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. 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
mmol/l)

< 100 mg/dl (2.6

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

Konsensus PERKENI
< 150 mg/dl (1.7

2005

Complications of Diabetes
Mellitus
Chronic Complications of
Diabetes Mellitus
Microvascular
Retinopathy
(nonproliferative/proliferative)
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 is the leading cause of ESRD in the US.
Individuals with diabetic nephropathy almost always have
diabetic retinopathy.
The stages of diabetic nephropathy are :
Hyperfiltration
Microalbuminuria
Overtproteinuria
Declining GFR
End stage renal failure

Microalbuminuria is defined as 30 to 300 mg/d in a 24-h

collection or 30 to 300 g/mg creatinine in a spot collection
(preferred method).
The appearance of microalbuminuria (incipient nephropathy)
in type 1 DM is an important predictor of progression to
overt proteinuria (300 mg/d) or overt nephropathy.
Hypertension more commonly accompanies
microalbuminuria or overt nephropathy in type 2 DM

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;numbness
Loss of pain perception

Altered sensation:
Paraesthesiae
Dysaesthesiae

Pain
Burning
Hyperalgesia/allodynia
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 raised
provides 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:
Unknown:

No in insulin in response to glucose

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

Thank you