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Insulin

Husaini Umar
Natural History of Type 2 DM

Normal islet cell

Deposition of amyloid
in T2DM
Insulin
Insulin actions include :
• Ability of insulin to lower circulating glucose
concentrations
 Suppress glucose production : liver
 Stimulate glucose utilization : muscle plus fat

• Additional metabolic, vascular & mitogenic actions


Frederick Banting

and

Charles Best
(Toronto, 1921)

Marjorie
Insulin History
1869
Found “Islets of Langerhans”

1921 – 1983
Years of animals insulin

1983 – 1996
Years of highly synthetic purified Human Insulin
( Mixtard, Actrapid, Insulatard )

1996
Years of Insulin Analogues

Future ?
Inhaled, Oral Insulin
Sejarah Perkembangan
insulin

 1921 : penemuan insulin


 s/d 1983 : era insulin hewan
Menggunakan ekstrak pankreas hewan (sapi / babi)
 1983 : era Human insulin
Menggunakan rDNA manusia untuk menghasilkan insulin
 1999 : era insulin modern (analog) dimulai
Menggunakan teknologi bioengineering untuk memodifikasi
rantai DNA human insulin untuk membuat insulin baru yang
lebih baik dalam hal farmakologi
Saccharomyces cerevisiae
Disadvantage of Human Insulin
Period of unwanted
hyperglycemia
Normal insulin secretion
at mealtime
Change in serum insulin

Human insulin

Period of unwanted
hypoglycemia

Baseline
level

Time (h)
SC injection
Structural Design Human Insulin NovoRapid (Insulin
Levemir (Insulin Detemir)
Asp

Phe Gly
Phe Arg
Tyr Glu
Thr Gly
Pro
Pro Cys
Lys
Thr Val
A21 Asn Cys
B29
Tyr Leu
Gly Lys
A1 Asn Tyr
Ile Glu Leu
Val Leu Ala
Glu
Gln Glu
Gln
Tyr Val
Cys Leu Leu
Cys Thr Ser Ile Cys Ser
His
Ser
Gly
Cys
Gln His Leu
B1 Phe Val Asn
Structural Design Human Insulin
Insulin Lispro (Humalog)
Insulin glargine (Lantus )

Phe Gly
Phe Arg
Tyr Glu
Thr Gly
Pro
Pro Cys
Arg Lys
Arg Thr Val
A21 Asn Cys
B29
Tyr Leu
A1 Gly Asn Tyr
Ile Glu
Gly Leu
Val Leu Ala
Glu
Gln Glu
Gln
Tyr Val
Cys Leu Leu
Cys Thr Ser Ile Cys Ser
His
Ser
Gly
Cys
Gln His Leu
B1 Phe Val Asn
Change in serum insulin A More Physiologic Insulin

Normal insulin
secretion at mealtime

Novorapid

Baseline
Level

Time (h)
SC injection
Profil Insulin Analog sangat mirip dengan Insulin Endogen

---- Insulin endogen

Levemir

---- NovoRapid

NovoMix

Makan Makan Makan Sebelum tidur


Pagi Siang Malam
New treatment paradigms for
type 2 diabetes
Stepwise treatment

Diet/ Oral Oral Oral


Insulin
exercise monotherapy combination +/- insulin

Early aggressive
combination therapy
Proactive management of glycaemia:
early combination approach
Diet
and exercise
OAD
monotherapy
10
OAD
combinations OADs
uptitration
HbA1c (%)

9 OAD
+ basal insulin OAD + multiple daily
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; 7: 625–31.
TIPE INSULIN
Tipe Insulin Onset Peak/Puncak Duration Duration
(Jam) (Jam) Efektif Maksimal

Rapid Acting
Human Lyspro 0,25-0,5 0,5 – 2,5 <5 4–5
Human Aspart <0,20 1–3 3–5
Short Acting
Human Regular 0,5 – 1,0 2–3 4–6 5–7

Intermediate Acting
Human NPH 2–4 4 – 10 10 – 16 14 – 18
Human Lente 3–4 4 – 12 12 – 18 16 – 20
Long Acting
Human Ultralente 6 – 10 14 – 24 18 – 20 20 - 36
Insulin Glargine 2-4 Peakless 20 -24
Combinations
Mixtard
Novomix
Indications of Insulin Treatment
Indication for the use of insulin in
Type 2 DM
• In severe metabolic decompensation
• Ketoacidosis
• Hyperosmolar non ketotic coma
• Lactic acidosis
• Severe stress :
Systemic infection
Major surgery
• Weight loss within a short period of time
• Pregnancy if diet does not succeed to control
glycemia
• OHA failure or contra-indication of OHA
Combination Therapy in T2DM:
Insulin Plus Oral Hypoglycemic Agents
Insulin Plus Sulphonylurea - BIDS
Some insulin is endogenous, with natural
secretory pattern
Biguanide Plus Insulin
Reduces hepatic insulin resistance
May achieve better control with less insulin
Can reduce weight gain
Alpha Glucosidase Inhibitor Plus Insulin
Reduces posotprandial glucose level
Thiazolidinedione Plus Insulin
Reduces peripheral insulin resistance
Reduces insulin requirement
Must balance TZD and insulin carefully to minimize
weight gain
Benefits of Insulin and Oral Agents Combination

• Improves glycemic control


Treats multiple physiologic abnormalities
• Less insulin is needed to achieve good glycemic
control
• Reduces potensial for weight gain
• Patients:
• more practical and less frightening
• improved psychological acceptance, patients
continue the oral drugs
• less / minimal education is needed
• treatment can be started in an
• outpatients-setting
• better compliance, and cost may be less
Glycemic Control: Recommended goals

Measurement Normal IDF1 ADA/EASD2 AACE3 PERKENI

A1c* <6% <6.5% <7% <6.5% < 7%

Fasting Gluc <100 <110 90-130 <110 80-110

PP (2h) Gluc <140 <155 <180 <140 80-145

* Realistic Target: Lowest A1c possible without unacceptable adverse effects

 IDF = International Diabetes Federation


 ADA = American Diabetes Association.
 AACE = American Association of Clinical Endocrinology
1. Global guideline for type 2 diabetes clinical guidelines taskforce (Brussels: IDF,2005)
2. Nathan DM et al. Diabetologia 2006;49:1711-21.
3. http://www.aace.com/pub/odimplementation/roadmap.pdf
When to Start
Insulin Therapy ?
Insulin can be initiated anytime
• Traditionally, insulin had been reserved as the last line of therapy
• Considering the benefits of normal glycemic status,
insulin can be initiated earlier, as soon as is required.

Inadequate + + +
Lifestyle 1 OAD 2 OAD 3 OAD

Initiate Insulin
Indication: Permanent Not permanent
T1DM Infection
OAD failure Pregnancy
OAD Contra Indication Hospitalized
Diabetic Ketoacidosis Perioperative
How to Start
Insulin Therapy ?
1. If Fasting BG is elevated, start for basal insulin
with long acting insulin (Levemir)

2. If Prandial BG is elevated, start for prandial


/bolus insulin with rapid acting insulin
(NovoRapid)
3. If Fasting and Post Prandial are elevated :
- Oral agent with basal insulin
- premix insulin (NovoMix)
- basal/bolus as in multiple daily injection (MDI)
Treatment Based on Type of Hyperglycemia

BASAL – PRANDIAL CONCEPT

Fasting Hyperglycemia Prandial

Treat fasting hyperglyc. first


Continue oral agent
SMBG is important

Basal Insulin (Levemir) Prandial Insulin (NovoRapid)


All patients with type 1 DM were given insulin as
soon as diagnosis was established.

In type 1 DM, there is lack of endogenous insulin,


whether basal or prandial.
Total daily insulin count (TDI) = 0,5
unit x weight (kg)
or
Sum of last doses
For ex., BW 60 kg, TDI = 30 u

Total prandial insulin (TPI) Total basal insulin (TBI)


= 60% of TDI = 40% of TDI
(60% x 30 u = 18 u) (40% x 30 u = 12 u)

Breakfast dose Lunch dose Dinner dose


Bedtime dose = TBI
= 1/3 of TPI = 1/3 of TPI = 1/3 of TPI
(40% x 30 u = 12 u)
(1/3 x 18 u = 6 u) (1/3 x 18 u = 6 u) (1/3 x 18 u = 6 u)

Initiation insulin therapy in Type 1 DM. Cheng and Zinman, Joslin’s Diabetes Mellitus, 2005
Initiation of Insulin regimen in T2DM

1. PERKENI : Type 2 Diabetes Treatment Algorithm


2. A Consensus statement of the American Diabetes Association
and the European Association for the Study of Diabetes.
(ADA/EASD)
3. Algorithm by An American Association of clinical
Endocrinology
Updated PERKENI Type 2 Diabetes Treatment Algorithm

Diabetes STEP 1 STEP 2 STEP 3

Healthy life style Healthy life style


+
Mono therapy Healthy life style
Note: + Healthy life style
1. Therapy failed if 2 OAD Combination +
target of HbA1c <
7% is not achieved Alternative option, if : Combination 2 OAD
within 2-3 months
• No insulin is available +
for each step
• The patient is objecting insulin Basal insulin
2. In case of no HbA1c
test, the use of blood • Blood glucose is still not optimally
glucose level is also controlled
permitted. Average
blood glucose level Healthy life style
for a few BG test in Insulin
one day can be +
Intensification*
converted to HbA1c 3 OAD Combination
(ref: ADA 2010)

*Intensive Insulin: use of basal insulin together with insulin prandial


A Consensus statement of the American Diabetes Association and the European
Association for the Study of Diabetes. (ADA/EASD)

Tier 1 Well –validated core therapies


Lifestyle + Metformin Lifestyle + Metformin
At diagnosis : + +
Lifestyle Basal Insulin Intensive insulin
+ Lifestyle + Metformin
Metformin +
Sulfonylurea
STEP 1 STEP 2 STEP 3

Tier 2 Less well-validated therapies Lifestyle + Metformin


+
Lifestyle + Metformin Pioglitazone
+ +
Pioglitazone Sulfonylurea
Lifestyle + Metformin
+
GLP-1 agonist Lifestyle + Metformin
+
Basal Insulin
ADA EASD Position Statement 2012
How to Intensify
Insulin Therapy ?
Stepwise Intensification of Treatment
for Continuity of Control

FBG at target
HbA1c > target
Basal bolus
FBG > target Additional prandial doses
HbA1c > target as needed

HbA1c > target


Basal plus
Add prandial insulin at main meal

Basal
Add basal insulin and titrate

Oral agents
Lifestyle changes

Progressive deterioration of -cell function


Adapted from Raccah D et al. Diabetes Metab Res Rev 2007;23(4):257-64.
Treatment Modalities
•  Combination of basal (bed-time) insulin
with oral hypoglycemic agents
•  Basal plus
- Basal + 1
- Basal + 2
- Basal + 3 (Basal – bolus)

Sliding – scale
The Novo Syringe
1925 – First home use syringe
Insulin Injection Development
1989 1920s 1925
1960

From syringes to safe


and convenient portable
1985 pens with insulin
cartridges

More insulin pen introductions in the 1990’s


Suntikan pada
Daerah gluteus
Lokasi penyuntikan :
1. Lengan atas bagian luar
2. Paha atas bagian depan
3. Abdomen (kec. 2 inci dari pusat)
4. Daerah pantat ( gluteus )
Cara mengkocok
Insulin sebelum
injeksi
Teknik Injeksi Insulin pada
Lengan atas bagian luar
Contoh cara penyuntikan pada abdomen
NovoFine 6 mm
– safe and effective deposition
2.5 mm

6 mm
needle

8 mm

12 mm
needle
Kendala dalam terapi Insulin

I don’t want it.!

It hurts ! Expensive !

Drug Hypoglycemia !
addiction ?