Insulin to Diabetes

In 1552 BC
Diabetes 1st Described In Writing
Earliest known record of diabetes
mentioned on 3rd Dynasty Eqyptian
papyrus by physician Hesy-Ra:
mentions polyuria as a symptom.
250 BC, Apollonius of Memphis
coined the name "diabetes
meaning "to go through" or siphon.
He understood that the disease
drained more fluid than a person
could consume.
.
 Early Diabetes Discoveries

In the 1869, Paul Langerhans, a

German medical student announced in
a dissertation, that the pancreas
contains two systems of cells.

1889 Oskar Minkowski and Joseph von

Mering in France, removed the
pancreas from a dog to determine the
effect of an absent pancreas on
digestion
 The Discovery of Insulin
(Toronto 1921)

Fred Banting (1891-1941) Charles H. Best (1899-1978) John J.R. McLeod (1876-1935)

James B. Collip
(1892-1965)
Marjorie (?-?)
Leonard Thompson

The first patient to receive injections of

pancreatic extract on January 11, 1922. He was
14. The young Toronto resident had been
diabetic since 1919. He weighed only 65 pounds
and was about to slip into a coma and die. At
first he received Dr, F. Bantings and Dr. Charles
Bests extract. Two weeks later he used the
purified extract of Dr. J.B. Collip and
Thompson's symptoms began to disappear; his
blood sugar returned to normal and he was
brighter and stronger. Thompson lived another
13 years with the insulin. He died at the age of
27 due to pneumonia, a complication of his
diabetes
5
Learning Objectives
Describe the Pharmacotherapy of type 2 DM
List the Management of diabetes: OHA and
Insulin
Describe Insulin and mechanism.
Understand Insulin exogenous
List Indication of Insulin exogenous
Discuss the Rationale of treating to target
Discuss Early Insulinitation and Its Impact
Insulin serum
U/ml
Prandial secretion

Breakfast Dinner

Lunch
40
Snack
Basal

hour
0

Insulin secretion (Rosenzweigh,1994)

PATHOPHYSIOLOGY
of
HYPERGLYCEMIA
 Brain
+ + Normal
Glucagon Plasma
Pancreas Liver
Insulin glucose

+ Fat &
Muscle

Figure : Regulation of plasma glucose

Brain
+ + Diabetic
Glucagon Plasma
Pancreas Liver
Insulin glucose

J*ad
+ Fat &
Muscle
Pathogenesis of Type 2 Diabetes

Glucose uptake/
utilization

-cell Dysfunction Type 2 DM Insulin resistance

FASTING PRANDIAL
HYPERGLYCEMIA Hyperglycemia HYPERGLYCEMIA

LIVER MUSCLE
 1st phase

Normal

NIDDM

2nd phase
Basal
minutes

0 5 100
Insulin release in vitro in response to glucose stimulation
 Types of Oral Agents for Type 2 DM

Insulin sensitizers
Biguanides (metformin)
Thiazolidinediones

Insulin secretegogues
Sulfonylurea (glyburide)
Repaglinide , Netaglinide

Carbohydrate absorption blockers

Acarbose
Insulin and mechanism
 Jenis dan lama kerja insulin
Berdasar lama kerja

insulin kerja cepat (rapid acting insulin).

insulin kerja pendek (short acting insulin)
insulin kerja menengah (intermediate acting insulin)
insulin kerja panjang (long acting insulin)
insulin campuran (premixed insulin)
 MACAM INSULIN DAN LAMA KERJANYA

Type of insulin Onset of action Monitored Effect*

Mealtime insulin (clear)
Insulin lispro (rapid-acting) 5-15 minutes 2 hours
Regular (short-acting) 30-60 minutes 4 hours
Background Insulin (clear)
Insulin Glargine 60 minutes 12 hours
Background Insulin (cloudy)
NPH and Lente (intermediate- 2-4 hours 8-10 hours
acting)
Ultralente (long-acting) 3-5 hours 10-12 hours
Jenis, Efek puncak, dan Lama Kerja Insulin
Macam insulin Unit/cc Awitan Efek puncak Lama kerja
(Jam) (Jam)
Kerja Cepat
Lispro (Humalog)
U-100 5-15 menit 30-90 3-5
Aspart menit

Kerja Pendek
Reguler U-100 30-60 menit 30-90 3-5
(Humulin-R, Actrapid) menit

Kerja Menengah
Humulin-N U-100 2 4 jam 4-10 jam 10-16
Insulatard Human

Campuran U-100 30-60 Dua puncak 10-16

Humulin 30/70 menit
Humalog Mix25,
Mixtard 30/70
Novomix30

Kerja Panjang U-100 1 2 jam Tanpa puncak

Lantus (glargine)
Levemir (Detemir)* Modified from Joslin*s Diabetes Mellitus 2005
Soluble insulin-
short acting

NPH insulin
suspension
intermediate
acting

ZN insulin
suspension
intermediate
acting

Premix insulin
30/70 - biphasic
Evolusi dalam Regimen Insulin

HumaPen Ergo II
HumaPen LUXURA
 INSULIN ANALOGS
Modified structure of the human insulin
resulting altered physicochemical,
biological, and pharmacological properties
 INSULIN ANALOGS
Short-acting
- Lispro (Humalog/HumalogMix25)
- Aspart (NovoRapid/NovoMix30)
Basal (Long-acting)
- Glargine (Lantus)
- Levemir
 GLARGINE

The True Basal 24 hours duration

of action - Peakless Insulin Analog
 GLARGINE :
Molecular design
 Structure of Lispro (Humalog)
Phe Gly
Phe Arg
Tyr
Glu
Thr Gly
LYS
Cys
B30 PR
Thr O 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
Phe Val Asn Gln His
 Humalog (insulin lispro injection [rDNA origin])
[Lys (B28), Pro (B29)] - Human Insulin Analog (recombinant
DNA origin)
S S
A-chain
1 21

S
S

S S
B28 B29
1 30
LYS PRO

B-chain

Analog insulins
Modify time action of human insulin toward a more
physiologic profile
Improve patient convenience
Rasionale of Rapid-Acting Insulin
Analogues :
to reduce the tendency of insulin
(injected subcutaneously) to form
dimers and hexamers
thereby avoid the necessity to inject
well in advance of meal
Exogenous insulin administration
is not physiologic

More physiologic profile of insulin

preparation is needed
 Dissociation of Insulins
Regular Human Insulin
concentration 10-3 M 10-3 M 10-5 M 10-8 M peak time
2-4 hr

= phenol

formulation
capillary membrane

Analog Humalog (Insulin Lispro)

concentration 10-3 M 10-3 M 10-3 M peak time
1 hr
= phenol

formulation transient

Ciszak E et al. Structure 1995;3:615-622.

Contoh Pemberian HumalogMix25
 Apakah HumalogMix25/
Premixed Insulin itu?
Premixed biphasic human insulin
30% soluble + 70% NPH insulin
25% soluble + 75% NPH insulin
Keseimbangan antara kenyamanan & kontrol
2 suntikan per hari
1/2 Total dosis pagi hari sesaat sebelum/
sesudah sarapan
1/2 Total dosis sesaat sebelum/sesudah
makan malam
 Profil Aksi dari HumalogMix25
/Premixed ?
Premixed insulin
(bi-phasic human insulin)
Onset: dalam 30 menit
Efek Maksimal: 2-8 jam
Durasi: 24 jam
Berespon pada peningkatan
kadar GD :
Fase pertama - cepat
Fase ke-2 lambat & panjang
Insulin HumalogMix25/
Premixed dalam 24 jam

2 Injeksi perhari
Events after subcutaneous injection of soluble regular insulin : concentration of
hexameric insulin are lowered by diffusion in the interstisial spabe allowing
dissociation into dimers and monomers which pass more readily through the
capillary membrane (Lee and Zinman,1998)
Cara Penyuntikan Insulin
- Suntikan di bawah kulit (subkutan),
- Khusus : intramuskular atau intravena secara bolus
atau drip.
- Arah alat suntik tegak lurus terhadap permukaan kulit

- Lokasi penyuntikan dan rotasi tempat suntik.

- Cara penyuntikan maupun cara penyimpanan insulin

- Semprit insulin dan jarumnya dapat dipakai lebih dari

satu kali oleh pasien diabetes yang sama.

- Perhatikan kesesuaian konsentrasi insulin (jumlah

unit/cc) dengan semprit yang dipakai (jumlah
unit/cc dari semprit).
 Penyimpanan Insulin

Dalam lemari es 20 - 80 hingga

kadaluarsa
Pada suhu ruang (30 derajat
Celcius), insulin stabil selama 30
hari
Hindari suhu yang ekstrim (terlalu
panas atau terlalu dingin)
Jangan Gunakan Insulin bila:

Tanggal kadaluarsa
telah lewat
Insulin berubah warna
Ada gumpalan
Insulin beku atau terkena
panas
Larutan insulin memisah,
tidak bercampur
 Insulin Infusion -Compatibility
Insulin is compatible with :
Isotonic glucose (5% or 10% dextrose)
Isotonic sodium chloride
Isotonic potassium chloride
Ringers Lactate (lactate, sodium chloride,
potassium chloride, calcium chloride & water)
Ringers Chloride (sodium chloride, potassium
chloride, calcium chloride & water)
 Insulin diperlukan pada keadaan:
Penurunan berat badan yang cepat
Hiperglikemia berat yang disertai ketosis
Ketoasidosis diabetik
Hiperglikemia hiperosmolar non ketotik
Hiperglikemia dengan asidosis laktat
Gagal dengan kombinasi OHO dosis hampir
maksimal
Stres berat (infeksi sistemik, operasi besar, IMA,
stroke)
Kehamilan dengan DM/diabetes melitus gestasional
yang tidak terkendali dengan perencanaan makan
Gangguan fungsi ginjal atau hati yang berat
Kontraindikasi dan atau alergi terhadap OHO
Efek samping terapi insulin

- hipoglikemi
- reaksi imunologi
 PROFIL INSULIN SUBKUTAN

Lispro Regular NPH/Lente Insulin Ultralente

Aspart (fast) (slow) Glargine (very slow)
(very fast) (slow)

7 am 12 pm 7 pm 12 am 7 am
Early insulin initiation for type 2
diabetes:
why, what and how
Why early insulin in type 2 diabetes?
1. What is Diabetes in clinical reality in
Indonesia ?
2. Why consider early insulin?
 Diabetes in clinical reality - Europe

Distribution of HbA1c in The challenges in clinical

3,658 insulin-treated type 2
reality2
500 patients1
Number of patients

Providers:
78.0% 7.0%
400 More than half delay
insulin until absolutely
300 essential
Patients:
200
Over half not on insulin
100 worry about starting
insulin
0 48% feel it would mean
5.0 7.5 10.0 12.5 15.0
HbA1c (%) that they had not
7% properly followed their
previous treatment
1. IMS Disease Analyzer UK, December 2004 update, IMS Disease Analyzer Germany Complete,
November 2004 update (Germany and UK data combined). 2. DAWN study. Diab Care 2005;28(11):2673-2679; Data on file
 Diabetes in clinical reality Global
2000 2030
Ranking Country People with Country People with
diabetes diabetes
(millions) (millions)
1 India 31.7 India 79.4
2 China 20.8 China 42.3
3 US 17.7 US 30.3
4 Indonesia 8.4 Indonesia 21.3
5 Japan 6.8 Pakistan 13.9
6 Pakistan 5.2 Brazil 11.3
7 Russia 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

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

Target A1c
 -cell defect Vs insulin resistance
Patients with diet failure 57 years after diagnosis
-cell defect more progressive than insulin resistance

80 60

Insulin sensitivity (%)

60
Beta-cell function (%)

40

40

20
20

0 0
0 2 4 6 0 2 4 6
Years from diagnosis
Levy J et al. Diabet Med 1998;15:290
 OAD failure
A 58 year old man presented for care in 1999
Put on glibenclamide 2.5 mg BID
A1c of 7.8%
Over the subsequent 6 years,
glibenclamide was increased to 10 mg BID
A1C is 10%
No complications or comorbidities
Weighs 70 Kg. BMI 24.

Additional oral therapy unlikely to achieve goals

Oral agents lower A1C 1-2%
Thus patients with an A1C > 9% will not reach target
DeWitt DE, Dugdale DC. Prim Care Clin Office Pract 2003;30:543-56
Efectivity of therapy

Decreased : glucose 70-80 mg/dl

Insulin secretagogue
A1C 1.5 2.0 %
Mean A1C 7.1 7.8 %

Chronic

Failure : 3- 10 % / years
10- 20 % : 5 10 years
UKPDS : A1C increased 1st Years : 6.1 %
10th years : 8 %
( with combination therapy)
UKPDS:
Deterioration in -Cell Function over Time

100

80
-Cell Function (% )

60

40

20

0
-10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6
Time (years)

Adapted from UKPDS Group. Diabetes. 1995;44:1249-1258.

 Intensive management of glycaemia:
early combination approach
Diet
and exercise
OAD
monotherapy
10 OAD
combinations OADs
uptitration
9 OAD
+ basal insulin OAD + multiple daily
HbA1c (%)

insulin injections
8

HbA1c = 7%
7

HbA1c = 6.5%
6
Duration of diabetes

OAD = oral anti-diabetic Del Prato S et al. Int J Clin Pract 2000
Campbell IW. Br J Cardiol 2000.
 1st phase

Normal

NIDDM

2nd phase
Basal
minutes

0 5 100
Insulin release in vitro in response to glucose stimulation
 Blunted prandial insulin secretion
Healthy individuals
Patients with type 2 diabetes
800
Insulin secretion (pmol/min)

700
Endogenous insulin
600 production decreases
500 as the disease
progresses
400
At diagnosis, only
300
50% of beta-cell
200 function remains
100 (UKPDS, Diabetes
1995)
0
0600 1000 1400 1800 2200 0200 0600
Time

Polonsky KS et al. New Engl J Med 1988; 318:12311239.

 Early insulin treatment
Hyperglicaemia

Insulin Resistance
Resting of cell
Liver
Pancreas Muscle

Glycemic control
The dual-release insulin concept
Physiological insulin profile:
- meal-related peak
- basal component Profiles are
schematic

Rapid-acting insulin
analogue together with
a basal insulin analogue
provide physiological insulin
replacement

Premix analogues such as Physiological insulin profile

HumalogMix25 mimic
physiological insulin secretion
Soluble insulin aspart
Protamine crystallised
insulin aspart
HumalogMix25/NovoMix30
 Summary Question 1:
Why early insulin in type 2 diabetes?
What is Diabetes in clinical reality?
Diabetes is a Global Public health
problem
21.3 million Indonesian affected
Why consider early insulin?
To improve glucose control in terms of
A1c levels, -cell function, treat OAD
failure, PPG control, blunted 1st phase
insulin response
What is early insulin therapy?
1. What are the recommended goals for
glucose control?
2. What are the criteria for early insulin in
type 2 diabetes?
3. What are the Preferred characteristics of
a starter insulin
 Glucose control : recommended goals

Measurement Normal IDF1 ADA2 AACE3

A1c* <6% <6.5% <7% <6.5%
Preprandial <100 <110 90-130 <110
Postprandial <140 <155** <180** <140
(2h)
* DCCT-referenced assays- Normal Range 4-6%; ** Peak value

Realistic Target--- Lowest A1c possible without unacceptable adverse effects

1. Global guideline for type 2 diabetes clinical guidelines taskforce (Brussels: International Diabetes Federation,
2005). 2. Diabetes Care 2005;28(Suppl 1):S4-S36. 3. http://www.aace.com/pub/odimplementation/roadmap.pdf
Criteria for early insulin initiation
Trial of OADs
Familiar with h/o patient atleast 1 year
FPG > 140 mg/dl, PPPG > 180 mg/dl
Effective insulin therapy

Insulin
+
Delivery device
+
Patient education/support
 Preferred characteristics of a
start insulin
Simple start
Once-daily dosing
Option to intensify with same insulin
Effective HbA1c control with 1, 2 or 3
injections
Coverage of both FPG and PPG
Low incidence of hypoglycaemia
Easy to use insulin device

UK Primary Care Insulin Initiation, August 2005

 Summary
What is early insulin therapy?

What are the recommended goals for

glucose control?
ADA recommends A1c<7%, FPG<130,
PPG<180
What are the criteria for early insulin in type
2 diabetes?
Trial of OAD, 1-yr history, FPG>130, PPG>180
What are the Preferred characteristics of a
starter insulin?
Safe, effective, simple, easy to use
How to practice early insulin
therapy in type 2 diabetes?

1.How insulin regimens have

evolved?
2.How newer insulins (analogues) are
designed?
3.How has clinical evidence evolved?
Evolution of insulin regimens begins
with understanding Physiological Insulin Secretion Profile

75
Breakfast Lunch Dinner
Plasma Insulin U/ml)

50

25

4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00

Time
 Bolus regimens
1920s, 1st insulin
Short-acting, acid pH
Only bolus regimen
Breakfast Lunch Dinner No basal insulin
Plasma Insulin

HumulinR/ HumulinR/ HumulinR/

Actrapid Actrapid Actrapid

4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00

Time
 Basal/Bolus regimens
1940s,
1st long-acting insulin
NPH, Neutral pH
Basal-bolus possible
Breakfast Lunch Dinner Ideal,
but too many injections
Plasma Insulin

HumulinR/ HumulinR/ HumulinR/

Actrapid Actrapid Actrapid

HumulinN/Insulatard HumulinN/Insulatard

4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00

Time
 Split-Mixed regimens
1961, 1st combination
ActRapid, neutral pH
Breakfast Lunch Dinner Split-mix became possible
Plasma Insulin

Actrapid + Insulatard Actrapid + Insulatard

4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00

Time
 Premix regimens
1964,
Fixed dose combination
Mixtard
Breakfast Lunch Dinner Premix becomes choice
Plasma Insulin

Humulin 30/70 or Mixtard Humulin 30/70 or Mixtard

(30% reg + 70% intermediate) (30% reg + 70% intermediate)

4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00

Time
 Summary: How the regimens evolved?
1964,
Fixed dose combination
Premix regimens
Mixtard
Premix becomes choice

1961, 1st combination

Split-mixneutral
ActRapid, regimens
pH
Split-mix became possible
1940s,
1st long-acting insulin
NPH, Neutralregimens
Basal-Bolus pH
Basal-bolus possible
Ideal,
but too many injections
1920s, 1st insulin
Short-acting, acid pH
Bolus regimens
Only bolus regimen
No basal insulin
Premixed insulin: the most widely used
Premixed insulin
40% of human insulin
used world over

Advantages of premixed
Increased dosage accuracy
Increased efficacy
Enhanced convenience

Increased compliance &

better long-term outcomes1

Turner HE & Mathew DR. Eur J Clin Pharmacol 2000;56: 19-25;

 How insulin analogues are designed? :
Shortcomings of human insulins
Physiological insulin profile:
basal component
meal-related peaks
Period of unwanted
hyperglycemia Period of unwanted HumulinR/Actrapid fails to
hypoglycemia match normal insulin peak

HumulinN/Insulatard provides
basal insulin replacement but

together (Humulin30/70 or
Mixtard) these fail to re-create
the physiological insulin profile
 Shortcomings of human insulins give
rise to barriers
DIPPAP 2 - 53% Fear of hypo
Fear of hypoglycemia
Convenience issues
Inconvenient timing of injection DIPPAP 2 35%
Complicated regimen
to be taken 30 minutes before meal
Compliance
lifestyle to fit therapy
Hyperglycemia immediately after meal
Hypoglycemia before next meal
Patient survey ORG-MARG 2002 34% Fear of inj
Fear of injection

Kapur A et al. Int J Diab Dev Countries 1998;18:124-130

What are the reasons for the shortcomings
of human insulin?

Here you see a bolus of insulin delivered

in the Subcutaneous space..
 What are the reasons for the shortcomings of
insulin?
That has to dissolve in SC fluids and dissociate into monomers..

Dissociation in subcutaneous tissue

Subcutaneous
tissue

Mol/l 10-3 10-4 10-5 10-8

Diffusion

Capillary
membrane

Adapted from Brange J et al. Diabetes Care 1990;13:923

 Insulin analogue
Monomer
Insulin (inside a vial/cartridge) is a
hexamer (aggregate of 6 molecules) in its
stable state.
Conventional insulins are hexamers, they
take time (starting from 30 min before
meal) to break into monomers in SC
Human insulin
space.
hexamer
Newer insulin analogues are readily
available as monomers..
Insulin Analogue : example Insulin Lispro
(Humalog)
Phe Gly
Phe Arg
Tyr
Glu
Thr Gly
LYS
Cys
B30 PR
Thr O A21 Asn Cys Val
Tyr
Leu
Better kinetics than Humulin R
Gly
Asn
Tyr
Ile

Better safety than HumulinLeuR

Glu
Leu
Val

Better glycemic control than

Gln Humulin R
Glu Ala

Gln Glu
Tyr
Val
Cys Leu
Cys Thr Ser Ser
Ile Cys Leu

His
Ser
Gly
Cys
Leu
Phe Val Asn Gln His
 Premix analogue matches therapy to
physiology
Normal physiological
75

Breakfast Lunch Dinner

Human insulin (Human 30/70)
Plasma Insulin U/ml)

Slow to appear ~ Unwanted high sugar levels

50
Slow to disappear ~ Unwanted low sugar levels (Hypo)

Premix Analogue
Matches normal

25

4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00

Time