Type 2 Diabetes Mellitus:

The Disease and Its Management

Dr. PANDJI MOELJONO, Sp.PD

SUBDEP PENYAKIT DALAM FK. UNIV. HANG TUAH

RUMKITAL Dr. RAMELAN

Penderita DM 2010:
Dunia :

Asia

87%

: 111%

90% NIDDM are closely related to OBESITY

DIABESITY

(Zimmet, International Congress of Endocrinology, Sydney 2000)

Definisi
Diabetes mellitus is a group of metabolic
diseases characterized by hyperglycemia
resulting from defects in insulin secretion,
insulin action, or both (Expert Committee on the
Diagnosis and Classification of Diabetes mellitus 2002)

Long-term damage, dysfunction, and failure

of various organs especially the eyes, kidneys,
nerves, heart, and blood vessels

Symptoms :
Polyuria
Polydipsia
Weight loss
Sometimes polyphagia
Blurred vision

Diagnosis
Symptoms of diabetes plus glucose > 200 mg/dl
or
Fasting plasma glucose > 126 mg/dl
or
2-h plasma glucose > 200 mg/dl during an OGTT

Keluhan Klinis Diabetes

Keluhan klasik +
GDP

Keluhan klasik -

>126

<126

>126

>200

<200

>200

110-<126

<110

mg/dl

GDS

110-200

mg/dl

ulang GDS atau GDP

>126
>200

<126

TTGO 2 jam

<200
>200

DIABETES MELLITUS

140-200
TGT

GDPT

<140
NORMAL

III. Klasifikasi Etiologis DM

1. Diabetes Tipe-1 (destruksi
sel beta)
Autoimun
Idiopatik

2. Diabetes Tipe-2 ( resistensi

insulin disertai defek sekresi
insulin atau sebaliknya)

3. Diabetes Tipe lain

A. Defek genetik fungsi sel beta
MODY 1,2,3. DNA
mitokondria
B. Defek genetik kerja insulin
C. Penyakit eksokrin pankreas;
Pankreatitis, tumor pankreas,
pankreatektomi, pankreopati
fibrokalkulus

D. Endokrinopati
Acromegali, sindroma
Cushing, Feokromositoma,
hipertiroidisme
E. Karena obat/zat kimia
Vacor, pentamidin, asam
nikotinat, Glukokortikoid,
hormontiroid, tiazid, Dilantin,
interferon alfa
F. Infeksi : rubellakongenital, CMV
G. Sebab imunologi yang jarang :
Antibodi anti insulin
H. Sindroma genetik lain:
Sindroma Down, Klinefelter,
Turner dll.

4. Diabetes Gestasional

Type 1 Diabetes

Type 2 Diabetes

Absolute insulin deficiency

identified by :

Combination of :

Serological evidence of
autoimmune process
in the pancreatic islet
Genetic markers

Insulin resistance and

Inadequate compensatory
insulin secretory response

The Pathophysiology of Type 2 DM

Pancreas
LIVER

GLYCOGENOLYSIS

Insulin supply or action

GLUCONE
O
GENESIS

HGP

G LYCOGEN

GLUCOSE

FFA

LIPOLYSIS

ADIPOSE TISSUE

Lactic Acid

G L UC O S E

Glycemic Control

HbA1c
cross-sectional, median values

}0.9%

Conventional
8

HbA1c (%)

UK

S
D
P

Intensive

7
6.2% upper limit of normal range

6
0

6
9
12
Years from randomisation

15

UKPDS Group Lancet 1998;352:837-53

UK

S
D
P

Glycemic Control

An intensive glucose control policy of HbA1c

7.0 % vs 7.9 % reduces the risk of:

12% any diab.-related endpoints p=0.030

25% microvascular endpoints

p=0.010

24 % for cataract extraction

p = 0.046

16 % myocardial infarction

p = 0.052

21 % for retinopathy at 12 yrs

p=0.015

33% for albuminuria at 12 yrs

p=0.000054

Incidence of MCI and Microvascular Complications by

Category of Updated Mean HbA1c (UKPDS Population)
MCI
Microvascular endpoints

Updated mean HbA1c

10
Stratton IM et al BMJ; 321 : 405-412. 2000

Conclusion
The UKPDS has shown that intensive blood glucose
control reduces the risk of diabetic complications, the
greatest effect being on microvascular complications
(and less on macrovascular com-lications)
Observational Study using the updated mean HbA1c in
the UKPDS population reveales that the rate of
increase of risk for microvascular disease with
hyperglycemia is greater than that for macrovascular
disease
The lower the glycemia the lower the risk of complications

Management
A. Aim
Short term :
Eliminate symptoms
Maintain general well being

Longer term :
Prevent complications
Reduce morbidity
and mortality

Strategy :
Normalizing glucose,
lipid, and insulin levels

Activities :
Management with holistic
approach and self care
principles

Treatment Modalities

Diet/Medical nutrition therapy

Exercise
Anti hyperglycemic agents
Education
Pancreas transplantation
Cloning treatment (experiment)

Diet/Nutrition Therapy/Meal planning

Nutrient Composition of Diabetic Diet
PERKENI

A D A and B D A

(Indonesian Soc.of Endoc.)

20-25%

10-15%

30%

60-70%

Carbohydrate

Fat

10-15%

55%

Protein

Carbohydrate

Fat

Protein

Exercise
30 minutes: 3 - 4 times / week
Continuous
Rhytmical
Interval
Progressive
Endurance training

Anti Diabetic Agents

Hypoglycemic Agents
Anti Hyperglycemic Agents

Sites of Action of Antihyperglycemic Ag

Pancreas
2. Insulin
secretagogue

GLYCOGENOLYSIS

3. Metformin
TZD
HGP

1. Insulin

GLUCOSEN

4. Acarbose

GLUCONEO
GENESIS

Intestine

+
+

Adipose tissue

3. Metformin
TZD

1a. 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

The Suppression Hepatic Glucose Production

Pancreas

LIVER
GLYCOGENOLYSIS

Insulin
HGP

GLUCONEO
GENESIS

ADIPOSE TISSUE

GLUCOSE N

The Stimulation of Glucose Uptake

Pancreas

LIVER
GLYCOGENOLYSIS

Insulin
HGP

G LYCOGEN

GLUCOSE N
Glucose
Uptake

GLUCONEO
GENESIS

ADIPOSE TISSUE

G L UC O S E

The Stimulation of Lipogenesis in Adipose Tis

Pancreas

LIVER
GLYCOGENOLYSIS

Insulin
HGP

GLUCONEO
GENESIS

GLUCOSE N
Glucose
Uptake

FFA

+
ADIPOSE TISSUE

G LYCOGEN

Lipogenesis

G L UC O S E

Alternative Routes for Insulin Delivery

Route

Advantage

Disadvantage

Intraperitoneal

Portal absorption
Good bioavailability
Physiologic profiles

Pump equired
Catheter blockage
Infection risk
Risk of large insulin
reservoir

Intravenous

Good bioavailability
Physiologic Profiles

Pump required
Catheter blockage
Phlebitis
Hyperinsulinemia

Nasal

Physiologic profiles
Easy use
No device required

Nasal irritation
Low bioavailability
Interference by resp.
infection

Alternative Routes for Insulin

Delivery(cont.)
Route

Advantage

Disadvantage

Pulmonary

Physiologic profiles
Simple device
Easy use

Low bioavailability
Variable absorption

Oral

Easy use
Acceptable

Low bioavailability
Variable absorption

Alternative Routes for Insulin

Delivery(cont.)
Implantable Pumps
MiniMed Implantable Pump (MIP) Model
2000
Infusaid Model 100

Artificial and Bio-artificial Pancreas

System
Islet Transplantation
Fetal and Neonatal Pancreas
Transplantation

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

The Pharmacology of Insulin

Onset
(h)

Lispro Aspart
Regular
NPH

0.10-0.25
0.10-1.0
1.0-3.0

Peak
(h)

0.75-2.0
1.0-4.0
5.0-7.0

Duration Miscibility with Variability in

(h)
Lispro or
absorption
Reg. insulin
4.0-5.0
4.0-10
13-18

Yes w RI
+/- w lispro

Minimal
Moderate
High

Pre-mixed (70/30,50/50,lispro mix 75/25) equivalent to sum of above components

Lente
Ultra lente
Glargine

1.5-4.0
2-6
2-4

4.0-8.0
8.0-12
None

13-20
18-30
-24

+/+/NO !!!
precipitate

High
Very High
Moderate to
high

Buse BB Diabetes Spectrum 2000

Insulin available in Indonesia

Short acting insulin
Actrapid Human U 40, U100
Humulin R U40, U100
Regular Insulin U40
Intermediate acting insulin
Monotard U40, U100
Insulatard U40, U100
Humulin N U40, U100
NPH U40

Long acting insulin

PZI U40
Ultratard U100
Penfil
Actrapid penfil
Insulatard penfil
Mixtard 30/40 penfil
Humulin R penfil
Humulin 30/70 penfil

1 b. Insulin Analogues
Genetic engineering
Main aim : Solubility reduction
Substitution/addition of amino acid residue of
insulin
Short acting :
Lispro: B28-lysine, B29-proline
X14
: B28-aspartate
Long acting:
B31-B32 arginine, A21-glycine

Immunogenicity

2. Insulin Secretagogues
Induce insulin secretion
Potentiate nutrient-induced insulin
secretion
Antagonize inhibitors of insulin secretion
Calcium, Cyclic AMP and Adrenoreceptor
Manipulator
Other Insulin secretagogues

Insulin Secretagogues (cont.)

ATP-sensitive Potassium Channel Inhibitors
Long acting :Sulphonylureas
Short acting :
Repaglinide : Benzoic acid derivative
Nateglinide : Phenyl alanine derivative

Sulphonylureas
Have been a mainstay of type 2 diabetes treatment for >
40 years
Bind to an SU receptor (SUR) on the-cell which leads
to depolarisation of -cell membrane and stimulates
insulin secretion
First generation : chlorpropamide
Second generation
: glibenclamide, glipizide,
gliclazide
Third generation
: glimepiride
Attention : Hypoglycemia (less in glipizide GITS and
glimepiride)

Mode of Action of Sulphonylureas

Depolarisation

ATP Sensitive
K+ Channel

Ca 2+

Voltage Dependent
Ca 2+Channel (VDCC)

SU

Islet cell
SUR

Closed
ATP
ADP
Glucose

Glucokinase

Metabolism

Am. acid

Open

Ca 2+
Proinsulin
INSULIN
C-PEPTIDE
SS 01

3. Insulin Sensitizers (1)

Metformin

Anti hyperglycemic not hypoglycemic

Do not target -cell
Suppress HGP (hepatic glucose production)
Enhance tissue sensitivity to insulin to promote
uptake of glucose into muscle
Cardioprotective effect on obese
patients(UKPDS)
Often used in combination with Sus
Little effect on post prandial hyperglycemia
Gastrointestinal discomfort

Insulin Sensitizers (2)

Thiazolidinediones
Anti hyperglycemic not hypoglycemic
Increase expression of transmembrane glucose
transporters (GLUT 1 and GLUT 4)
Increase insulin-stimulated glucose disposal
Increase insulin-stimulated glucose uptake and
metabolism by muscle and fat
Suppression of hepatic glucose production
Reduce plasma triglycerides
Pioglitazone
Rosiglitazone

4. Inhibition of CHO digestion

and absorption
Alpha glucosidase inhibitors
acarbose
Plant fibre supplements
guar gum
bran

Alpha Glucosidase Inhibitors

(Acarbose)
Ingested with meals
Delay the digestion of complex
carbohydrate
Competitive inhibition of alpha
glucosidase in the intestine
Blunting postprandial glucose spikes
Gastrointestinal side effects

Oral Anti Hyperglycemic Agents that Have Potential

Effect of Overcoming Peaks and Valleys
Pharmacological
Dietetic

Specific

Non-specific

Reduced carbohydrate
intake
Spreading carbohydrate
intake
Carbohydrate according
to 24 hr blood
glucose profile
Dietary fibres
Low glycemic index food

Acarbose
Repaglinide
Nateglinide
Insulin lispro
Nasal/pulmonary
insulin
Glucagon-like
peptide-1
Amylin analogues

Sulphonylurea
glipizide GITS
glimepiride
Metformin
Thiazolidinediones
Long acting insulin

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

Oral Hypoglycemic Drugs Available in Indonesia

Initial dose
mg/day

Maximal dose
mg/day

Sulphonylurea
Glibenclamide
Gliclazide
Glipizide :
Glipizide GITS
Gliquidone
Chlorpropamide
Glimepiride

2,5
80
5
5
30
50
0,5

15-20
240
20
20
120
500
6

Meglitinide
Repaglinide
Nateglinide

1.5 mg
120 mg

8 mg
360 mg

Metformin

500

3000

Alpha glucosidase inhibitor

Acarbose
50

300

Frequency of
administration /day
1-2 X
1-2 X
2-3 X
1-2 X
1X
1X
1X
3X
3X
1-3 X
3X

ADA Treatment Goals for Glycemic Control

Glycemia

Normal

Average Preprandial
<110
Fasting Glucose (mg/dL)
Average Postprandial
Glucose (mg/dL)
HbA1C (%)

Goal

Further Action
Required*

80 to 120

<80
>140

<140

<160

>180

<6

<7

>8

Further Action Required = Get off your rear and DO something

Adapted from the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus
Diabetes Care 1999;22:S32-S41

Proposed New Treatment Paradigm

for Type 2 Diabetes
Medical Nutrition Therapy, Exercise , Education and SMBG
HbA1c < 7 %
Consider oral
monotherapy

Target not Met

HbA1c 7- 8 %
Add
insulin sensitizer
or secretagoque
Target not Met

Full Insulin therapy

With Or without Oral agent(s)

HbA1c > 8 %
Add
insulin sensitizer
and secretagoque
Target not Met
Start Insulin or
add Third oral agent

Complications :
Acute :

Ketoacidosis
Nonketotic
Hyperosmolar syndrome

Chronic :
Microangiopathy

Macroangiopathy

Retinopathy
Nephropathy
Neuropathy

CAD
PVD
Stroke

Treatment Priority
of Type 2 DM

Glucose control as
near to normal as
reasonably possible

Control of Insulin resistance:

Hyperinsulinemia, Obesity,
Glucose intolerance,
Dyslipidemia, Hypertension,
Procoagulant state

Microvascular
disease

Macrovascular
disease

Control of Insulin Resistance

Hyperglycemia
Dyslipidemia
Insulin
resistance

Hypertension
Obesity
Pro-coagulant State
PAI-1,Factor VII, Fibrinogen

Intervention/Control

Cardiovascular
disease