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Complications

of Diabetes
Mellitus

Assesment of Glycemic Control

Urinalysis
Glycosuria

Limitations of urinalysis : renal threshold (varies


between individual);
urinary concentration (fluid
intake
and
urine
concentration
may
effect);
neuropathic
bladder
(reduce
the
accuracy);
hypoglycemia (this can not be detect)

Urinary ketones

Semi-quantitatif test for acetoacetat; Ketosis-prone


diabetes

Glycated haemoglobin

HbA1c is formed by the post-translational, non-enzymatic glycation


Glycaemic targets
Frequency of measurement (every 3 or 6 months)
Limitations of HbA1c measurements : daily patern of blood
glucose levels? ; blood loss/haemolysis/reduced red cell (low
HbA1c)

Blood glucose

Before breakfast (fasting)


2 hour post prandial

ADA, AACE and IDF


Glycaemic Goals
Biochemical
index
HbA1c (%)

ADA1,2

AACE
3

<7

< 6.5

IDF4
(Western
Pacific
region)
< 6.5

mg/dl mmol/l mg/dl mmol/l mg/dl mmol/l


Fasting/preprand
90130 5.07.2 < 110 < 6.0 < 110 < 6.1
ial plasma
glucose
Postprandial
< 180 < 10.0 < 140 < 7.8 < 145 <8.0
plasma glucose

1. ADA. Diabetes Care 2004; 27: S1535; 2. ADA Diabetes Care 2002; 25: S3549;
3. Feld S. Endocrine Pract 2002; 8 (Suppl 1): 4082; 4. Asian-Pacific Type 2 Diabetes Policy Group.
Type 2 diabetes: Practical targetsand treatment.
treatment. 4th Edn; Hong Kong: Asian-Pacific Type 2 Diabetes Policy Group, 2005.

Current Indonesian Society


of Endocrinology (Perkeni)
treatment targets

HbA1c

< 7%

Fasting BG < 100 mg/dl


Post prandial BG < 140 mg/dl
Blood pressure

< 130/80 mmHg

LDL-cholesterol < 100 mg/dl (2.6 mmol/l)


HDL-cholesterol
Men > 40 mg/dl (1.1 mmol/l)
> 50 mg/dl (1.3 mmol/l)
Triglycerides

Women

< 150 mg/dl (1.7 mmol/l)


Konsensus PERKENI
2005

Complications of Diabetes
Mellitus
Chronic Complications
of Diabetes Mellitus
Microvascular

Retinopathy
(nonproliferative/proliferativ
e)
Nephropathy
Neuropathy
- Sensory and motor
(monoand polyneuropathy)
- Autonomic

Macrovascular
Coronary artery disease
Peripheral vascular disease
Cerebrovascular disease

Acute
Complications of
Diabetes Mellitus
Hyperglycemia
crisis

Diabetic ketoacidosis
Hyperglycemia
hyperosmolar State
Lactic acidosis

Hypoglycemia

Pathophysiology of
Microvascular
Complications

Activation of Protein Kinase C

Diabetic Retinopathy

Diabetic Retinopathy
Blindness is primarily the result of progressive diabetic
retinopathy and clinically significant macular edema .
Diabetic retinopathy is classified into two stages:
nonproliferative and proliferative.
Nonproliferative diabetic retinopathy : marked by retinal
vascular microaneurysms, blot hemorrhages, and cotton
wool spots
The appearance of neovascularization in response to retinal
hypoxia is the hallmark of proliferative diabetic retinopathy .
Duration of DM and degree of glycemic control are the best
predictors of the development of retinopathy; hypertension
is also a risk factor
The most effective therapy for diabetic retinopathy is
prevention.

Diabetic Nephropathy

Pathophysiology of Diabetic
Nephropathy
Hyperglycemia

Renal
vasodilatation
Increased glomular
filtration rate

Protein glycation

Increased
intraglomerular
capillary pressure
Hypertension
Increased
protein excretion

Microalbuminuria or
macroalbuminuria

Glomurular
damage

Nephropathy

Diabetic Nephropathy

Diabetic Nephropathy Treatment


The optimal therapy for diabetic nephropathy is
prevention.
Interventions effective in slowing progression from
microalbuminuria to overt nephropathy include:

near normalization of glycemia,


strict blood pressure control, and
administration of ACE inhibitors or ARBs, and
treatment of dyslipidemia.

Blood pressure should be maintained at 130/80 mmHg


in diabetic individuals without proteinuria.
A slightly lower blood pressure (125/75) should be
considered for individuals with microalbuminuria or
overt nephropathy
A consensus panel of the ADA suggests modest
restriction of protein intake in diabetic individuals with
microalbuminuria (0.8 g/kg per day) or overt
nephropathy (<0.8 g/kg per day)

Diabetic Neuropathy

Mechanism of Nerve Damage in


Diabetes
METABOLIC

myoinositol

VASCULAR

glucose

Altered membrane
potensial

Slow nerve
conduction

sorbitol

nerve
oedema

AGE
formation

Arterial
narrowing
vasoconstriction

NO
production

Impairing
axonal transport

Vessel
occlusion

H2O

Diabetic Neuropathy
Diabetic neuropathy occurs in approximately 50% of
individuals with long-standing type 1 and type 2 DM .
The development of neuropathy correlates with the
duration of diabetes and glycemic control; both
myelinated and unmyelinated nerve fibers are lost.
Several stage :
Intraneural biochemical abnormalities; sorbitol
accumulation, myoinositol depletion
Impairement of electrophysiological measurement ;
decreased nerve conduction velocity; asymptomatic
Clinical neuropathy; detectable using clinical
methods; maybe symptomatic. Histological changes
evident
End stage complications. Exp are ulceration and
Charcot neuroarthropathy; major derangements of
neural structure and function.

Clinical Features
Symmetrical Sensorimotor
Neuropathy

Symptoms
Loss of sensation ;

Anaesthesia;numbne
ss
Loss of pain
perception

Altered sensation:
Paraesthesiae
Dysaesthesiae

Pain
Burning
Hyperalgesia/allodyni
a
Neuralgia
lancinating pain
Cramps ; restless leg

Signs
Sensory loss
Diminished/absent
tendon reflexs
Muscle wasting and
weakness
Autonomic
dysfunction
Foot uleration

Burning, feeling like the feet are on fire

Stabbing, like sharp knives

Freezing, like the feet are on ice,


although they feel warm to touch

Lancinating, like electric shocks

Treatment of Symmetric
Neuropathy
Glucose control
Pain control
Tricyclic antidepressants
Amitriptyline,desipramin, nortriptilin, trazodone

Anticonvulsants
Carbamazepine, gabapentin

Topical creams
capsaicin

Foot care

Autonomic Neuropathy
DM-related autonomic neuropathy can involve multiple
systems, including the cardiovascular, gastrointestinal,
genitourinary, sudomotor, and metabolic systems.
Autonomic neuropathies affecting the cardiovascular
system cause a resting tachycardia and orthostatic
hypotension.
Gastroparesis and bladder emptying abnormalities are
often caused by the autonomic neuropathy seen in DM
(discussed below).
Hyperhidrosis of the upper extremities and anhidrosis
of the lower extremities result from sympathetic
nervous system dysfunction.
Anhidrosis of the feet can promote dry skin with
cracking, which increases the risk of foot ulcers.
Autonomic neuropathy may reduce counterregulatory
hormone release, leading to an inability to sense
hypoglycemia appropriately ((hypoglycemia
unawareness)

Pathophysiology of
Macrovascular
Complications

Macrovascular Complication
Macrovascular complications of diabetes mellitus
are condition characterized by atherosclerotic
occlusive disease of cerebral, myocard and lower
extremities.
Atherothrombosis is the most common cause of
macrovascular complications
Atherothrombosis is characterized by a sudden
(unpredictable) atherosclerotic plaque disruption
(rupture or erosion) leading to platelet activation
and thrombus formation
Atherothrombosis is the underlying condition that
results in events leading to myocardial infarction,
ischemic stroke, amputation and vascular death

Atherogenesis A Complex
And Progressive Process1
Pathology of Atherogenesis
Initiation:
Accumulation of lipids at
vascular junctions
experiencing high shear
forces

Inflammatory cytokines induce


expression of adhesion molecules

Macrophages
bind to and enter
intima wall

Uptake of Lipids by
Macrophages

Macrophages
become foam
cells & fatty
streak formed

Chemo-attractants such as PDGF


released from activated macrophages

Smooth muscle
cells (SMCs)
migrate into the
intima

Result: Atherosclerotic
plaque2

Adapted from: P Libby, The Vascular Biology of Atherosclerosis, in: Braunwald


E, Zipes DP & Libby P 6th Edition, Heart Disease: a Textbook of Cardiovascular
Medicine 2001: London: WB Saunders. 2. Davies MJ. Heart 2000;83:361-66, with permission from the BMJ Publishing Group

Atherothrombosis Has Multiple


Manifestations
Ischemic stroke

Myocardial
infarction

Transient ischemic attack

Angina:
Stable
Unstable

Peripheral arterial disease:


Intermittent claudication
Rest pain
Gangrene
Necrosis
Adapted from: Drouet L. Cerebrovasc Dis 2002;13(suppl 1):16

Macrovascular Disease in
Diabetes Mellitus
Cardiovascular and cerebrovascular disease account
for up 70% of death in patients with type 2 DM
All patients with type 2 diabetes have greater
predipostition to macrovascular disease, often having
a constellation of risk factors, which have been term
insulin resistance.
It has been hypotethesized that insulin resistance and
hyperinsulinemia (environmental and genetic factors),
are central to development :

Glucose intolerance
Hypertension
Dyslipidemia
Coagulopathy

These factors promote accelerated atherosclerosis,


explaining the increased risk of macrovascular
disease.

Diabetes and Macrovascular


Disease

Libby and Plutsky. Circulation. 2002.

Strategies for Reducing


Macrovascular Complications
Prevention proven intervention trials
Hyperglycemia
Dyslipidemia
Hypertension
Antiplatelet therapies

Prevention suggested by
epidemiologic analysis
Disorders of thrombolysis
Endothelial disorders

The Diabetic Foot

Diabetic Foot Disease


Approximately 15% of individuals with DM develop a
foot ulcer, and a significant subset will ultimately
undergo amputation (14 to 24%risk with that ulcer or
subsequent ulceration).
Syndrome of diabetic foot disease
Peripheral neuropathy, peripheral vascular disease
and tissue infection
Risk factors for foot ulcers or amputation include: male
sex, diabetes 10 years duration, peripheral neuropathy,
abnormal structure of foot (bony abnormalities,callus,
thickened nails), peripheral arterial disease, smoking,
history of previous ulcer or amputation, and poor
glycemic control.
The plantar surface of the foot is the most common site
of ulceration.
Ulcers may be primarily neuropathic (no accompanying
infection) or may have surrounding cellulitis or
osteomyelitis.

Pathophysiology of Diabetic
Foot
Neuropathy

Motor
dysfunction

Abnormal
Foot posture

Microvascular
disease

Neuropathy Neuropathy
Reduced pain
Sensation and
proprioception

Increased foot
prssure

Dry, cracked
skin

Poor tissue
nutrition and
oxygenation

Cheiroarthropathy
Arteriovenous
shunting

Callus

Trauma

Mechanical,
thermal,
chemical

Ulcer
Ischemia

Macrovascular
disease

Acute Complication of
Diabetes Mellitus
Hyperglycemia crisis
Diabetic ketoacidosis (DKA)
Hyperglycemic Hyperosmolar State
(HHS)

Hypoglycemia

Pathophysiolgy of Hyperglycemia
Crisis

Diabetic Ketoacidosis (DKA)


DKA was formerly considered a hallmark of
type 1 DM
The symptoms and physical signs of DKA
Symptoms : Nausea/vomiting, Thirst/polyuria,
Abdominal pain, Shortness of breath
Physical findings : Tachycardia, Dry mucous
membranes/reduced skin turgor, Dehydration /
hypotension, Tachypnea / Kussmaul
respirations/respiratory distress, Abdominal
tenderness (may resemble acute pancreatitis or
surgical abdomen), Lethargy /obtundation /
cerebral edema / possibly coma

Precipitating Factors

Inadequate insulin administration


Infection (pneumonia/UTI )
Gastroenteritis/sepsis
Infarction (cerebral, coronary, mesenteric,
peripheral)
Drugs (cocaine)
Pregnancy

HHS: Differences from DKA


Patients usually older- typically 60 or more
Major pathophysiologic differences
longer uncompensated osmotic diuresis
greater volume depletion
Acidemia (pH > 7.3) and ketosis are mild
Higher mortality often 30-50%
primarily due to underlying vascular or infectious
event
Occurs in Type 2 diabetics, often mild or unrecognized

Definition of HHS
Extreme hyperglycemia
Increased serum osmolality
Severe dehydration without significant ketosis or
acidosis

Joslins Diabetes Mellitus, 13th ed

Precipitating Factors

Infection ( the most common)


Cerebrovascular accident
Alcohol abuse
Pancreatitis
Myocardial infarction
Trauma
Drugs

Clinical Findings of HHS


HHS should be suspect : elderly patient with or without
the preexisting diagnosis of diabetes who exhibits acute
or subacute deterioration of CNS function and severely
dehydrated
Tachycardia
Low grade fever
Low or normal blood pressure
Dehydration dry mucous membrane, absent axillary
sweat, poor skin turgor.
Nausea, vomiting, distension, and pain-gastroparesis is
due to hypertonicity
Lethargy, hallucinations, and psychosis

Laboratory Findings
DKA

HHS

Priority in the Treatment of


Hyperglycemia Crisis
Replacing volume deficits normal saline
according to BP, urine output and CVP value
for old age, total deficits around 6-9 liters.
Correcting hyperosmolarity to 300
milliosmoles/L
Managing any underlying illnesses
Insulin ; RI 0.15u/kg bolus then 0.1/kg/hr
infusion until blood sugar about 250mg/dl or
osmo about 315

Approach to Therapy
Correcting the hyperosmolar state
and dehydration is the initial aim
of therapy.
Insulin therapy should be
undertaken only after the patient
is stable hemodynamically.
Glucose and H2O

H2O lost in urine

Loss of ECF, vascular collapse and death

Hypoglycemia

Clinical Manifestations of
Hypoglycemia

Whipples triadsymptoms consistent with


hypoglycemia,a low plasma glucose concentration,and
relief of those symptoms when the plasma glucose
concentration is raisedprovides compelling evidence
of hypoglycemia.
Symptoms of hypoglycemia can be divided into two
categories, neuroglycopenic and neurogenic
(autonomic) symptoms.
Neuroglycopenic symptoms are the direct result of CNS
neuronal glucose deprivation. They include behavioral
changes, confusion,fatigue or weakness, warmth, visual
changes, seizure, loss of consciousness,and,if hypoglycemia is
severe and prolonged, death. ( BG < 20 mg/dL )
Neurogenic symptoms are the result of the perception of
physiologic changes caused by the autonomic nervous system
discharge triggered by hypoglycemia. ( BG 50 mg/dL )
They include adrenergic symptoms such as
palpitations,tremor, and anxiety and cholinergic symptoms
such as sweating,hunger, and paresthesias.
Cholinergic symptoms,at least sweating, are thought to be
mediated by acetylcholine released from sympathetic
postganglionic neurons.

Comprehensive Risk Factors for


Hypoglycemia in Diabetes
Premise: Iatrogenic hypoglycemia in type 1 diabetes is the
result of the interplay of therapeutic insulin excess and
compromised glucose counterregulation.
1. Absolute or relative therapeutic insulin excess (the
conventional risk factors)
a. Insulin doses excessive,ill-timed, wrong type
b. Decreased food intake
c. Increased glucose utilization (e.g.,exercise)
d. Decreased glucose production (e.g.,alcohol)
e. Increased sensitivity to insulin (e.g.,after exercise,during the
night,glycemic control, weight loss)
f. Decreased insulin clearance (e.g.,renal failure)

2. Compromised glucose counterregulation


a. Absolute insulin deficiency (C-peptide negativity)
Cell destruction:
No in insulin in response to
glucose
Unknown:
No in glucagon in response to
glucose
b. History of severe hypoglycemia or aggressive therapy per se
(lower glucose goals,lower hemoglobin A1c)

Management of Acute
Hypoglycemia
Acute hypoglycemia
Patient
conscious

Patient
unconscio
us

Oral glucose
(10-20gr)

Recovere
d
Acute hypoglycemia

30-50 ml Dextrose 40% or


Glucagon 1mg sc/im

Check BG after
15-20 min

Not
recoverd

Patient
unconscio
us
10% glucose
IV infusion

Patient
conscious
Repeat oral
glucose

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