CURRICULUM VITAE

Data Pribadi
Nama lengkap : Prof. Dr. John MF Adam, SpPD-KEMD
Tempat / Tgl. Lahir : Manado, 26 April 1938
Alamat : Jl. Chairil Anwar 3
Pangkat : Pembina Utama Madya/Guru
Besar/IV-d
Jabatan : Kepala Sub. Bagian Endokrin dan
Metabolik Fakultas Kedokteran
Universitas Hasanuddin
Kepala Pusat Diabetes dan Lipid
Rumah Sakit Dr.Wahidin
Sudirohusodo
Direktur Medis Rumah Sakit Akademis
Jaury Jusuf Putera Makassar
Riwayat Pendidikan
Dokter umum:
Fakultas Kedokteran UNHAS Makassar, 1965
Spesialis Ahli Penyakit Dalam:
Fakultas Kedokteran UNPAD Bandung, 1976
Konsultan Endokrinologi-Metabolik 1986
Pendidikan luar negeri
Erasmus University Rotterdam / Endokrinology Unit, 1982
Keanggotaan profesi kedokteran
Dalam negeri
IDI, PAPDI, PERKENI, PERSADIA, PUSKI, PERGEMI, PERKI,
Luar negeri
IDF, ADA, EASD, AFES, Professional Membership of Diabetes
and Pregnancy ADA
 INSULIN
PAST, PRESENT
AND FUTURE

John MF Adam

Diabetes and Lipid Center Dr. Wahidin Sudirohusodo Hospital

Sub-Division of Endocrinology and Metabolism
Department of Internal Medicine
Faculty of Medicine Hasanuddin University
Makassar
HISTORY OF DIABETES AND MELLITUS

DIABETES - Areteus in the 2nd century AD

Diabetes = Syphone
“ melting down of the flesh and limbs
into urine “

MELLITUS - John Rollo 1797 “ mellitus = honey ”

First literature used diabetes mellitus

SUGAR IN URINE - Michel Chevreul 1815

“ Diabetic urine was glucose “
 HISTORY OF INSULIN

1869 Paul Langerhans

Clusters of cells “ island “ scattered through the gland
“ islets of Langerhans “

1909 Jean De Meyer

Using the name of INSULINE ( = island in Latin) for glucose
lowering substance in the islets of Langerhans

1921 Frederick Banting and Charles Best (Toronto, Canada)

extracted insulin from the pancreas
The first “patient” is a pancreatectomized dog named Marjorie

1922 January 11 the first patient got insulin Leonard Thompson

(14 years old)

1923 Nobel prize was awarded to Banting and McLeod

 Paul Langerhans
(1847 – 1888)
Islands of Langerhans
Frederick Banting

and

Charles Best
(Toronto, 1921)

Marjorie
 Leonard Thompson
The first patient to receive
insulin in January 1922
 THE DISCOVERS OF INSULIN
a. b.

a. Frederick G Banting
(1891-1941)

b. James B Collip
(1892-1965)

c. JJR MacLeod
(1876-1935)

d. Charles H Best d. c.
(1899-1978)
 HISTORY OF INSULIN
1921 – 1983
Years of animals insulin

1983 – 1996
Years of highly synthetic purified human insulin
( Actrapid, insulatard )

1996
Years of insulin analogues

Future ?
Inhaled, Oral insulin
1921 – 1983
Years of animals insulin

The difference in amino acid composition between

beef and porcine insulin and human insulin was
long thought to be responsible for
the immunogenicity of these animal insulins
in humans
1983 – 1996
Years of highly synthetic purified human insulin
(Actrapid, Insulatard)

1. The action of regular insulin subcutaneous reaches a maximum

about two hours after injection, making it necessary to inject the
insulin at half on hour before meal

2. Subcutaneous insulin lasts several hours which may lead to

hypoglycemia

3. Intermediate and long acting insulin do not provide an

appropriate 24 hours basal serum insulin concentration
 160 B L D
Plasma
140 glucose
Insulin secretion
mg / dl

120 in normal subject

100

80
B = Breakfast, L = Lunch, D = Dinner

80
70 Plasma insulin
60
mU / l

50
40
30
20
10
0

07.00 12.00 18.00 24.00 07.00

GLUCOSE AND INSULIN HOMEOSTASIS IN NORMAL, NON – DIABETIC PEOPLE (n=8)

Means + 2 SD
Bolli GBMarchi RDD, et al. Insulin analogues and their potential in the management diabetes mellitus. Diabetalogi 1999; 42: 1151 - 1167
480 80

Plasma glucose
70
400
60

320
50

240 40

30
160
20
80
10

0 0

07.00 12.00 18.00 24.00 07.00

= Short acting human Insulin

 HUMAN INSULIN MOLECULES
Purified human insulin molecules have a high tendency for self –
association to form hexamers, the predominant form present in the insulin
vials the patients use

Insulin hexamer Insulin dimers Insulin monomers

Minimal diffusion Limited diffusion Rapid diffusion

Capillary membrane

Insulin in blood

Hollemen F, Hoekstra JBL. Insulin Lispro. The New Engl J of Medicine 1997; 337: 176 - 183
480 80
Plasma glucose
400 70

60
320
50
240
40

160 30

20
80
10

0 0

07.00 12.00 18.00 24.00 07.00

= Insulin analogues aspart

 INSULIN ASPART
120

100
Insulin aspart

80

60

40
Regular Insulin

20

0
0 1 2 3 4 5 6 7 8 9 10 11 12

Hollemen F, Hoekstra JBL. Insulin Lispro. N Engl J Med 1997; 337: 176 - 183
1996
Years of insulin analogues

Modified insulin molecules the so-called analogues

of insulin = insulin analogues

Insulin aspart

Insulin lispro

Insulin glargine

Insulin detemir
 HUMAN INSULIN

A chain S S
Gly IIe Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Glu Leu Glu Asn Tyr Cys Asn
1 5 10 15 21
S S

S S
B chain
Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly
Glu Arg Gly
1 5 10 15 20 Phe
Phe
25 Phe
Tyr
Pro Thr
30 The Lys
 HUMAN INSULIN
A chain S S
Gly IIe Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Glu Leu Glu Asn Tyr Cys Asn
1 5 10 15 21
S S

S S
B chain
Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly
Glu Arg Gly
1 5 10 15 20 Phe
Phe
25 Phe
Tyr
Pro Thr
30 The Lys

INSULIN LISPRO
A chain S S
Gly IIe Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Glu Leu Glu Asn Tyr Cys Asn
1 5 10 15 21
S S

S S
B chain
Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly
Glu Arg Gly
1 5 10 15 20 Phe
Phe
25 Phe
Tyr
Thr
Lys
30 The Pro
 HUMAN INSULIN
A chain S S
Gly IIe Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Glu Leu Glu Asn Tyr Cys Asn
1 5 10 15 21
S S

S S
B chain
Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly
Glu Arg Gly
1 5 10 15 20 Phe
Phe
25 Phe
Tyr
Pro Thr
30 The Lys

INSULIN ASPART
A chain S S
Gly IIe Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Glu Leu Glu Asn Tyr Cys Asn
1 5 10 15 21
S S

S S
B chain
Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly
Glu Arg Gly
1 5 10 15 20 Phe
Phe
25 Phe
Tyr
Thr
Asp
30 The Lys
 HUMAN INSULIN
A chain S S
Gly IIe Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Glu Leu Glu Asn Tyr Cys Asn
1 5 10 15 21
S S

S S
B chain
Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly
Glu Arg Gly
1 5 10 15 20 Phe
Phe
25 Phe
Tyr

Pro Thr
30 The Lys

INSULIN GLARGINE
A chain S S
Gly IIe Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Glu Leu Glu Asn Tyr Cys Gly
1 5 10 15 21
S S

S S
B chain
Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly
Glu Arg Gly
1 5 10 15 20 Phe
Phe
25 Phe
Tyr
32 31 30
Pro Thr
Human insulin Arg Arg The Lys
A chain 21 amino acids
B chain 30 amino acids
THE USE OF INSULIN
ANALOGUES
 HUMAN INSULIN
A chain S S
Gly IIe Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Glu Leu Glu Asn Tyr Cys Asn
1 5 10 15 21
S S

S S
B chain
Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly
Glu Arg Gly
1 5 10 15 20 Phe
Phe
25 Phe
Tyr

Pro Thr
30 The Lys

INSULIN DETEMIR
A chain S S
Gly IIe Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Glu Leu Glu Asn Tyr Cys Gly
1 5 10 15 21
S S

S S
B chain
Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly
Glu Arg Gly
1 5 10 15 20 Phe
Phe
25 Phe
Tyr
29
Pro Thr
Human insulin FA Lys
A chain 21 amino acids
B chain 30 amino acids
 MODES OF INSULIN INJECTION

Morning After noon Evening Night

INSULIN EFFECT

REG REG REG

NPH / LENTE

Meals Meals Meals

 MODES OF INSULIN INJECTION

Morning After noon Evening Night

INSULIN EFFECT

REG REG REG

NPH / LENTE

Meals Meals Meals

 MODES OF INSULIN INJECTION

Morning Evening Night

INSULIN EFFECT

REG
REG

NPH / LENTE

Meals Meals Meals

Premix = Mixtard
 MODES OF INSULIN INJECTION

Morning Evening Night

INSULIN EFFECT

NPH
OHO Glargine

22.00 24.00 06.00

Meals Meals Meals

MODES OF INSULIN INJECTION

Continuous subcutaneous
insulin infusion (CSII)

INSULIN PUMP
INJECTION DEVICE DEVELOPMENT IN THE 80S
AND 90S HAS ADDRESSED THESE ISSUES

1920s More insulin pen introductions in 1990s

the…
1925

1989 From syringes to safe

and convenient portable
1985pens with insulin
cartridges 1960
 THE USE OF INSULIN ANALOGUES

Which patient may benefit from of insulin analogues?

Mostly type 1 diabetes mellitus

Type 2 diabetes who need combination therapy

oral hypoglycemic and insulin
COMBINATION THERAPY IN TYPE 2 DIABETES
ORAL HYPOGLYCEMIC AGENT AND INSULIN

Glargine

22 : 00
NPH
06 : 00 12 : 00 18 : 00 24 : 00 06 : 00

“ Less nocturnal hypoglycemia and better post- dinner glucose

Control with bedtime insulin glargine compared with bedtime NPH
insulin during insulin combination therapy in type 2 diabetes “

Yki – Jarvinen H et al. Diabetes Care 2000; 23: 1130 - 1136

INSULIN IN THE FUTURE?
INHALED, TRANSDERMAL and ORAL INSULIN
NON INJECTABLE INSULIN DELIVERIES

Transdermal insulin delivery

Oral insulin delivery

Pulmonary insulin delivery Buccal insulin delivery

 INHALED INSULIN
Treatment Satisfaction with inhaled insulin in patients with type 1
diabetes
Gerber RA et al. Diabetes Care 2001; 24: 1556 - 1559
Preprandial inhaled insulin plus bedtime ultralente injection
compared to 3 – 4 subcutaneous insulin injection
Conclusions : Inhaled insulin maintains glycemic control and
provides greater overall Satisfaction and
convenience than subcutaneous insulin

Intensive therapy with Inhaled Insulin via the AERx Insulin

Diabetes Management System ( Type 2 diabetes )
Hermansen K et al. Diabetes Care 2004; 27: 162 – 167
Inhaled Insulin plus bedtime NPH insulin injection versus short
acting insulin plus bedtime NPH insulin injection
Conclusions : Inhaled Insulin Preprandial plus bedtime NPH is as
effective as preprandial injection plus bedtime NPH
 ORAL INSULIN

A Novel Per-Oral Insulin Formulation :

Proof of Concept Study in Non – Diabetic Subjects

Kidrom M et al. Diabet Med 2004; 21: 354 – 357

Conclusions : Insulin in combination with special delivery agent is

absorbed through the GI in a biologically active form
SUMMARY

Tight glycemic control is the target of treatment in diabetic

patients to prevent chronic vascular complications

New pharmacologic agents is now available for better

control, oral hypoglycemic agents as well as insulin

At present the new insulin analogues is more effective and

convenience compared to human insulin

The route of insulin administered is still the problem for

patients to receive injection in the future, oral, and inhaled
insulin may help to solve the patients compliance to reach
the goal of treatment
 INTENSIVE INSULIN THERAPY IN CRITICALLY ILL PATIENTS

100 100

Intensive treatment Intensive treatment

96 96
Survival in ICU (%)

In-Hospital Survival
92 92

(%)
Conventional treatment
88 88 Conventional treatment

84 84

84 84

0 0
0 20 40 60 80 100 120 140 160 0 50 100 150 200 250

A Days after Admission B Days after Admission

Kaplan-Meier Curves Showing Cumulative Survival of Patients Who Received Intensive Insulin
Treatment or Conventional Treatment in the Intensive Care Unit (ICU)
Patients discharged alive from the ICU (Panel A) and from the hospital (Panel B) were considered to
have survived. In the both cases, the differences between the treatment groups were significant
(survival in ICU, nominal P=0.005 and adjusted P<0.04; in-hospital survival, nominal P=0.01). P values
were determined with the use of the Mantel-Cox log-rank test.

Berghie GV, Wouters P, Weekers F, Verwaest C. N Engl J Med 2001;354-19

 INTENSIVE INSULIN THERAPY IN CRITICALLY ILL PATIENTS

Conventinal treatment
30 24 Intensive treatment
21
25
18
No. of Deaths

No. of Deaths
20
15
15 12

10 9
6
5
3

0 0
0-7 8-18 16-23 24-31 32-39 40-47 0-7 8-18 16-23 24-31 32-39 40-47

A APACHE II Score B TISS-28 Score

Number of Deaths in the Intensive Care Unit According to the Acute Physiology and Chronic Health
Evaluation (APACHE II) Score (Panel A) and the Simplified Therapeutic Intervention Scoring System
(TISS-28) Score (Panel B) in the First 24 hours.
Highre APACHE II scores indicate more severe illness, and higher TISS-28 scores indicate a higher
number of therapeutic interventions.

Berghie GV, Wouters P, Weekers F, Verwaest C. N Engl J Med 2001;354-19

IMPLEMENTATION OF A SAFE AND EFFECTIVE INSULIN INFUSION
PROTOCOL IN AMEDICAL INTENSIVE CARE UNIT

MICU Insulin Infusion Protocol

400

Historical Control (n=47)

350
IIP Patients (n=69 infusions)

300
Blood Glukose (mg/dL)

250

200

150

100

50

0
Time 0 0 to 11 12 to 23 24 to 35 36 to 47 48 to 59 60 to 71
Time (hours)

Performance of the IIP (data points refresent the firs 72 h of insulin infusion)
All blood glucose (BG) levels shown as means + SD

Goldberg PA, Siegel MD, et all. Diabetes Care 2004;27:461-467

IMPLEMENTATION OF A SAFE AND EFFECTIVE INSULIN INFUSION
PROTOCOL IN AMEDICAL INTENSIVE CARE UNIT
BG comparison: vs. Historical Control
400

Historical Control (n=47)

350
IIP Patients (n=69 infusions)
Blood Glukose (mg/dL)

300

250

200

150

100

50

0
Time 0 0 to 11 12 to 23 24 to 35 36 to 47 48 to 59 60 to 71
Time (hours)
Comparison of glycemic control between 69 IIP-guided insulin infusion patients () and 47 hyperglycemic (>200
mg/dl) historical control patients(■). The figure plots mean blood glucose (BG) levels (+SD) by 12-h time intervals.
The numbers on the graph represent the number of remaining patients during each 12-h time interval. For all but
time 0 and the first 12-h time period, P < 0.001 for all comparison between IIP patients and historical control patients.

Goldberg PA, Siegel MD, et all. Diabetes Care 2004;27:461-467

 A REVIEW OF THE DIGAMI STUDY:
INTENSIVE INSULIN THERAPY DURING AND AFTER MYOCARDIAL
INFARCTIONS IN DIABETIC PATIENTS

Eligible patients:
1240

Randomized patients Excluded patients

620 620

Uncapable 280 (45%)

Control Group Infusion Group
Unwilling 238 (38%)
314 306
Outside area 40 (7%)
In prior studies 62 (10%)

A schematic presentation of the patient population included in the Diabetes Mellitus Insulin-Glucose Infusion in
Acute Myocardial Infarction (DIGAMI) study. Adapted from reference 1.

Cummings J, Mineo K et all. Diabetes Spectrum1999;2

ELLIOTT P JOSLIN, and frontpiece of his 1916 textbook