Basal-Bolus

Insulin Therapy
in Type 2 Diabetes Mellitus
Sarwono Waspadji
Jakarta Diabetes and Lipid Center,
Division of Endocrinology and Metabolism,
Department of Medicine, School of Medicine,
University of Indonesia,
Salemba 6, Jakarta, Indonesia

Insulin Therapy In T1DM

Intensive Insulin Therapy has been used
since long time ago in the treatment of T1DM

Basal Bolus coverage the available insulin

preparations into program that take into account
the unique dietary, exercise and other habits
of the patients to mimic as closely as possible
physiological insulin delivery - i.e. provide insulin
in approximately the correct amount when needed
and not provide it when unnecessary

Insulin Therapy in T2DM

T2DM is not a homogeneous disease, however
the trend is now toward more physiological

Insulin regimen like those commonly used

in type 1 DM

Pola Bifasik
Sekresi Insulin atas Rangsang Glukosa
Kadar glukosa tinggi
Sekresi Insulin

Fase I

Fase II
Basal

5 menit Waktu

The Physiological Insulin Profile

70
60

Short-lived, rapidly
generated
prandial insulin peaks

Normal free insulin

levels
from genuine data
(mean)

50

Insulin 40
(mU/L)

Low, steady, basal

insulin profile

30
20
10
0
060
0

090
0

120
0

Breakfas
t

150
0

Lunch

180
0

210
0

Dinner

Adapted from Polonsky, et al. 1988.

240
0

030
0

060
0

Loss of Early-phase Insulin Secretion

in Type 2 Diabetes

120
100

Normal
20g
glucose

80
60
40
20
0

30 0

Type 2 diabetes
Plasma insulin (U/ml)

Plasma insulin (U/ml)

Pattern of insulin secretion is altered early in type 2 diabetes

30 60 90 120
Time (minutes)

Ward WK, et al. Diabetes Care 1984;7:491502.

120

20g glucose

100
80
60
40
20
0

30 0

30 60 90 120
Time (minutes)

24-hr Insulin Profiles in

Normal, IGT & Late Type 2
160
Diabetic Subjects
Insulin (U/mL)

140
120
100
80
60

IGT
Early Type 2

40

Type 2 diabetes

20

Normal

0
0800

1200

1600
2000
Clock time (hours)

Polonsky KS et al. Horm Res 1998; 49: 17884.

2400

0400

Available Insulin in Indonesia

 Regular (short acting)

Actrapid, Humulin
0

12

18

24

Rapid acting Analogues

Humalog, Novorapid

Isophanes/NPH
(Intermediate)

Insulatard, Humulin N

Basal analogues

Glargine, Detimer
0

12

18

24

Berbagai Regimen Terapi Insulin

Normal 24 Hr Insulin Profiles & Bd

Plasma Insulin

Bd premix

Bd premix

premix

Basal/Bolus Treatment Program

Breakfast

Lunch

Dinner

RI, Aspart,
Lispro
or Glulisine

Plasma
insulin

Glargine
Or Detemir

4:00

8:00

12:00

16:00

Time

20:00

24:00

4:00

8:00

Berbagai macam kemungkinan

Model Basal Bolus lain
Drip short acting insulin dengan syringe pump 24 jam +
Prandial short acting insulin
Drip short acting insulin dengan syringe pump 24 jam +
Correction dose insulin setiap 6 jam
Drip short acting insulin dengan syringe pump 24 jam +
Drip short acting insulin tambahan 2 jam prandial

The Basal/Basal Plus strategy for T2DM

Stepwise intensification of treatment for continuity of control
FBG at target
HbA1c above target

Basal bolus
Additional prandial
doses as needed

FBG above target

HbA1c above target

Basal Plus
Add prandial insulin at main meal

HbA1c above target

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 (in press).

10

Mengapa Basal Bolus Insulin Terapi

Plasma insulin concentration

(mU/L)

Insulin Secretion Pattern

Hyperglycemic clamps
glucose (mmol/L)

150

15 mmol/L

100
15

10 mmol/L

10
7.5
120 min.

7.5 mmol/L

50

40

80

Type 2 DM on diet

40 80 120 min.

Normal controls
Hosker JP et al. Metabolism. 1989;38:767-772.

Plasma insulin concentration

(mU/L)

Restoration of Early Peak

Insulin Secretion
Hyperglycemic clamps
glucose (mmol/L)

150

15 mmol/L

100
15
10 mmol/L

50

15
10
7.5

7.5 mmol/L
0

40

80

120

Type 2 DM on diet

10
7.5
min.

40

80

120

min.

Type 2 DM on Gliclazide

Normal
Hosker JP et al. Metabolism. 1989;38:767-772.

Beneficial Effects of Insulin on Glycemic Control and B-cell Function in

Newly Diagnosed T2DM with Severe Hyperglycemia After Short-Term
Intensive Insulin Therapy
Harn-Shen Chen et al. Diabetes Care. 2008; 31(10): 1927-

Objective: to evaluate whether treatment with insulin is advantageous

compared with OAD in newly diagnosed T2DM with severe
hyperglicemia after short-term insulin therapy

Glycemic control:
Proportion of pts with A1c < 7 % insulin group > OAD.
HOMA B index, Insulin AUC, Insulinogenic index
of Insulin group improved significantly compared to OAD
Adverse events
no severe hypoglycemia in both groups
minor hypoglycemia NS
BW: Increase 71.4 + 10.6 to 73.1 +11.6 (Insulin)
71.7 + 21.3 to 72.5 + 18.8 (OAD group)

Editorials
Mayer B Davidson
No need for the needle (at first)
Agree/ accept Harn-Shen suggestion ?
There is little clinical evidence that insulin should be the
initial treatment for T2DM
Just as one should not rush to judgement, one should
carefully examine clinical evidence when deciding on
treatment for T2DM

Editorials:
Mayer B Davidson
No need for the needle (at first)

OAD should be the initial treatment for T2DM as long as

A1c level of <7 can be achieved.
Easier for both patients and providers
OAD should be increased to maintain the goal.
As soon as OADs are unable to meet target,
insulin should be initiated.

This not being done properly. Often too late

The biggest problem is to overcome the clinical inertia,
the insulin resistance of both patients and providers

Algorithm for the Metabolic Management of Type 2 Diabetes

Tier 1: Well-validated core therapies
At Diagnosis:
Lifestyle
+
Metformin

Lifestyle+Metformin
+
Basal Insulin
Lifestyle+Metformin
+
Sulphonylurea

STEP 1
STEP 2
Tier 2: Less well-validated therapies
Lifestyle+Metformin
+
Pioglitazone
No Hypoglycemia
Oedema
Bone loss

Lifestyle+Metformin
+
GLP-1 Agonist
Nathan et al. Diabetologia 2009
Nathan et al. Diabetes Care 2009

Lifestyle+Metformin
+
Intensive Insulin

No Hypoglycemia
Weight loss
Nausea / vomiting

STEP 3
Lifestyle+Metformin
+
Pioglitazone
+
Sulphonylurea

Lifestyle+Metformin
+
Basal Insulin

Road Map to Achieve Glycemic Goals: Nave to Therapy (Type 2)

Achieve ACE
Glycemic Goals
( FPG, PPG, and A1C )

Initial
A1C%

Assess FPG
and PPG

Preferred:
Metformin4
TZD10,11
AGI
DPP-4 Inhibitor

If 6.5% A1C Goal

Not Achieved

Monitor / adjust Rx to

Initial Therapy

Lifestyle

Modification

6-7

Intervention

Continuous
Titration of Rx
( 2 - 3 months )

Alternatives
Glinides
SU (low dose)
Prandial insulin5,8

maximal effective dose

to meet ACE Glycemic

Intensify Lifestyle
Modification
Intensify or combine Rx
including incretin mimetic*1

Goals

If 6.5% A1C Goal

Not Achieved

Lifestyle

Modification

7-8

* Available as exenatide

Target: PPG
and FPG

Combine Therapies 6,7

Alternatives
Metformin
Prandial insulin5,8
Glinides
Premixed insulin
AGI
preparations8
TZD
Basal insulin
SU
analog9
DPP-4 Inhibitor

ACE Glycemic Goals

6.5% A1C
< 110 mg/dL FPG
< 110 mg/dL Preprandial
< 140 mg/dL 2-hr PPG

1 Indicated for patients not at goal despite SU and/or

metformin or TZD therapy; incretin mimetic is not
indicated for insulin-using patients
4 Preferred first agent in most patients
5 Rapid-acting insulin analog (available as lispro, aspart and
glulisine), inhaled insulin, or regular insulin
6 Appropriate for most patients
7 2 or more agents may be required
8 Analog preparations preferred
9 Available as glargine and detemir
10 A recent report (NEJM; 6/14/07) suggests a possible link of
rosiglitazone to cardiovascular events that requires further evaluation.
11Cannot be used in NYHA CHF Class 3 or 4
Endocr Pract. 2007;13:260-268

Access Roadmap at:

www.aace.com/pub

Monitor / adjust Rx to
maximal effective dose
to meet ACE Glycemic
Goals

Intensify Lifestyle
Modification
Intensify or combine Rx,
including incretin mimetic
with SU, TZD, and/or
metformin

ACE/AACE Diabetes Road Map Task Force

Paul S. Jellinger, MD, MACE, Co-Chair
Jaime A. Davidson, MD, FACE, Co-Chair
Lawrence Blonde, MD, FACP, FACE
Daniel Einhorn, MD, FACP, FACE
George Grunberger, MD, FACP, FACE
Yehuda Handelsman, MD, FACP, FACE
Richard Hellman, MD, FACP, FACE
Harold Lebovitz, MD, FACE
Philip Levy, MD, FACE
Victor L. Roberts, MD, MBA, FACP, FACE

2007 AACE. All rights reserved. No portion of the Roadmap may be altered,
reproduced or distributed in any form without the express permission of AACE.

Road Map to Achieve Glycemic Goals: Nave to Therapy (Type 2)

Achieve ACE
Glycemic Goals
( FPG, PPG, and A1C )

Initial
A1C%
Lifestyle

Modification

8-9

Target: FPG
and PPG

Intervention
Combine Therapies
to Address FPG and PPG7
Prandial insulin5,8
Metformin
Premixed insulin
TZD10,11
preparations8
SU

NPH
Glinides
Other approved
DPP-4 Inhibitor
combinations
Basal insulin analog9

Continuous
Titration of Rx
( 2 - 3 months )

If 6.5% A1C Goal

Not Achieved

Monitor / adjust Rx to
Intensify Lifestyle Modification

maximal effective dose

to meet ACE Glycemic
Goals

Intensify or combine Rx including

prandial insulin5,8, incretin
mimetic1, or amylin analog**
(with prandial insulin5,8)

If 6.5% A1C Goal

Not Achieved

Lifestyle

Modification

9 - 10

** Available as pramlintide

Target: FPG
and PPG

Combine Therapies
to Address FPG and PPG7
Prandial insulin5,8
Metformin
Premixed insulin
TZD
preparations8
SU
NPH
Glinides
Other approved
Basal insulin analog9 combinations

ACE Glycemic Goals

6.5% A1C
1 Indicated for patients not at goal despite SU and/or
< 110 mg/dL FPG
metformin or TZD therapy; incretin mimetic is not
indicated for insulin-using patients
< 110 mg/dL Preprandial
5 Rapid-acting insulin analog (available as lispro, aspart and
< 140 mg/dL 2-hr PPG
glulisine), inhaled insulin, or regular insulin
7 2 or more agents may be required
8 Analog preparations preferred
9 Available as glargine and detemir
10 A recent report (NEJM; 6/14/07) suggests a possible link of
rosiglitazone to cardiovascular events that requires further evaluation.
11 Cannot be used in NYHA CHF Class 3 or 4
Endocr Pract. 2007;13:260-268

Access Roadmap at:

www.aace.com/pub

Monitor / adjust Rx to
maximal effective dose

Intensify Lifestyle Modification

to meet ACE Glycemic

Initiate or intensify insulin

therapy or add incretin mimetic1

Goals

ACE/AACE Diabetes Road Map Task Force

Paul S. Jellinger, MD, MACE, Co-Chair
Jaime A. Davidson, MD, FACE, Co-Chair
Lawrence Blonde, MD, FACP, FACE
Daniel Einhorn, MD, FACP, FACE
George Grunberger, MD, FACP, FACE
Yehuda Handelsman, MD, FACP, FACE
Richard Hellman, MD, FACP, FACE
Harold Lebovitz, MD, FACE
Philip Levy, MD, FACE
Victor L. Roberts, MD, MBA, FACP, FACE
2007 AACE. All rights reserved. No portion of the Roadmap may be altered,
reproduced or distributed in any form without the express permission of AACE.

Road Map to Achieve Glycemic Goals: Nave to Therapy (Type 2)

Achieve ACE
Glycemic Goals
( FPG, PPG, and A1C )

Initial
A1C%

If 6.5% A1C Goal Not

Achieved

Monitor / adjust Rx to

Lifestyle

Modification

> 10

Intervention

Continuous
Titration of Rx
( 2 - 3 months )

Insulin
Therapy2,3

2 For selected patients presenting with an A1C of >10%,

certain oral agent combinations may be effective
3 Insulin sensitizer (metformin preferred) may be combined with
initial insulin therapy
8 Analog preparations preferred
9 Available as glargine and detemir
10 Available as lispro, aspart and glulisine

Endocr Pract. 2007;13:260-268

Basal insulin analog9

maximal effective dose

or NPH + prandial insulin8,10

Premixed insulin preparations8

to meet ACE Glycemic

Intensify Lifestyle
Modification

Goals

ACE Glycemic Goals

6.5% A1C
< 110 mg/dL FPG
< 110 mg/dL Preprandial
< 140 mg/dL 2-hr PPG

Access Roadmap at:

www.aace.com/pub

ACE/AACE Diabetes Road Map Task Force

Paul S. Jellinger, MD, MACE, Co-Chair
Jaime A. Davidson, MD, FACE, Co-Chair
Lawrence Blonde, MD, FACP, FACE
Daniel Einhorn, MD, FACP, FACE
George Grunberger, MD, FACP, FACE
Yehuda Handelsman, MD, FACP, FACE
Richard Hellman, MD, FACP, FACE
Harold Lebovitz, MD, FACE
Philip Levy, MD, FACE
Victor L. Roberts, MD, MBA, FACP, FACE

2007 AACE. All rights reserved. No portion of the Roadmap may be altered,
reproduced or distributed in any form without the express permission of AACE.

Road Map to Achieve Glycemic Goals: Treated Patients (Type 2)

Current
A1C%

Current Therapy

Continue Lifestyle
Modification

<6.5%

Continuous Titration of
Rx (2-3 months)

* Available as exenatide
** Available as pramlintide

Intervention

Monotherapy

Continue current therapy if all

ACE glycemic goals are met
Adjust therapy as needed to meet

or
Combination Therapy

ACE FPG and PPG goals

ACE Glycemic Goals

6.5% A1C
< 110 mg/dL FPG
< 110 mg/dL Preprandial
< 140 mg/dL 2-hr PPG

1 Analog preparations preferred

2 Prandial insulin (rapid-acting insulin analogs available as lispro,
aspart, glulisine, inhaled insulin, or regular insulin) can be added
to any therapeutic intervention at any time to address persistent
postprandial hyperglycemia
3 Available as glargine and detemir
4 A recent report (NEJM; 6/14/07) suggests a possible link
of rosiglitazone to cardiovascular events that requires further evaluation.
5 Cannot be used in NYHA CHF Class 3 or 4

Endocr Pract. 2007;13:260-268

Monitor / adjust Rx to
maintain ACE
Glycemic Goals

Access Roadmap at:

www.aace.com/pub

ACE/AACE Diabetes Road Map Task Force

Paul S. Jellinger, MD, MACE, Co-Chair
Jaime A. Davidson, MD, FACE, Co-Chair
Lawrence Blonde, MD, FACP, FACE
Daniel Einhorn, MD, FACP, FACE
George Grunberger, MD, FACP, FACE
Yehuda Handelsman, MD, FACP, FACE
Richard Hellman, MD, FACP, FACE
Harold Lebovitz, MD, FACE
Philip Levy, MD, FACE
Victor L. Roberts, MD, MBA, FACP, FACE
2007 AACE. All rights reserved. No portion of the Roadmap may be altered,
reproduced or distributed in any form without the express permission of AACE.

Road Map to Achieve Glycemic Goals: Treated Patients (Type 2)

Current
A1C%

to
8.5

Current Therapy

Continue Lifestyle Modification

6.5

Continuous Titration of
Rx (2-3 months)

* Available as exenatide
** Available as pramlintide

Monotherapy :
Glinides, SU, AGI, metformin,
TZD, DPP-4, premixed insulin
preparations, prandial2 or
basal insulin3

Combination Therapy:
Glinides, SU, DPP-4, AGI,
metformin, TZD, incretin
mimetic*, premixed insulin
preparations, prandial2 or
basal insulin3

Intervention
Intensify Lifestyle Modification
Initiate Combination Therapy
Incretin mimetic +
Metformin + SU or Glinide metformin and/or TZD
Metformin + TZD4,5 or AGI Basal3 or premixed
insulin preparations1
TZD + SU
DPP-4 + Metformin
Amylin analog** with
DPP-4 + TZD
prandial insulin2
Incretin mimetic* +
metformin and/or SU
Other approved combinations including
approved oral agents with insulin
Intensify Lifestyle Modification
Maximize Combination Therapy
Maximize Insulin Therapy
If elevated FPG, add or increase basal insulin 3
If elevated PPG, add or increase prandial insulin2
If elevated FPG and PPG, add or intensify basal3 +
prandial2 or premixed insulin therapy1
Combine with approved oral agents
Amylin analog** with prandial insulin2
Add incretin mimetic to patients on SU, TZD,
and/or metformin

ACE Glycemic Goals

6.5% A1C
< 110 mg/dL FPG
< 110 mg/dL Preprandial
< 140 mg/dL 2-hr PPG

1 Analog preparations preferred

2 Prandial insulin (rapid-acting insulin analogs available as lispro,
aspart, glulisine, inhaled insulin, or regular insulin) can be added
to any therapeutic intervention at any time to address persistent
postprandial hyperglycemia
3 Available as glargine and detemir
4 A recent report (NEJM; 6/14/07) suggests a possible link
of rosiglitazone to cardiovascular events that requires further evaluation.
5 Cannot be used in NYHA CHF Class 3 or 4
Endocr Pract. 2007;13:260-268

Access Roadmap at:

www.aace.com/pub

Monitor / adjust Rx
to maintain ACE
Glycemic Goals

Continuous Titration of
Rx (2-3 months)

Monitor / adjust Rx
to maintain ACE
Glycemic Goals

ACE/AACE Diabetes Road Map Task Force

Paul S. Jellinger, MD, MACE, Co-Chair
Jaime A. Davidson, MD, FACE, Co-Chair
Lawrence Blonde, MD, FACP, FACE
Daniel Einhorn, MD, FACP, FACE
George Grunberger, MD, FACP, FACE
Yehuda Handelsman, MD, FACP, FACE
Richard Hellman, MD, FACP, FACE
Harold Lebovitz, MD, FACE
Philip Levy, MD, FACE
Victor L. Roberts, MD, MBA, FACP, FACE
2007 AACE. All rights reserved. No portion of the Roadmap may be altered,
reproduced or distributed in any form without the express permission of AACE.

Road Map to Achieve Glycemic Goals: Treated Patients (Type 2)

Current
A1C%

Current Therapy

Continue Lifestyle
Modification

>8.5

Continuous Titration of
Rx (2-3 months)

Monotherapy
or
Combination Therapy

1 Analog preparations preferred

2 Prandial insulin (rapid-acting insulin analogs available as lispro,
aspart, glulisine, inhaled insulin, or regular insulin) can be added
to any therapeutic intervention at any time to address persistent
postprandial hyperglycemia
3 Available as glargine and detemir

Endocr Pract. 2007;13:260-268

Intervention
Intensify Lifestyle Modification
Initiate Insulin Therapy (Basal-Bolus)
Basal3 + prandial insulin2
Premixed insulin preparations1
Combine with approved oral agents

ACE Glycemic Goals

6.5% A1C
< 110 mg/dL FPG
< 110 mg/dL Preprandial
< 140 mg/dL 2-hr PPG

Access Roadmap at:

www.aace.com/pub

Monitor / adjust Rx to
maintain ACE
Glycemic Goals

ACE/AACE Diabetes Road Map Task Force

Paul S. Jellinger, MD, MACE, Co-Chair
Jaime A. Davidson, MD, FACE, Co-Chair
Lawrence Blonde, MD, FACP, FACE
Daniel Einhorn, MD, FACP, FACE
George Grunberger, MD, FACP, FACE
Yehuda Handelsman, MD, FACP, FACE
Richard Hellman, MD, FACP, FACE
Harold Lebovitz, MD, FACE
Philip Levy, MD, FACE
Victor L. Roberts, MD, MBA, FACP, FACE
2007 AACE. All rights reserved. No portion of the Roadmap may be altered,
reproduced or distributed in any form without the express permission of AACE.

Algorithm for Management of Type 2 DM without Metabolic Decompensation

Indonesian Society of Endocrinology 2007
Diagnosis Type 2 DM
Lifestyle changes

Blood Glucose Monitoring

(FPG, PPG, Bed time)

A1C (%)*

6.5-7

<6.
5

Continue

Monotherapy* :
Metformin
AGI
TZD
Specific Condition:
SU
Meglitinides
Short/Rapid-acting
Insulin analog

Target
Achieved

Continue
Treatment

Target
not
Achieved

7-8

8-10

Oral Combination
Oral## :
SU
Metformin
AGI
TZD
Meglitinides
Specific condition:
Short/Rapid-acting
Insulin analog
Pre-mixed
Insulin analog

Combination
Oral+Insulin :
Metformin
TZD
SU
Long-acting
Insulin
Short/Rapid-acting
Insulin analog
Pre-mixed
Insulin analog
NPH
Other Combination

Target
Achieved

Intensification
Therapy OR

Continue
Treatment

*surrogate average blood glucose

might be used

Target
not
Achieved

Intensification
Therapy OR

Target
Achieved

Continue
Treatment

>10

Target
not
Achieeved

Insulin Therapy:
Short/Rapid-acting
Insulin analog
NPH or
Long-acting
Insulin
Pre-mixed
Insulin analog
In selected Patients
with A1C> 10%
OHO Combination
might be effective

Target
not
Achieved

Target
Achieved
Continue
Treatment

Intensification
Therapy OR

Intensification of
Insulib Treatment
Basal+bolus

Correlation of A1c with Average Blood Glucose

A1c%

Glucose*

Glucose*** Glucose**(mg/dL)

135

126

70

100 ?

170

154

131

150 ?

205

183

194

200 ?

240

212

257

250 ?

10

275

240

319

300 ?

11

310

269

381

350 ?

12

345

298

444

450 ?

*From DCCT (USA and Canada) in Type 1 DM

**Based on average bed time blood glucose, with regression equation:
A1c % = 0,016 X BTBG + 4,891 (Dudy Mulyawan FKUI 2007), T2DM
***Based on ADAG (A1c Derived Average Glucose), data of 2700 glucose
measurement over 3 months per A1c in 507 adults with T1DM, T2DM and Non-DM

Bagaimana dan Kapan

Basal Bolus Insulin Terapi pada T2DM ?

Deleterious Effects of Hyperglycemia

On Treatment Outcome
Impaired immune system and infection
Impaired cardiovascular system
Thrombosis
Inflammation
Endothelial Dysfunction
Brain damage
Oxidative Stress
Clement et al. Diabetes Care. 2004;27: 553

Glukosa
ROS generation
Transient Oxidative stress NADPH oxidase
NFKB
Inflammation
ikB
AP-1 ------MMPs
Egr --------TF

Insulin
ROS generation
NADPH oxidase
NFKB , ICAM-1 ,MCP-1 ,CRP
ikB
Egr --------TF
PAI-1 , Ap-1 , MMPs

Neutralisasi efek
Pro-oksidatif &pro-inflamasi
asupan makanan

Supresi
inflamasi
dinding
arteri

Neutralisasi efek protrombotik

asupan makronurien
Perbaikan Kondisi

Aterosklerosis
Ruptur plak
Trombosis

Insulin Effects

Stimulate glucose transport

Stimulate amino acid transport Metabolic Effects
Stimulate lipid transport
Activate or inactivate cytoplasm & membrane
enzymes
Alter the rate of synthesis and degradation of various
proteins and specific mRNAs
Influence the processes of cell growth and
differentiation

Glucose uptake (muscle and adipocyte)

glucose

Glucose glycogen (muscle & liver)

+
s

sS
ss

Insulin

Acetyl co A fatty acid (adipocyte & liver)

(Na+, K+)-pump (adipocyte and muscle)
Protein synthesis (all cells)

Gene expression (all cells)

Amino acid uptake (all cells)

Side effects
Hypoglycaemia
Weight gain
Lipohypertrophy
Lipoatrophy
Insulin oedema
Allergic reaction

24-hr Insulin Profiles in Normal, IGT

& Late Type 2 Diabetic Subjects
160

Insulin (U/mL)

140
120
100
80
60

IGT
Early Type 2

40

Type 2 diabetes

20

Normal

0
0800

1200

1600
2000
Clock time (hours)

Polonsky KS et al. Horm Res 1998; 49: 17884.

2400

0400

Physiological Insulin Needs

Basal Insulin
Prandial Insulin
Insulin for coping stress condition
Many types of insulin and methods of
administration of insulin treatment aim at
similar goal:
optimal BG control
as physiologic and as convenient as possible

Indications for
Insulin Therapy in Type 2 DM
Glucose toxicity
Insufficient endogenous insulin production
Contraindication to oral therapy

Insulin therapy in Type 1 DM :

Absolute indication

Indikasi Insulin
Dekompensasi Metabolik Berat
Ketoasidosis, hiperosmolar non-ketotik dan
asidosis laktat
BB turun cepat tanpa penyebab lain yang jelas
Stres berat (infeksi sistemik, operasi > 3 jam)

Indikasi Insulin selain Dekompensasi

Metabolik Berat
Gagal dengan OHO dosis (hampir) maksimal

Terdapat kontraindikasi OHO

DM gestasional yang tidak terkontrol dengan diet
Keadaan-2 lain (HbA1c , GD akibat steroid )
Tipe 1

Indikasi Terapi Insulin Intravena

1.

Indikasi kuat (evidence based medicine)

Ketoasidosis Diabetikum
HyperOsmolar Nonketotic Coma (HONC)
Penyakit Berat / Kritis
Infark miokard atau syok kardiogenik
Periode pasca operasi kardiak

Indikasi Terapi Insulin Intravena

2. Indikasi relatif (evidence belum banyak bila
dilihat dari data-data outcome)
DM tipe 1 atau 2 yang perlu total parenteral
nutrition (TPN)
Persiapan operasi (perioperative care)
GD akibat terapi steroid dosis tinggi
Stroke
Strategi penentuan dosis insulin
Kehamilan dan persalinan
Infeksi, atau keadaan lain yang perlu GD ketat

Principles
Use a relatively narrow range of insulins, regimens
and devices

Makes it easier to gain a feel for these variables and is less

confusing

Start low and very gradually build up (Avoid

hypoglycaemia)
Regular blood glucose monitoring
Gradual increase in information
Patient empowerment

Insulin therapy
Insulin therapy aims to replicate the normal
physiological insulin response
Insulin regimens should be individualized
type of diabetes
willingness to inject
lifestyle
blood glucose monitoring
age
dexterity
glycaemic targets

Insulin initiation and dose

adjustment
There is no one perfect insulin regimen for either
Type 1 or Type 2 diabetes (hence the different
regimens used across the globe)
There are a number of simple principles which
can guide insulin initiation but an individuals
response cannot be predicted
Similarly for dose adjustment one can follow
simplified guidelines but these must be modified
depending on an individuals response

Adjusting insulin
Pattern management
Watch levels for 2-3 days
Address hypoglycaemia first
Aim for target fasting levels next
Adjust by 2-4 units or 10%
Wait 2-3 days

Which insulin to adjust when?

Blood glucose

Insulin to be changed

Fasting

Bedtime or supper intermediate- or longacting

Post-breakfast

Morning short- or rapid-acting insulin

Pre-lunch

Morning intermediate-acting insulin

Post-lunch

Morning intermediate-acting insulin or

lunchtime short- or rapid-acting insulin

Pre-supper (dinner)

Morning intermediate-acting insulin

Post-supper (dinner)

Supper-time short- or rapid-acting insulin

During the night

Supper-time or bedtime intermediateacting

Van den Berghe: in SICU setting

Intensive insulin therapy (target 80-110mg/dL)
Mean BG 103 mg/dL
reduced in SICU and hospital mortality
(van den Berghe et al. Crit Care Med. 2003;31:359-366).

Van den Berghe: in MICU setting

Intensive Insulin therapy (mean 110 mg/dL)
Conventional therapy (mean BG 161 mg/dL)
Intensive: less morbidity but not mortality
( van den Berghe et al. N Engl J Med. 2006;354:449-461)

The Nice-Sugar Study

ICU setting 3 or more consecutive days
Intensive (81-108 mg/dL)
Conventional (<180 mg/dL)
Outcome mortality at 90 days
3054 intensive control vs. 3050 conventional
Similar characteristic baseline
Primary outcome available for 3010 and 3012 respectively
829 (27.5 %) mortality in intensive control, OR 1.14
751 (24.9%) mortality in conventional group
Severe hypoglycemia (< 40 mg/dL)
206 (6.8%) in intensive control
15 (0.5 %) in conventional group

Blood Glucose Target

Critically ill surgical patients: as normal as possible
(110 140 mg/dL)*
Insulin is needed, IV protocol
Close to 110 mg/dL (A)
Critically ill non surgical pts: as normal as possible
(110 140 mg/dL)*
Insulin is needed, IV protocol
Keep BG < 140 mg/dL (C)
Non critically ill: as normal as possible, no specific goals
Insulin is preferred
FBG <126 mg/dL, Random BG<180-200 mg/dL (E)
* Some institutions might considered this blood glucose target as
over aggressive due to their cautious attitude toward hypoglycemia
A D A Clinical Practice Recommendation
Diabetes Care. 2009;32(suppl 1): S 32-33

Thank You

Management of Hyperglycemia
Inpatients:
In general they need quicker blood glucose
control. More aggressive control and lower
target.

Almost always need insulin

For those who are admitted for other
reasons and having good blood glucose
control, the T2DM treatment modalities
should not necessarily be changed

Management of Hyperglycemia
In Patients
General Principles:
Maximal blood glucose control, avoiding
hypoglycemia
Meticulous, Prudent, Individualized
Management of T2DM synchronized with other
disease management

In critically ill patients, more over in

metabolic decompensation, the blood
glucose target should be more
aggressive and achieved quicker

Strategies for Reduction of Diabetic

Cardiovascular Complications
Prevention of impaired glucose tolerance
Prevention of progression of IGT to Type 2 DM
Lifestyle Changes:
Patients should be encouraged to lose weight if necessary,
exercise and eat healthily
Prescription of appropriate medications

Aggressive glycemic control

Early combination therapy + Early Insulin Therapy ?
Choose medications which are able to retard an increase in
insulin resistance and beta cell failure

Aggressive treatment of established CV risk factors

Antihypertensive medications
Lipid modifying agents
Antiplatelet agents

How to control Hyperglycemia

Non Insulin : in general not suitable for
in patients
Sulphonylurea:

Longer duration of action

Predisposition to hypoglycemia
Nutrition inadequate
Do not facilitate rapid change
Metformin: some specific contra indication:
Congestive heart failure
Renal insufficiency
Elderly patients
COPD

Thiazolidinedione: longer onset

Others: effective only for postprandial hyperglycemia

How to control Hyperglycemia (conted)

Insulin
Subcutan: in patients in general can be succesfully
use to achieve good blood glucose control
short acting- rapid acting
Combination short acting &long acting
Combination basal long acting +
correction dose
Conventional sliding scale is not recommended
Intravenous/ Drip: BG Target can be achieved earlier
Strict BG monitoring is mandatory.

Insulin Intravenous-Drip
Has been proven to be safe and effective
in Keto Acidosis DM, together with other
modalities
Bolus 180 micro Unit / Kg BB (9 10 Unit bolus IV)
Drip 90 micro Unit / Kg BB/jam (5 6 unit per jam)
Drip 45 micro Unit /Kg BB/jam (2 - 3 unit per jam)

After achieving stable condition:

Lower unit per drip (1-2 unit/hour + correction dose s.c.)
In condition BG < 100 mg/dL, reduce drip unit - 1 unit
Fixed dose insulin s.c.
Further management in the ward

Instantly, Bed side, Meticulous, Continuous

BG monitoring BG is mandatory

In Non KAD patients who needs optimal BG control

Promptly:
Guidance similar to KAD protocol can be implemented
Intensive care setting
Instant, meticulous, continuous BG monitoring is
mandatory (conditio sine qua non)
Start with short acting insulin 45 micro U/BB/hour
Monitor hourly in the first 3-4 hours
Insulin drip dose might be titrated according to BG target
Glucose target achieved e.g. 200 250 mg/dL, drip continoe
Glucose > target e.g. 200-250, increase drip unit by 1/2 - 1 U/ hr
Glucose < 200, lower drip unit by 1/2 - 1 U / hour

After stable condition can be achieved, continue insulin

drip + correction dose s.c. every 4-6 hours as needed.
For instance < 150 (200), no correction dose
150 200 (250), correction dose s.c. 35 Unit,

Conclusion (1)

T2DM might end with chronic diabetic complications

BG and A1c must be controlled as normal as possible
without hypoglycemia
In OP setting, the BG target can be more leisurely,
slowly achieved, although should also be
aggressively accomplished (2-3 months)

Insulin might be necessary to achieve the target :

Combination OAD + insulin
Insulin only, with several possible methods
Insulin short acting / rapid acting
Insulin intermediate acting / long acting
Insulin mixed, premixed
Basal insulin + prandial

Conclusion(2)
In Hospitalized Patient setting:
Target should be achieved quickly and tightly
especially in critically ill patients.
OAD is less beneficial and rarely use

Many methods of insulin administration can be

used:
Intravenous / Drip
- KAD
- needs quicker BG control
Instant, meticulous and continuous monitoring
is mandatory

Subcutaneously :

Short acting / rapid acting

Intermediate acting / long acting
Insulin mixed / premixed
Combination Basal + prandial

Thank You

Matur Nuwun
Hibiscus rosasinenis

Thank You

Success Reaching Target Risk Factors With

Intensive Treatment Program
Intensive therapy
80

P<.001

P=.21

70
Patients (%)

Conventional therapy

P=.19

60

P=.001

50
40
30
20

P=.06

10
0

HbA1C
<6.5%

Cholesterol
<175 mg/dL

Triglycerides Systolic BP
<150 mg/dL <130 mm Hg

Gaede et al. N Engl J Med. 2003;348:390-3 (A).

Diastolic BP
<80 mm Hg

Short acting
Actrapid HM
Humulin R
NPH insulin
suspension
Intermediate
acting
Insulatard
HM
Humulin N

ZN insulin
suspension
intermediate
acting
Monotard
HM
Premix insulin
30/70
biphasic
Mixtard HM
Humulin

Evidence for Maximal Blood Glucose Control

In Critically ill Patients (intensive care setting)
Digami 1

Intensive intervention Group 172.8 mg/dL

Conventional Group 210.6 mg/dL
Long-term survival in intensive group increase
(Mamberg et al. J Am Coll Cardiol. 1995;26:57-65)

Digami 2

Morbidity in intensive treatment group decrease

Mortality not significantly different
(Mamberg. Europ Heart J. 2005;26:650-661)

Create-Ecla Blood glucose level positively correlated

with mortality
(JAMA. 2005: 293: 437-446)

Pola Sekresi Insulin Fisiologis

Insulin action
1. Increases glucose uptake, particularly in
muscle, liver and adipose tissue
2. Suppresses glucose output from the liver
3. Increases formation of fat
4. Inhibits breakdown of fats
5. Promotes amino-acid uptake and prevents
protein breakdown

Hyperglycemia screening in critically ill patients is

necessary. Hyperglycemia can be controlled early
and soon, in order to have better outcome
Hyperglycemia* include:
Known DM
New DM, just diagnosed during hospitalization.
confirmed to be DM after discharged
BG fulfilling DM diagnostic, become normal after
discharged (previous abnormality of glucose tolerance WHO classification 1985)
* In

the management of hyperglycemia, all are treated similarly

In hospital mortality of newly diagnosed DM is higher
than known DM

Normal 24 Hr Insulin Profiles & basal bolus

Plasma Insulin

Insulin Secretion Profiles in Type 2

Diabetic Patients and Healthy People
Insulin secretion (pmol/min)

800
Healthy people

700

Type 2 diabetic patients

600
500
400
300
200
100
6am

10am

2pm

6pm

Time

10pm

2am

6am

Insulin
A hormone secreted by the beta cells
Secreted in response to glucose or other
stimuli, such as amino acids
Normal response characterized by low basal
levels of insulin, with surges of insulin
triggered by a rise in blood glucose
Insulin

60
40
20
0
Breakfast

Lunch

Supper

Sekresi Insulin
Depolarisasi

ATP Sensitive
K+ Channel

Ca 2+

Voltage Dependent
Ca 2+Channel (VDCC)

Sel Islet
Tertutup
ATP
ADP
Glukosa

Glucokinase

Metabolisme

Terbuka

Ca 2+

Proinsulin
INSULIN

As. Amino
PEPTIDE-C
SS 01

Detemir/Glargine
160

Insulin (U/mL)

140
120
100
80
60

IGT
Early Type 2

40

Type 2 diabetes

20
0
0800

1200

1600
2000
Clock time (hours)

2400

0400

Factors affecting absorption

Lipohypertrophy
Dose of injection
Site and depth of injection
Exercise
Ambient and body temperature
Insulin type
Incomplete re-suspension
Nathan, 2009

Insulin Analog (Generasi Baru)

Modifikasi dengan mengubah,
mengganti atau menambah
asam amino ke dalam struktur
Insulin
Lispro dan Aspart: absorbsi
cepat dan durasi kerja lebih
singkat dibanding reguler
insulin
Glargin dan Detemir: absorbsi
lambat dan durasi kerja lebih
panjang

Injecting insulin
Should be given into subcutaneous
tissue
Skin of a very thin person may have to
be gently pinched
Insulin at room temperature less painful
Needle can be inserted at 45-90
45 for very thin people
90 for overweight people or when using
short needle

Swabbing with alcohol is not necessary

Insulin devices
Syringe and needle
Usually disposable, intended for one
injection only
May need to use doses divisible by 5
or 10 if visually impaired

Pens
Easy to use
Loading pen may be difficult for
elderly
Disposable pens

Insulin practicalities
Timing
Soluble insulin: 30-45 minutes pre-meal
Rapid-acting insulin analogues: no
more than 15 minutes pre-meal and
can be given post-meal
Intermediate- or long-acting insulins do
not have to be given in relation to a
meal

Insulin practicalities
Storage
One month in fridge or at room
temperature once the vial has been
opened
Must never be frozen
Store away from source of heat
If refrigeration not available store in clay
pot or hole in ground
May be damaged by direct sunlight or
vigorous shaking

Review question
1. One advantage that rapid-acting insulin
has over regular insulin is that it:
a.
b.
c.

Must be given immediately after the meal

Does not have to be kept in the fridge
Does not need a basal insulin to be given
as well
d. Has a short and predictable action time

Review question
2. Which of the following does not affect
the absorption of insulin?
a. The temperature of the insulin
b. The temperature of the area to be
injected
c. The amount of insulin to be injected
d. The type of injection device, i.e. pen or
syringe

Review question
3. Jonathan says his doctor has suggested he
take insulin four times a day. He asks if this is
not going to be too much insulin. What is your
best response?
a. It is not possible to take too much insulin, you
just have to eat more
b. The action of insulin taken four times a day is
closest to the action of endogenous insulin
c. Taking insulin four times a day will be very
difficult, and the results will not be much better
d. Your doctor feels that taking insulin four times a
day will make you pay more attention to your
diabetes

Review question
4. Suleen has been on insulin twice a day a mixture
of intermediate and soluble in the morning, and
again before dinner. Her records show that her
fasting levels are 10-12mmol/L (180-216mg/dl), but
the rest of the day, her levels are less than
8.5mmol/L (153mg/dl). What change(s) would you
suggest to her insulin regimen to improve her levels?
a.
b.
c.
d.

Suggest she eats less at dinner and more at lunch

Suggest she increases her soluble before dinner
Suggest she increases her intermediate before dinner
Suggest she moves her intermediate to bedtime and
decrease her soluble in the morning

Review question
5. The goal of bedtime insulin in the person
with type 2 diabetes who is on oral blood
glucose-lowering medicines is to:
a. Provide insulin to cover the bedtime snack
b. Reduce the fasting glucose level
c. Reduce the number of oral blood glucoselowering medicines
d. Prevent hypoglycaemia during the night

Education
the person with diabetes must be his
own doctor, biochemist and dietitian
R. D. Lawrence.

Insulin devices
Pumps
Insulin delivered every few
minutes over 24 hours
Require large commitment

Inhaled insulin
For bolus doses only
Large device
Unknown long-term effects on
lungs

Insulin Predictability of Basal Insulin

Pumps
Gold Standard Detemir
27%

Glargine
46%

NPH

Intrasubject Variability

59%

Lepore M, et al. Diabetes. 2000;49:2142-2148.

Heise TC, et al. Diabetes. 2003;52(suppl 1):A121.

24-hr insulin profiles in normal, IGT

& late Type 2 diabetic subjects
160

Insulin (U/mL)

140
120
100
80
60

IGT

40
Type 2 diabetes

20
0
0800

1200

1600

2000

2400

0400

Insulin Generasi Baru

Asparagine pada A21 human insulin
diganti dengan
glycine

Rantai
A
Rantai
B
Insulin glargine (HOE 901)
Analog human insulin kerja
panjang (24 jam)
Diproduksi dengan teknologi rDNA

Sesudah B-30, 2
arginine ditambahkan
pada B-31 dan B-32

Rosskamp RH et al, Diabetes Care 22 (Suppl. 2) 1999; B109-B113

Indications for insulin therapy

Type 1 diabetes
Women with diabetes who
become pregnant or are
breastfeeding
Transiently in type 2 diabetes in
special situations
In type 2 diabetes, inadequately
controlled on glucose-lowering
medicines (secondary failure)