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 ADA1,2 IDF4
AACE3 (Western
Pacific region)
HbA1c (%) <7 < 6.5 < 6.5
mg/dl mmol/l mg/dl mmol/l mg/dl mmol/l
Fasting/preprandial 5.07.2 < 6.1
90130 < 110 < 6.0 < 110
plasma glucose

Postprandial plasma
glucose < 180 < 10.0 < 140 < 7.8 < 145 <8.0

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 < 100
Konsensus PERKENI 2005
 Complications of Diabetes
Mellitus
Chronic Complications of Acute Complications of
Diabetes Mellitus Diabetes Mellitus
Microvascular Hyperglycemia crisis

Hypoglycemia

Macrovascular
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
 Hyperglycemia

Renal Protein glycation

vasodilatation Increased
intraglomerular
capillary pressure
Increased glomular
filtration rate
Hypertension
Increased
protein excretion

Microalbuminuria or Glomurular
macroalbuminuria 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
 METABOLIC VASCULAR

myoinositol
glucose
Altered membrane
potensial
Arterial
Slow nerve sorbitol narrowing
conduction AGE
formation
nerve vasoconstriction
oedema 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 Signs
Loss of Sensory loss
sensation ; Diminished/absent tendon
Anaesthesia;nu reflexs
mbness
Muscle wasting and
Loss of pain
perception weakness
Autonomic dysfunction
Altered
sensation: Foot uleration

Paraesthesiae
Dysaesthesiae
Pain
Burning
Burning, feeling like the feet are on fire Freezing, like the feet are on ice,
although they feel warm to touch

Stabbing, like sharp knives 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 Inflammatory cytokines induce
experiencing high shear expression of adhesion molecules
forces

Macrophages
bind to and enter
intima wall
Macrophages
become foam Chemo-attractants such as PDGF
Uptake of Lipids by cells & fatty released from activated macrophages
Macrophages streak formed

Smooth muscle Result: Atherosclerotic

cells (SMCs) plaque2
migrate into the
intima

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 Transient ischemic attack

Myocardial
infarction 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.
 Neuropathy

Motor Neuropathy Neuropathy Microvascular

dysfunction disease

Reduced pain
Sensation and
proprioception
Abnormal
Foot posture

Increased foot Dry, cracked

prssure Poor tissue
skin nutrition and
Cheiroarthropathy oxygenation

Arteriovenous
shunting
Callus

Ulcer
Mechanical,
Trauma thermal, Macrovascular
chemical Ischemia
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 Patient
conscious unconscious

Oral glucose 30-50 ml Dextrose 40% or

(10-20gr) Glucagon 1mg sc/im

Recovered Check BG after Not

recoverd
15-20 min

Acute hypoglycemia Patient

unconscious Patient
conscious

10% glucose Repeat oral

glucose
IV infusion
Thank you