

•accuracy
SoloSTAR® is 100% accurate in the laboratory1 to ISO3 dose
standards
• SoloSTAR® is 100% accurate when used by patients2
•different
In a dose accuracy study with 60 patients, each delivering 6
doses, SoloSTAR® was 100% accurate2 to ISO3
laboratory dose accuracy standards

Lantus® % of delivered Passes ISO Apidra® % of delivered Passes ISO

doses within standard doses within standard
ISO standard

ISO standard 
60 x 10 u 100%

60 x 5 u 100%

60 x 40 u 100%

60 x 15 u 100% 
60 x 80 u 100% 60 x 30 u 100%

―In a random sample hospitalized diabetic patients delivered very precisely insulin
doses using both Lantus® SoloStar® and Apidra® SoloStar®‖ 2

1 Clarke A, Spollett G Expert Opinion in Drug Delivery 2007; 4(2): 165-174

2 Hermanns N, Diabetologie und Stoffwechsel, 2008, 3 (Supplementum 1)
3 Pen-injectors for medical use, EN ISO 11608-1:2000
 Insulin Pumps

 Mechanism:
– Small externally worn device
– Teflon catheter inserted into abdomen
– Uses only rapid or short acting insulins
– Continuous basal rate of insulin infuses Implantable insulin pump
– Before each meal, patient administers a programmed bolus of insulin
 Advantages:
– Flexibility, No intermediate insulins used
 Disadvantages:
– Pump dysfunction:
• Dislodged, kinked, batteries out, etc.
– Numerous blood samples necessary Mini Med Continuous Glucose
– Cost if insurance will not pay Monitoring System (CGMS)
 Insulin Pumps (USA)

508

MiniMed insulin pumps  Disetronic Insulin pump

Paradigm

Animas Insulin Pump

Implantable insulin pump

Alternative Insulin Delivery System
 Pulmonary Approach

 Insulin delivered through the oral

cavity can also be considered to have
its uptake in the pulmonary bed.
However, the idea of pulmonary
delivery of insulin is not a new idea,
as the first report of inhaled insulin
was noted in 1925.
 The high permeability of the lung’s
large surface area makes it an ideal
route for the administration of
insulin. The lung has hundreds of
millions of alveoli that are richly Exubera –Inhale Corporation
vascularised and where drug Dry powder insulin inhaled
absorption takes place
 Inhaled Insulin

 The rationale:
 We know that medicine can be
absorbed from the lung (e.g. Asthma
Rx)
 How big is the lung?
 The pluses: Oralin - Generex Corp.
oral mucus membrane
 It works (insulin is absorbed) insulin application
 Insulin is absorbed in similar fashion to
Humalog (Lyspro)
 Consistent & reproducible action of the
insulin
 ~ action to Humalog/Novo-rapid
 Inhaled Insulin

 The negatives:
 Dose is ten times greater than normal insulin dose (only 10 percent is
absorbed)
 Where is the rest going (?swallowed, ?absorbed)
 Buccal absorption is better
 Still need an injection of basal insulin
 Increased absorption if have upper respiratory tract infection or
smoker
 Increased absorption if smoker
 ? Lung toxicity (2 of 4 studies showed impaired lung function)
 2 patients found to have pulmonary fibrosis (by CT: ? There
already)
 How do we titrate the dose?
 Intranasal Approach

 Delivery of insulin using an intranasal approach was first

suggested over 65 years ago, but it was not until the 1980s
that this approach was seriously evaluated. Feasibility has
been demonstrated, as intranasal insulin (60 or 120U)
given pre-meal to 17 patients with type 2 diabetes and
compared with placebo resulted in reductions in
postprandial glucose at both 60 and 120 minutes.
 Jet Injectors

 This approach is appealing because of the lack of

needles,but the discomfort associated with jet
injectors is not reported to be less than that observed
with injections.
 Iontophoresis

 Iontophoresis refers to transdermal delivery of insulin or other

peptides by a direct electric current.

 However, iontophoresis enhances the transdermal delivery of

drug ions into the skin and surrounding tissues using low level
electrical current.
 Low-Frequency Ultrasound

 It has been estimated that the permeability achieved by 1

hour of sonophoresis performed three times daily may allow
for a typical daily dose of insulin (about 36U) to be delivered
transdermally.
 Transfersomes

 Transfersomes are lipid vesicles made of soybean of

deformability, which makes them flexible enough to pass
through pores much smaller than themselves.
 Gastrointestinal Delivery

 Insulin molecules lend to be too large and hydrophilic to

cross the mucosa. Uptake of insulin via the
gastrointestinal tract is limited by an extremely low
bioavailability (i.e. 0.5%).

 An additional limitation is the extensive enzymatic and

chemical degradation of insulin within the enzymatic
barrier of the gastrointestinal tract mucosa.
 Buccal Delivery

 Oral insulin delivery that relies upon uptake by the

buccal mucosa and oropharynx appears to be feasible
for more widespread clinical testing, as insulin
appears to be rapidly absorbed into the systemic
circulation with this approach.
 Buccal insulin, therefore, has also demonstrated proof
of concept; unfortunately, the studies to date
demonstrating efficacy are presented as abstracts
only, and safety and adverse effect profiles for this
approach have not been presented for large numbers
of subjects.
 Insulin therapy in type 2 Diabetes

 The emergence of type 2 diabetes in

childhood and adolescence is alarming,
especially as these patients progress to
chronic complications, potentially at a very
young age pausing a public health
problem.
Proposed algorithm for the management of youth
with T2DM (Silva Arslanian, 2007).
 The recent advances in diabetes technology
including:
 newer and more powerful oral agents
 insulin analogs that provide a more physiological
delivery of insulin
 insulin infusion devices
 accurate and less invasive methods of assessing
glycemic control
[offer great promise that improved, if not ideal, glycemic
control and associated health-related benefits might be
achieved, thus reducing or preventing the long-term
complications of diabetes (Kenneth et al.,2005)]