DIABETIC COMPLICATIONS

Luthfan Budi Purnomo

Bagian Penyakit Dalam
Fakultas Kedokteran UGM/RSUP Dr. Sardjito Yogyakarta
 DIABETIC COMPLICATIONS

ACUTE CHRONIC
Microangiopahty
Hypoglycemia Retinopathy
Nephropathy
Neuropathy
Diabetic ketoacidosis Cardiomyopathy

Macroangiopathy
Hyperglycemic hyperosmolar state Peripheral arterial disease
Coronary heart disease
Stroke

Diabetic foot/ulcer
 HYPOGLYCEMIA
• Hypoglycemia is a blood glucose value of less
than 50 mg/dl
• Clinically, it is defined by Whipple triad: low
plasma glucose level, symptoms consistent
with hypoglycemia, and resolution of
symptoms with correction of plasma glucose
 Symptoms
Adrenergic symptoms (catecholamine mediated):
diaphoresis, palpitations, pallor, tachycardia,
apprehension, anxiety, sensation of hunger,
headache, weakness, restlessness

Neuroglycopenic symptoms:
reduced intellectual capacity, irritability,
confusion, abnormal behavior,
convulsion, coma
Physiologic response in hypoglycemia

• Blood glucose 56-48 mg/dl

* adrenalin secretion
* diaphoresis, tremor
* reduced function of central nervous system
• Blood glucose <48-36 mg/dl
* reduced consciousness
• Blood glucose <36-18 mg/dl
* coma, convulsion
• Blood glucose <18 mg/dl
* permanent brain damage
 Syndromes of compromised glucose
counterregulation in type 1 diabetes mellitus
• Defective glucose counterregulation
• Impaired awareness of hypoglycemia
• Elevated glycemic threshold during intensive therapy
• Elevated glycemic threshold following recent
hypoglycemia
• Elevated glycemic threshold during ß-adrenergic
blockade

Autonomic failure

The syndromes may occur in advanced type 2 diabetes mellitus

(insulin-deficient)
Schematic diagram of the concept of hypoglycemia-
associated autonomic failure in T1DM

Insulin deficiency IDDM

No glucagon responses to decreased glucose levels

 Epinephrine Imperfect insulin

responses responses

Episodes of hypoglycemia

Hypoglycemia-associated autonomic failure

@ symptomatic responses (awareness)

@ autonomic (including epinephrine) responses
 Risk factors
• Tight glycemic control
• Age
• Duration of diabetes
• History of hypoglycemia
• Sleeping
• Alcoholism
• Fasting
• Increased insulin sensitivity: fitness, body weight
• Clearance/metabolism of drugs: renal or hepatic
insufficiency
 Mechanisms by which drugs increase
the hypoglycemic effect of sulfonilureas
• Increase in half-life due to inhibition of metabolism
or excretion rate: ethanol, phenylbutazone, coumarin
anticoagulants, chloramphenicol, doxycycline,
sulfonamides, allopurinol
• Competition for albumin-binding sites:
phenylbutazone, salicylates, sulfonamides
• Inhibition of gluconeogenesis, increase in glucose
oxidation, or stimulation of insulin secretion: ethanol,
ß-adrenergic drugs, monoamine oxidase inhibitors,
tranylcypromine,
 Management of hypoglycemia:
Prevention
1. Early familiarization with the symptoms of
hypoglycemia
2. Do reviewing at intervals
3. Explain the relationship between insulin
administration, timing of meals, and exercise
4. Explain methods of self-treating hypoglycemia
5. Choose appropriate insulin regimens, dose
schedules with appropriate therapeutic goals
 Management of hypoglycemia:
Treatment
• Mild hypoglycemia: oral glucose 15-20 g, wait 10-15 min
then check blood glucose. If glucose level does not
increase ≥18 mg/dl, give oral glucose again
• Sever hypoglycemia: solution 50 ml of dextrose 50%
given intravenously, check blood glucose in 20 min. If
it is still hypoglycemia administrate once again
• Glucagon 1.0 mg s.c/i.m/i.v. adverse effects include
nausea, vomiting, and headache. Contraindicated to
sulfonylureas-induced hypoglycemia. Ineffective in
patient who is anorectic, or with protracted
hypoglycemia
 DIABETIC KETOACIDOSIS/DKA

HYPERGLYCEMIC HYPEROSMOLAR STATE

(HHS)
lactic acid↑
• Pencetus umumnya infeksi , pencetus lainnya:
CVA, alcohol, pancreatitis, infark miokard,
trauma, obat-obatan, terapi insulin yang tidak
adekuat
•
 HHS: signs & symptoms
• Excessive thirst
• Increased urination
• Weakness
• Leg cramps
• Confusion
• Rapid pulse
• Convulsions
• Coma
 Signs & symptoms of DKA

• Deep, rapid breathing

• Sweet, fruity smell on breath
• Loss of appetite
• Nausea
• Fatigue
• Vomiting
• Weakness
• Fever
• Confusion
• Stomach pain • Drowsiness
• Weight loss
 1 jam I
jam II

NaCl
0,45%

dextran L
icu,
CVP NaCl 0,9% 500 cc + RI 50 U, 20 tts

pH<7,2 + shock
pCO2 ↓  ?
konsentrasi maksimal
25 mEq KCl dlam 500 cc
CHRONIC DIABETIC COMPLICATIONS
DIABETIC NEPHROPATHY
Chronic Kidney Disease/CKD
 Definition of diabetic nephropathy
• Diabetic nephropathy (DN) is defined by either
macroalbuminria (a urinary albumin excretion of
greater than 300 mg/day or urinary albumin:
creatinine ratio/ACR >30 mg/mmol) or by abnormal
renal function and with existing diabetic
retinopathy
• Microalbuminuria (earliest sign of DN or incipient
DN) is defined by a urinary albumin excretion of
30-300 mg/day or ACR >2,5 mg/mmol in men and
>3,5 in women

(DeFronzo, 2005; Augustine and Vidt, 2003)

 Pathogenesis of diabetic nephropathy

METABOLIC
METABOLIC HEMODYNAMIC
Glucose Flow/Pressure

PKC-ßII Vasoactive hormones

(A-II, Endothelin)
AGEs
Cytokines
Vascular
TGF-ß VEGF Vascular
Extra-cellular matrix permeability
Cross-linking Extra-cellular
matrix
Proteinuria
Extra-cellular matrix
accumulation
 Flowchart for diagnosis of diabetic nephropathy
Annual dipstick
Urinalysis for protein
Positive Negative

Previously positive Test for microalbuminria

on ≥2 occasions over Positive
previous 12 months
YES NO
YES NO
ACR >2,5 mg/mmol
or >3,5 mg/mmol
Retinopathy + Retest over next
12 months
YES NO
YES
Positive
Confirm with
2 samples if
2/3 positive
Retest over next
Clinical nephropathy YES NO 6 months
Microalbuminuria

Jones et. al., 2006

 Natural course of diabetic nephropathy

-3 0 3 Time (years) 15 20 25

120 150 150 GFR (mL/mnt) 120 60 <10

1.0 0.8 0.8 Serum creatinine (mg/dL) 1.0 >2.0 >10
15 10 10 Serum urea nitrogen (mg/dL) 15 >30 >100

Microalbuminuria

-3 0 3 10 15 20 25
Prior to Onset of Onset of Onset Onset ESRD
onset of diabetes diabetic of of
diabetes glomerulosclerosis proteiuria azotemia

(DeFronzo, 2005)
 Features that suggest non-diabetic kidney
disease
• Rapid deterioration in renal function
• Sudden development of nephrotic syndrome
• Heavy hematuria/red cell casts
• Absence of diabetic retinopathy
• Short duration of type 1 diabetes
• Clinical or laboratory evidence of non-
diabetic systemic disease
• Blood pressure higher than expected for
degree of proteinuria Jones et. al., 2004
 Risk factors of diabetic nephropathy
• Blood glucose level
• Blood pressure
• Male sex
• Duration of diabetes
• Total cholesterol level
 Treatment of diabetic nephropathy
• Blood glucose control
• Blood pressure control
• Protein restriction
• Cholesterol lowering

(Steele, 2001)
 The role of blood pressure control
• Normotensive, normoalbuminuric T1D patients:
There is no evidence that antihypertensive treatment
prevents or delays the onset of microalbuminuria (Jones
et al., 2004)
• T2D patients:
Blood pressure control reduces the development of
microalbuminuria (Jones et al., 2004)
• ACEIs reduce 75% UAER after 1 year treatment in T1D
patients
• Irbesartan 300 mg in 2 years treatment reduces 32% the
development of clinical nephropathy (in T2D patients)
• Target of blood pressure 130/80 mmHg. Once renal
function starts to decline and proteinuria reaches 1 g/d
T 125/75 mmHg
• Each 10 mmHg reduction improves the relative decline in
renal function by 0.18 ml/min/mo (Steele, 2001)
 Blood pressure goal and recommended agents
Goal blood Blood pressure agents of
pressure choice
T1DM <130/80 ACEI, ARB if ACEI not
tolerated; diuretic as second-
line agent
T2DM <130/80 ARB, ACEI as alternative,
diuretic as second-line agent
ARB in conjunction with
DM with macroalb. <130/80 diuretic, beta blocker or CCB
as third-line agent
DM with CHF <130/80 ACEI, beta blocker as second-
line agent
DM with CAD <130/80 Beta blocker followed by ACEI,
diuretic as third-line agent
(Augustine and Vidt, 2003)
 The role of protein restriction

• Protein restriction (0.8-1.0 g/kg body weight/d)

reduces the decline in glomerular filtration rate
(relative risk of the decline in GFR: 0.56) (Steele,
2001)
• Dietary protein intake amounting to >20% of total
energy was linked to the presence of
microalbuminuria (Jones et al., 2004)
• Protein and phosphate restricted diet reduced a
decline of GFR of only 0,26 ml/min/mo (Evants and
Capell, 2000)
• RDA protein of 0.8 g/kg body weight/d or 10% of
total calories (Evants and Capell, 2000)
DIABETIC FOOT
Neuropathic ulcer
 TERJADINYA AMPUTASI PADA KAKI DIABETIK
DIABETES MELLITUS

Penyakit pembuluh Neuropati otonom Neuropati perifer

darah tepi
Aliran Indera Gerak
 Keringat darah raba
Sumbatan Aliran
oksigen, nutrisi,
Resorpsi
antibiotik Kehilangan
tulang Atropi
Kult kering, rasa sakit
pecah Kerusakan
sendi Kehilangan
Luka sulit
sembuh Trauma bantalan
Kerusakan lemak
kaki
Tumpuan berat
yang baru
Sindrom jari biru INFEKSI ULKUS
Gangren
Gangren mayor
AMPUTASI
KLASIFIKASI KAKI DIABETIK (WAGNER)
• Grade 0: tanpa ulkus, 1 atau lebih faktor risiko
(neuropati sensorium perifer, kelainan bentuk tulang,
kulit kering dll)
• Grade 1: ulkus dengan 2 atau lebih faktor risiko
(neuropati sensorium perifer ditambah 1 atau lebih
faktor risiko). Ulkus terbatas pada jaringan kulit
• Grade 2: ulkus sampai jaringan bawah kulit, kadang
sampai tendon atau selaput sendi
• Grade 3: seperti grade 2 tetapi tidak respon terhadap
perawatan lokal, atau dengan nekrosis jaringan secara
cepat
• Grade 4: gangren terbatas pada jari kaki
• Grade5: gangren luas sampai kaki
 TANDA-TANDA NEUROPATI PERIFER
• Perubahan indera raba
• Berkurangnya indera raba
• Hilangnya rasa senuhan dan posisi
• Tidak berkeringat
• “Kapalen”
• Ulkus tropik disertai infeksi
• Perubahan bentuk kaki
• Kaki teraba panas
 TANDA-TANDA PENYAKIT PEMBULUH
DARAH PERIFER
• Nyeri berulang
• Kaki dingin
• Nyeri malam hari
• Nyeri saat istirahat
• Denyut nadi hilang
• Rambut kaki dan jari tidak tumbuh
• Kuku menebal
• Gangren
TUJUAN TATALAKSANA KAKI DIABETIK
Tatalaksana kaki diabetik

Pencegahan amputasi
anggota gerak bawah

1. Identifikasi faktor risiko

2. Pengobatan penyakit akut
3. Pencegahan munculnya
problem lanjutan

EDUKASI
 FAKTOR RISIKO ULKUS DAN AMPUTASI
• Jenis kelamin laki-laki
• Lamanya sakit diabetes
• Retinopati/nefropati
• Kadar gula darah tinggi
• Kehilangan indera raba pada tungkai
• Sebelumnya pernah ulkus atau amputasi
• Perubahan bentuk kaki
DIABETIC EYE DISEASE
Stage of diabetic retinopathy

• Non-proliferative (background): venous dilatation

• Preproliferative
• Proliferative (neovasculiration)
Examination of the eyes in diabetic patients
When to examine:
• On diagnosis
• Annually after 5 years of diabetes or if aged >30 years at
diagnosis, or if background retinopathy alone is present
• Three- to 6-monthly if retinopathy is more severe than
background
• Immediately if any change in vision or visual symptoms occur
Examination should include:
• Visual acuity
• Afferent pupillary defect
• Ophthalmoscopy through dilated pupils unless
contraindicated
DIABETIC NEUROPATHY
A classification of diabetic neuropathy
Rapidly reversible phenomena
• Distal sensory symptoms
• Reduced nerve conduction velocity
• Resistance to ischaemic conduction failure
Established neuropathy
Focal and multifocal neuropathies
• cranial mononeuropathies
• Thoracoabdominal neuropathy
• Focal limb neuropathies
• Asymmetric proximal lower limb motor neuropathy
Symmetrical neuropathies
• Sensory/autonomic polyneuropathy
• Proximal lower limb motor neuropathy
Cardiovascular autonomic function tests
Blood pressure test
• Blood pressure response to standing up (fall in systolic blood
pressure): 10 mmHg (normal), 11-29 mmHg (borderline), ≥30
mmHg (abnormal)
• Blood pressure response to sustained handgrip (increase in
diastolic blood pressure): ≥16 mmHg (normal), 11-15 mmHg
(borderline), 10 mmHg (abnormal)
Prevention of chronic diabetic complications
• Tight control of diabetes
• Control of risk factors
- blood pressure
- dyslipidemia
- overweight
- cessation of smoking
• Specific intervention according the chronic
complication: diabetic foot, diabetic nephropathy,
etc.
 TARGET KENDALI DIABETES

BAIK SEDANG BURUK

Gula darah puasa (mg/dl) 80-<100 100-125 ≥126

Gula darh 2 jam (mg/dl) 80-<140 140-179 ≥180
A1C (%) <6,5 6,5-8 >8
Kolesterol total (mg/dl) <200 200-239 ≥240
Kolesterol LDL (mg/dl) <100 100-129 ≥130
Kolesterol HDL (mg/dl) >45
Trigliserid (mg/dl) <150 150-199 ≥200
IMT (kg/m2) 18,5-<23 23-<25 ≥25
Tekanan darah (mmHg) 130/80 130-140/ >140/90
80-90