Management of

Diabetes Mellitus
Division of Endocrine and Metabolic
Departement of Internal Medicine
Haji Adam Malik General Hospital

General Therapeutic Objectives

Achieve a normal blood glucose level

(reduced symptoms)
Minimize risk of long-term complications
(microvascular and macrovascular) resulting
from sustained high blood sugar.
Gain adequate control of diabetes by
ensuring compliance with a management
plan.
Maintain a healthy lifestyle as near normal as
possible.

The Principle of Management

Education

of diabetes
Lifestyle management
Diet
Exercise
Interventional

of pharmacology

Oral treatment
Insulin

Treatment:
stepwise approach
+
+
3

medicine

exercise

Oral plus
insulin

Combination of
oral medicines

2 One oral
1 Diet &

+ 5 Insulin

Nutritional Recomendation

Energy needs
Basal energy requirements (BER) : 25-30 kcal/kg of
desirable body weight
Desirable body weight/Ideal body weight (IBW) :
Formula Brocca modified: 90%x {Body Length
(cm)-100}x1kg
Additional energy required :
Activity level
Sedentary 10% of BER
Moderate 20% of BER
Strenuous 50% of BER
Infections :10-20%
Obese patients : reduced energy 20-30% of BER

Nutritional Recommendations for

All Persons with Diabetes

Protein : 1520% of kcal/d (10% for those with

nephropathy)
Saturated fat : <7% of kcal/d (7% for those with
elevated LDL)
Polyunsaturated fat :<10% of kcal; avoid transunsaturated fatty acids
Carbohydrate : 6070% of total calories
Use of caloric sweeteners, including sucrose, is
acceptable.
Fiber (2035 g/d) and sodium (<3000 mg/d) levels
as recommended for the general healthy population
Cholesterol intake <300 mg/d

Physical Exercise and Insulin

Resistance

muscle glucose uptake

whole body glucose disposal
risk of developing Type 2 DM

Exercise

GLUT4

acute &
long-term

is recruited to the plasma membrane

independently of insulin
Effective in Type 2 diabetics because muscle
GLUT4 expression is normal

Regular exercise has been shown to improve blood

glucose control, reduce cardiovascular risk factors,
contribute to weight loss, and improve well-being.

The FITT Prescription

for Exercise
requency:

How often should you exercise?

(3 to 5 times per week)

ntensity:

How hard should you exercise?

60 to 70% maximum HR (maximum HR : 220 age)

Start at 50%-60% maximum HRR and slowly increase to 70%; within
6 wk, work at 85% HRR or from 50%-90% of maximal heart rate

ime:

How long should each workout be?

(20 to 60 minutes per session)
20-30 min/day of continuous activity for first 3 wk,
then 30-45 min/day for next 4 to 6 wk, and
60 min/day as maintenance

ype:

What type of exercise ?

Aerobic (walking, running, swimming, cycling, dance )
Anaerobic ( tennis, badminton )

Exercise Program
Others:
C =
R =
I
=
P =
E =

continues
rhytmic
interval
progressive
endurans/aerobik

Safe for any complications

Continues
Start with low intensity, go slowly

Pathophysiology-based
Therapy for Type 2 Diabetes
Defect in insulin sensitivity
exercise
weight reduction
troglitazone
metformin
Defect in insulin secretion
sulfonylureas (mild defect)
insulin (severe defect)

Pathophysiology-based Therapy
of Type 2 Diabetes
Increased hepatic glucose output
metformin > troglitazone
insulin (sulfonylurea)
Carbohydrate absorption (post-prandial
hyperglycemia)
acarbose
Insulin Resistance
troglitazone > metformin

Oral Therapy for Type 2 Diabetes

Target Sites of Action
Adipose
tissue

Sulfonylureas
Repaglinide

Pancreas

Gut

Insulin secretion

Glucose
uptake

Acarbose
Miglitol

FFA output

Hyperglycemia

Rosiglitazone
Pioglitazone

Metformin
Rosiglitazone
Pioglitazone

Liver
Hepatic
glucose
output

Rosiglitazone
Pioglitazone
Metformin

Glucose
absorption

Muscle
Glucos
e uptake

Classification of Oral Antidiabetic Agent

1.

2.

Oral hypoglycemic agent :

Insulin secretagogues :
sulphonylureas
meglitinides
Oral anti-hyperglycemic agent :
- Insulin sensitisers :
biguanides
thiazolidinediones/glitazones
- Alpha glucosidase inhibitor :
acarbose

INSULIN
SECRETAGOGUE
Sulfonylurea

Repaglinide

-GLUCOSIDASE
INHIBITORS
Acarbose
Voglibose
INSULIN SENSITIZERS
Thiazolidinediones
( Rosiglitazone,
Pioglitazone )

Metformin

Side of action Mode of action

Primary action

Sulfonylurea
receptors in
pancreatic betaislet cells

Stimulates
closing of
K+ dependent ATP
channels, which lead
to membrane
depolarization and
insulin release by
exocytosis

insulin secretion

Repaglinide
receptors in
pancreatic betaislet cell

Stimulates
closing of
K+ dependent ATP
channels, which lead
to membrane
depolarization and
insulin release by
exocytosis

insulin secretion

Small intestine

Competitive inhibition
carbohydrate
of -glucosidase in the absorbtion
small intestines

PPAR receptors in Binds to PPAR

insulin-sensitive
receptors ( nuclear
tissue
receptors that regulate
gene transcription ) in
tissue
Unknown
Unknown

insulin sensitivity /
peripheral glucose
uptake
hepatic glucose
production

Oral agents
Drug classes

Examples

Sulfonylureas

Glimepiride
Glipizide

Principal mode of
action

Key issues

Stimulates insulin
secretion

Hypoglycemia

Stimulates insulin
secretion

Less
hypoglycemia

Weight gain

Glyburide
Gliclazide
Meglitinides

Repaglinide

No weight gain
D-phenylalanine
derivatives

Nateglinide
(Starlix)

Stimulates insulin
secretion first
phase

Fast acting
Low rates of
hypoglycemia
No weight gain

Oral agents
Drug classes

Examples

Biguanides

Metformin

Principal mode of
action
Key issues
Decrease hepatic
glucose
production

GI upset
Renal function
Lactic acidosis

Thiazolidinediones Rosiglitazone Improves

Liver enzymes
Pioglitazone peripheral insulin Weight gain
sensitivity
Fluid retention
CHF
Alpha-glucosidase Acarbose
inhibitors
Miglitol

Delay
carbohydrate
absorption

Flatulence

Classification and Pharmacokinetic of

Sulphonylureas
Generation

Generic name

Brand
name

First

Chlorpropamide Diabenese

Second

Glibenclamide
Glipizide

Gliclazide

Third

Gliquidon
Glimepiride

Daonil
Minidiab
GlocotrolXL
Diamicron
Diamicron
-MR
Glurenorm
Amaryl
Gluvas
Amadiab
Metrix

Mg/tab

Daily
dosage

Duration
of effect

100-250

100-500

24-36

2,5-5
5-10
5-10

2,5-15
5-20
5-20

12-24
10-16
12-16

80
30

80-320
30-120

10-20
24

30
1,2,3,4
1,2,3,4
1,2,3,4
1,2,3,4

30-120
0,5-6
1-6
1-6
1-6

6-8
24
24
24
24

Adverse Effects of Sulfonylureas

Severe

hypoglycemia

Overdose
Early in treatment
Most common with glybenclamide
Weight

gain
Erythema, skin reactions
Blood dyscrasias (abnormal cellular
elements)
Hepatic dysfunction and other GI
disturbances

Contraindications for Sulfonylureas

Pregnancy
Surgery
Severe

infections

Severe

stress or trauma

Severe

hepatic or renal failure

Insulin therapy should be used in all of

these

Meglitinides

Mechanism of action:
decrease ATP-sensitive K+ conductance
Action is glucose dependent
High potency
Elicited insulin release is rapid and brief
Taken with meals for postprandial hyperglycemia
Reduced risk of long-lasting hypoglycaemia

Side effects :

Hypoglycemia

Weight gain

Safe at higher levels of creatinin than

sulphonylureas

Biguanides

Mechanism of action: antihyperglycemic

Correct elevated hepatic glucose output
Inhibit gluconeogenesis
Inhibit glucose-6-phosphatase activity
glycogen sparing
insulin resistance
Mediated by activation of 5AMP-activated protein
kinase (AMPK) in hepatocytes and muscle
Do not increase insulin secretion
Not hypoglycemic, even at high doses
Side Effects :

diarrhea and abdominal discomfort

lactic acidosis if inappropriately prescribed

Therapeutic Actions of Metformin:

Pancreas
Impaired
Insulin secretion

Increased
glucose
production

Liver

Hyperglycaemia

Metformin

Decreased
glucose
uptake

Muscle

Metformin Improves insulin sensitivity

and peripheral glucose uptake
METFORMIN

Insulin

Plasma membrane
Insulin receptors

Glucose transporter
translocation and activation
Enzymatic effects on
metabolic pathways

Glucose
metabolism
and storage

Glucose

Thiazolidinediones

Antihyperglycemic

Do not increase

CH3

insulin secretion

ROSIGLITAZONE

O
NH

Increase insulin

sensitivity in liver

and muscle

Reduce hepatic glucose output

Improve lipid profiles

Side effects :

PIOGLITAZONE

weight gain, edema

contraindicated with abnormal liver

function

O
NH

Insulin resistance

Glucose

Insulin

Insulin
receptor

Translocation

X Synthesis GLUT 4
mRNA

PPAR +RXR

PPRE

promoter
Muscle
Cells

transcription

Coding reg

Modified from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental and Clinical Text, 2nd Ed.

TZD reduce insulin resistance

Insulin

Insulin
receptor

Glucose
Transloca
ti

on

Synthesis GLUT 4

PPRE

transcription

promoter
Muscle
Cells

mRNA

+ RXR

TZ
D

A
TZV
D

PPAR

Coding reg

Modified from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental and Clinical Text, 2nd Ed.

 glucosidase inhibitors (Acarbose)

Mechanism of action: competitive and reversible
inhibitors of glucosidase in the small intestine
Delay carbohydrate digestion and absorption
Smaller rise in postprandial glucose

Clinical use
For mild to moderate fasting hyperglycemia
with significant postprandial hyperglycemia
Taken with the first bite of a meal

Adverse effects:
Gastrointestinal disturbances; Flatulence,
nausea, diarrhea Use gradual dose titration
Contraindicated with inflammatory bowel
disease and cirrhosis

Clinical Uses of Insulin

Type 1 diabetes mellitus
Type 2 diabetes mellitus uncontrolled on
maximal combination therapy with oral agents
Gestational diabetes

Hyperglycemic emergencies
Total pancreatectomy patients
Acute or chronic hyperglycemia provoked by:

Infection or trauma
Steroid therapy
Endocrinopathies such as hyperthyroidism
Other types of secondary diabetes

INDICATION OF INSULIN THERAPY

1.
2.

3.

4.
5.
6.
7.

Type 1 DM
Malnutrition Related Diabetes Mellitus
(MRDM)
Type X - DM (OHO and Insulin
dependent)
Diabetic Coma
DM + Operation
DM + Pregnancy
Type 2 DM in certain condition

INDICATION OF INSULIN THERAPY

Type 2 DM in certain condition

DM + secondary failure
DM + Celulitis/Gangren/Infeksi lainnya
DM + underweight
DM + Fracture
DM + Chronic Hepatitis / Cirrhosis
DM + Pulmonary TBC
DM + Graves Disease
DM + Cancer
DM + Severe liver dysfunction
DM + Late stage Nephropaty
Type 2 DM with Early Insulin Therapy

Normal Insulin Secretion

The Basal-Bolus Insulin Concept
Endogenous Insulin

Insulin Effect

Bolus Insulin
Basal Insulin

HS

Time of Administration
B, breakfast; L, lunch; D, dinner; HS, bedtime.
Adapted from:
1. Leahy JL. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002.
2. Bolli GB et al. Diabetologia. 1999;42:1151-1167.

Basal Insulin
Menurunkan produksi glukosa
antar makan dan malam (overnight)
Bervariasi per individu
50 60 % dari kebutuhan harian

Bolus Insulin
(Mealtime or Prandial)
Mengatasi hiperglikemia setelah makan
Meningkat segera dan mencapai puncak
dalam 1 jam
10-20% dari total insulin tiap kali makan

Summary of bioavailability
characteristic of the insulin
Insulin Type

Onset

Peak Action

Duration

Ultra short
acting

Insulin
5-15
lispro/aspart minutes

1-1,5 hours

3-4 hours

Short-acting

regular

15-30
minutes

1-3 hours

5-7 hours

Intermediate Lente, NPH

acting

2-4 hours

8-10 hours

18-24 hours

Long acting

Ultralente

4-5 hours

8-14 hours

25-36 hours

Insulin
glargine

6-8 hours

24 hours

Insulin Preparations
Ultra
fast/ultra
short-acting

regular

Plasma [Insulin]

Short-acting

Lispro/aspar
t

NPH

Intermediateacting

lente
ultralente

Long-acting
glargine

Ultra long-

12

16

20

24

Figure. Pharmacokinetincs on various insulin drugs, and insulin from

pancreas
http://www.medscape.com/viewarticle/501976_6

Action Profiles of Insulin

Analogues

Aspart, lispro 4-5 hours

Regular 68 hours
NPH 8-16 hours

Ultralente 1824 hours

Plasma
insulin
levels

Glargine 24 hours

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Hours

Adverse Effects of Insulin Therapy

Hypoglycemia
Especially dangerous in Type 1 diabetics
Glucose or glucagon treatment
Allergy and resistance to insulin
Local cutaneous reactions or systemic
Switch to less antigenic form or desensitization
Lipohypertrophy
Due to lipogenic effect of insulin when small area used for
frequent injections
Absorption from such sites is unpredictable
Lipoatrophy
Due to impurities: switch to highly purified insulin
Lipogenic effect of insulin can repair lesion
Insulin edema- transient, rare