Chronic Complication

of
Diabetes Mellitus

GLYCEMIC GOALS IN ADULT

IDF

AACE

ADA

HbA1C (%)

< 6.5

6.5

< 7.0

Fasting/preprandial glucose
(mmol/L / mg/dL)

< 6.0 / < 110

< 6.0 / < 110

3.9-7.2/ 70-130

2-h postprandial glucose

(mmol/L / mg/dL)

< 7.8 / < 140

< 7.8 / < 140

< 10.0 / < 180*

*ADA recommends that postprandial glucose measurements should be made

1- 2h after the beginning of the meal
IDF
: International Diabetes Federation
AACE : American Association of Clinical Endocrinologist

Diabetes: A malignant vascular disorder

the most frequent
cause of new cases
of blindness among
adults aged
20 to 74.

Stroke
2-4 x risk for stroke
and coronary heart
disease

Diabetic
Retinopath
y

Diabetic
Nephropat
hy for ~40% of
Accounts
all new cases of
end-stage renal
disease (ESRD).

Cardiovascular
disease

Myocardiac infarct
Diabetic
Neuropat
hy common cause of
Most

Most common
cause of death in
diabetics

lower limb amputation

National Diabetes Information Clearinghouse. Diabetes StatisticsComplications of Diabetes.

http://www.niddk.nih.gov/health/diabetes/pubs/dmstats/dmstats.htm#comp.

Retinopathy (%)

Relation of FPG, 2hrPG,

A1C to Retinopathy : Pima Indians
15

FPG
2hPG
A1C

10

0
FPG (mg/dL) 70- 89- 93- 97- 100- 105- 109- 116- 136- 2262hPG (mg/dL) 38- 94- 106- 116- 126- 138- 156- 185- 244- 364A1C (%)
3.4- 4.8- 5.0- 5.2- 5.3- 5.5- 5.7- 6.0- 6.7- 9.5-

ADA Expert Committee. Diabetes Care 2003;26(S1):S5-S

Relation of FPG, 2hPG,

A1C to Retinopathy : Egypt

Retinopathy (%)

50
40

FPG
2hPG
A1C

30
20
10

0
FPG (mg/dL) 57- 79- 84- 89- 93- 99- 108- 130- 178- 2582hPG (mg/dL) 39- 80- 90- 99- 110- 125- 155- 218- 304- 386A1C (%)
2.2- 4.7- 4.9- 5.1- 5.4- 5.6- 6.0- 6.9- 8.5- 10.3-

ADA Expert Committee. Diabetes Care 2003;26(S1):S5-

Retinopathy (%)

Relation of FPG, 2hPG,

A1C to Retinopathy : NHANES III
15

FPG
2hPG
A1C

10

0
FPG (mg/dL)
2hPG (mg/dL)
A1C (%)

42- 87- 90- 93- 96- 98- 101- 104- 109- 12034- 75- 86- 94- 102- 112- 120- 133- 154- 1953.3- 4.9- 5.1- 5.2- 5.4- 5.5- 5.6- 5.7- 5.9- 6.2-

ADA Expert Committee. Diabetes Care 2003;26(S1):S5-

UKPDS: Reducing HbA1c Associated with

Reduction in Risk of Microvascular Endpoints
Risk of microvascular endpoints by HbA1c level
10
Hazard ratio

p<0.0001

n=3,642
# of events=323

37% decrease per 1%

reduction in HbA1c

0.5
5%

6%

7%

8%

9%

10%

Updated mean HbA1c concentration

Reference category (HR 1.0) is HbA 1c <6% with log linear scales. P value reflects contribution of
glycemia to multivariate model. Data adjusted for age at diagnosis of diabetes, sex, ethnic
group,
smoking, presence of albuminuria, systolic blood pressure, HDL-C, and
triglycerides.

Stratton IM et al. BMJ 2000;321(7258):405-12.

UKPDS: Reducing HbA1c Associated with

Reduction in Risk of Fatal / Non-Fatal MI
Risk of fatal and non-fatal MI by HbA1c level
10
n=3,642
# of events=496

Hazard ratio

p<0.0001

14% decrease per 1%

reduction in HbA1c

0.5
5%

6%

7%

8%

9%

10%

Updated mean HbA1c concentration

MI, myocardial infarction. Reference category (HR 1.0) is HbA 1c <6% with log linear scales. P value
reflects contribution of glycemia to multivariate model. Data adjusted for age at diagnosis of diabetes, sex,
ethnic group, smoking, presence of albuminuria, systolic blood pressure, HDL-C, and triglycerides.
Stratton IM et al. BMJ 2000;321(7258):405-12.

Lessons from UKPDS: better control

means fewer complications
EVERY 1%
reduction in HBA1C

1%

REDUCED RISK*

Deaths from diabetes

- 21%

Heart attacks

- 14%

Microvascular complications

- 37%

Peripheral vascular disorders

- 43%
*p<0.0001

UKPDS 35, BMJ 2000; 321:

Hyperglycemia
AGE formation

Glucose autoxidation

Sorbitol pathway
Antioxidants

Oxidative Sress
Lipid peroxidation
Leukocyte adhesion
Foam cell formation
TNF a

Endothelial dysfunction
NO Endothelin
Prostacyclin
TXA2

Hypercoagulability
Fibrinolysis
Coagulability
Platelet reactivity

Vascular complications

Retinopathy

Nephropathy

Neuropathy

Early Diagnosis of Chronic

Complication

Retinopathy
Its recommended to perform a routineretinal check up each year
Methods:
direct opthalmoscope
indirect opthalmoscope with slit-lam biomicroscope
retinal photography

Early referral

Nephropathy
Started with microalbuminuria, macroalbuminuria,
decrease in renal filtration rate which ends in renal
failure
Early detection of microalbuminuria is required,
followed by referring to a more experienced
physician
If GFR<30 its recommended to consult to the
nephrologists (kidney specialist)

Coronary Heart Disease

CHD, need to be more cautious especially to those
who have historical CHD
Stress test and rest ECG

Peripheral Vascular Disease

Need for patients counseling self-treatment
Need to examine:
deformation of foot and leg
neuropathy
decrease of foots blood flow

Diabetic foot care

Chronic complications treatment

and management

Glycemic control
Blood pressure control
Lipid control
Others : healthy lifestyle and diet scheduling
Some distinctive methods:

Retinopathy with photo coagulation

Nephropathy with dialysis: hemodialysis or peritonial
CHD with stent installment
Peripheral vascular disease with metabolic and
infection control, foot rest
Neuropathy symptomatis

The American Diabetes Associations

Standards of Medical Care in Diabetes

Blood Pressure Goal for Patients with Diabetes and
Hypertension

Patients with diabetes should be

treated to a blood pressure < 130/80
mmHg.
In pregnant patients with diabetes
and chronic hypertension, blood
pressure target goals are 110-129
andat every
65-79
mmHg
mmHg
Blood pressuresystolic
should be measured
routine diabetes
visit
Measurement of BPin the office should be done by a trained
diastolic.
individual and
should follow the guidelines stablished for nondiabetic individuals.

The American Diabetes Associations

Standards of Medical Care in Diabetes

Treatment strategies
Patients with a systolic blood pressure of 130139
mmHg or a diastolic blood pressure of 8089mmHg
life style therapy* alone (max. of 3
months)
targets are not achieved,
addition of pharmacological agents. (E)
* Life style therapy consists of weight loss if overweight, DASHstyle dietary diet (sodium intake to <1,500 mg/day,

consumption of fruit and vegetables to 8-10 servings/day, low-fat

dairy products to 2-3 servings/day, avoiding excessive alcohol
consumption, physical activity)

Patients with more severe hypertension (systolic blood

pressure 140 or diastolic blood pressure 90 mmHg)
at diagnosis or follow-up
pharmacologic therapy in addition to lifestyle
therapy. (A)

Pharmacologic therapy for patients with diabetes

and hypertension ACE inhibitor or ARB
If needed a thiazide diuretic should be added
to those with an estimated GFR 30 ml/min per
1.73 m2 and a loop diuretic for those with an
estimated GFR < 30 ml/min per 1.73 m2. (C)

The American Diabetes Associations

Standards of Medical Care in Diabetes

Goals for Dyslipidemia Treatment in Patients with Diabetes
PRIMARY GOAL
Lowering LDL cholesterol to a target goal of
< 100 mg/dl (< 70 mg/dl with overt CVD)
SECONDARY GOAL
Lowering triglyceride levels (< 150 mg/dl)
and raising levels of HDL cholesterol (> 40
mg/dl in men and > 50 mg/dl in women).

The American Diabetes Associations

Standards of Medical Care in Diabetes

Treatment strategies
Life style modification and increased physical activity
should be recommended to improve the lipid profile in
patients with diabetes. (A)
First line drug therapy STATIN
If drug-treated patients do not reach the above targets on
maximal tolerated statin therapy, a reduction in LDL
cholesterol of 3040% from baseline is an alternative
therapeutic goal. (A)

From: Poor Control of Risk Factors for Vascular Disease Among Adults With Previously Diagnosed Diabetes
JAMA. 2004;291(3):335-342. doi:10.1001/jama.291.3.335

Figure Legend:

Includes only adults aged 20 years and older with previously diagnoseddiabetes who have information on
all 3 risk factors. Those with "good control"had all of these recommended levels; the relative SE
(SE/estimate 100%) was >30% and therefore the estimate should be interpreted with caution.Data from
the National Health and Nutrition Examination Survey III (NHANESIII) are age-standardized to the
NHANES 1999-2000 population using age groups20-39 years, 40-59 years, and 60 years and older. BP
indicates blood pressure;HbA1c, glycosylated hemoglobin.

Date of download: 10/11/2012

Copyright 2012 American Medical

Association. All rights reserved.

57.1% had a A1C of 7%,

45.5% had a blood pressure 130/80
mmHg, 46.5% had a total
cholesterol 200 mg/dl
Only 12.2% of people with diabetes
achieved all three
treatment
goals.

RISKESDAS 2007

*DDM

: Diagnosed DM

GLYCEMIC GOALS IN ADULT

IDF

AACE

ADA

HbA1C (%)

< 6.5

6.5

< 7.0

Fasting/preprandial glucose
(mmol/L / mg/dL)

< 6.0 / < 110

< 6.0 / < 110

3.9-7.2/ 70-130

2-h postprandial glucose

(mmol/L / mg/dL)

< 7.8 / < 140

< 7.8 / < 140

< 10.0 / < 180*

*ADA recommends that postprandial glucose measurements should be made

1- 2h after the beginning of the meal
IDF
: International Diabetes Federation
AACE : American Association of Clinical Endocrinologist

Type 2 Diabetes:
Progression from Underlying Defects

Insulin
Sensitivity

Insulin
Secretion

Macrovascular
Diseases

30%

50%

Type 2
Diabetes

50%

70%-100%

IGT

70%

150%

100%

100%

Impaired
Glucose
Metabolism

50%
40%
10%

Normal Glucose
Metabolism

Adapted from Groop.Diabetes Obesity Metab 1999;1(Suppl.1):S1-S7.

Pathogenesis

Myoinositol

Hyperglycemia

Nerve Na+

Na +-K+ ATPase
Nerve
myoinositol

Nerve
glucose

L-Arginine
NADPH

Protein
kinase C

Aldose
reductase

NO
synthase

AGE
formation

NADP
Sorbitol

Citrulline

Conduction
velocity

Mechanisms through which increased glucose

flux through the polyol pathway under
hyperglycemia conditions could impair various
aspects of nerve function

NO
production

NO
quenching

Vasodilation
Nerve blood flow

Pickup and Williams, Textbook of Diabetes, 1997

Diagnosis
Anamnesis, Pemeriksaan Fisik dan
Penunjang (Alat Ukur)

Palu Refleks
Palu Refleks

Monofilamen

Biotesiometer

Pengukur DJ

Klasifikasi Neuropati Diabetik

Diffuse Neuropathy
1. Distal symmetrical sensorimotor polyneuropathy
2. Autonomic Neuropathy
Sudomotor neuropathy
Cardiovascular autonomic neuropathy
Gastrointestinal neuropathy
Genitourinary neuropathy

3. Symmetric proximal lower limb motor neuropathy

Focal Neuropathy
1. Cranial neuropathy
2. Radiculopathy/ plexopathy
3. Entrapment neuropathy
Thomas, 1997

Klasifikasi Lain
Jenis Serabut Saraf

Neuropati Sensorik
Neuropati Otonom
Neuropati Motorik
Respons terhadap Terapi
Fenomena Reversibel Cepat
Manifestasi yang telah Menetap

Thomas PK. International Textbook of Diabetes Mellitus, 2004

Co-morbidity associated
with pain
Difficulty sleeping

60
55

Lack of energy
Drowsiness

39

Concentration difficulties

36

Depression

33

Anxiety

27
18

Poor appetite
0

10

20

30

40

50

60

70

% patients with moderate to very severe

discomfort due to symptoms (n=126)
Meyer-Rosberg K et al. Eur J Pain 2001;5:37989.

Successful Management of Neuropathic

Pain has a Positive Impact for the Patient
Diagnosis

Treatment of underlying conditions and symptoms

Improved
physical
functioning

Improved
quality of
sleep

Reduced pain
Improved
psychological
state

Improved
overall quality
of life

The earlier a diagnosis is made, the more

opportunities there are to improve patient outcomes

Therapy of Diabetic Neuropathy

2. Pain Management
1. Glucose control

Protein Kinase C inhibitor

3. Physiotherapy
(+ foot care)
4. Psychotherapy

Tricyclic Antidepressant,
Anticonvulsant (misal:
Gabapentin, Pregabalin)

Terapi Eksperimental: dasar Patogenesis

Myoinositol

Hyperglycemia

Nerve Na+
Aminoguanidin
Na +-K+ ATPase
Nerve
myoinositol

Nerve
glucose

L-Arginine
NADPH

Protein
kinase C
Inhibitor

Aldose
reductase
Inhibitor

Sorbitol
Conduction
velocity

NO
synthase

Citrulline

NO
production

AGE
formation

NO
quenching

Vasodilation

Painful diabetic neuropathy

Tricyclic antidepressants:
amitriptyline, desipramine, imipramine

Anticonvulsants:
carbamazepine, valproic acid, phenytoin, gabapentin

Selective serotonin reuptake inhibitors:

citalopram, paroxetine, sertralin, venlafaxine

Mexiletine, Capsaicin, Tramadol

NMDA (N-methyl-D-aspartate) receptor antagonist
Physical therapies:
transcutaneous electrical nerve stimulation (TENS),
acupuncture, spinal cord stimulation

Malik. Treat Endocrinol 2003, 2: 389-400

Diabetes

50
Females

40
Mortality Rate per 1000 Person-Years

No Diabetes (Framingham)

30
20
10
0
70

Males

60
50
40
30
20
10
0

0-3

4-7

8-11

12-15

16-19

20-23

Age-adjusted
mortality rate due
to coronary artery
disease in a cohort
of patients of the
Joslin
Diabetes
Center
whose
diabetes
was
diagnosed between
ages 35 and 62
years
and
who
came
to
center
soon
after
diagnosis and in
the non diabetic
participant of the
Framingham study ,
according to sex
and duration of
follow up

Duration of follow-up (years)

Joslins diabetes mellitus, Fourteenth Edition 2005: 803