Complication of diabetes melitue

1. COMPLICATIONS
OF DIABETES
MELLITUS

2. 
A metabolic disorder of various etiologies,
characterized by chronic hyperglycemia due
to insulin deficiency and/or insulin resistance
as well as increased hepatic glucose output.

3. Type 1
Type 2
Other causes
(Genetic defect of β cell function, genetic
defects of insulin action, disease of exocrine
pancreas, endocrinopathies, drug/chemicalinduced, infections and uncommon forms)
 Gestational DM




5. COMPLICATIONS OF DIABETES MELLITUS
ACUTE
• Diabetic Ketoacidosis
• Hyperglycemic
Hyperosmolar State
• Hypoglycemia
-Diabetic Foot Ulcer
-Infections
CHRONIC
• Microvascular
- Retinopathy
- Nephropathy
- Neuropathy
• Macrovascular
- Accelerated
arteriosclerosis
- Myocardial infarction
- Stroke
- Lower extremity
gangrene

6. CHRONIC COMPLICATIONS OF DIABETES MELLITUS

13. HCO3-
Hypertriglyceridemia
Resembles
Pancreatitis

16. Reduced insulin:glucagon ratio
↓
↑Lipolysis
↓
Fruity smell in
↑fatty acid
the breath
↓
Excess acetyl CoA
Ketonuria
↑Acetone
Metabolic
↓
acidosis
Ketonemia
↑ Ketogenesis
↓
Reduce HCO3↑Beta hydroxy butyrate (toxic to body)
Kussmaul
↓
respiration (to
Induce nausea/vomiting
compensate)‘air hunger’

17. Absolute insulin
deficiency/Increase counter
regulatory hormones
↓
↑Catabolism of carbohydrate, fats
and proteins
↓
Hyperglycemia
↓
Osmotic diuresis
↓
Polyuria and nocturia (loss of
electrolytes + fluid)
Nausea and
↓
Impairs
vomiting
Dehydration
renal
excretion of
↓
H+ and
Thirst center
ketone
↓
Polydipsia
Affect pH
dependent enzyme
Aggravate
acidosis

18. Increased chylomicrons in the blood (>1000mg/L)
↓
Obstruct capillaries
↓
Local ischemia and acidemia
↓
Local damage expose TG to pancreatic lipases
↓
TG → Fatty acids
↓
Further local injury + ↑ inflammatory mediators and free radicals
↓
Resembles Pancreatitis

19. 



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


Tachycardia
Dehydration/hypotension
Tachypnea
Abdominal tenderness (resembles
pancreatitis/surgical abdomen)
Lethargy/
Reduce alertness (obtundation)
Cerebral edema
Coma

20. 
severe ketoacidosis + histotoxic action of the
ketone bodies + disturbances in water and
electrolyte balance → reduced oxidative
metabolism of the central nervous system →
diabetic coma

21. 





Hyperglycemia: Test with dipstick, confirm
with venous blood glucose level
Ketonemia: test plasma with Ketostix. Finger
prick sample for β-hydroxybutyrate
Ketouria: measure urine ketone levels
Acidosis: measure
- pH of arterial blood
- bicarbonate in venous blood
Arterial blood gas
Urinalysis

22. Symptoms of hyperglycemia from history
Pulse: >100bpm/ <60bpm
Systolic BP <90 mmHg
Glasgow Coma Score <12/abnormal ‘Alert,
Voice,Pain, Unresponsive’ scale (AVPU)
 O2 saturation <92% on air (If normal
respiratory function)





23. 





Replace fluid losses
Replace electrolyte losses
Restore acid-base balance
Replace deficient insulin
Monitor blood glucose closely
Treat underlying cause

25. •
•
•
Usually occur in Type 2 DM
Caused by relative insulin deficiency and inadequate
fluid intake
Involved mostly elderly patients
Hyperglycemia
Dehydration
Ketosis
Decreased
consciousness

27. 


Dehydration
Stupor/Coma
Confusion
ABSENCE OF KETOACIDOSIS
No nausea, vomiting and Kussmaul respiration
(delays the seeking of medical attention


28. marked increase in plasma osmolarity
(reaches 340mOsm/L (280-295mOsm/L)
↓
Profound cellular dehydration
↓
severe loss of intracellular fluid in the brain cells
↓
Coma
Plasma osmolality =
(2(Na+ + K+) + glucose + urea) all in mmol/L

31. 

Due to insulin treatment for both Type 1 and Type 2
DM
Due to improper dosing with exogenous insulin or
by induction of endogenous insulin
Exercise, fasting, low glucose intake
↓
Hypoglycemia
↓
Low insulin, High Counter regulatory hormone
↓
Insulin treatment
X Restore blood glucose level
↓
Hypoglycemia
Release of glucagon

32. 








sweating
Confusion
Irritability
Headaches
Abnormal behaviour
Motor incoordination
Coma
Weakness
Convulsion

33. 

Rapid oral/IV glucose
IM glucagon

34. 1.Coronary heart disease
2.Peripheral arterial disease
3.Cerebrovascular disease

35. 


Also called ischemic heart disease.
Caused by a hardening or thickening of the
walls of the blood vessels that go to the
heart.
Blood supplies oxygen and other materials to
the heart for normal functioning. If the blood
vessels to the heart become narrowed or
blocked by fatty deposits, the blood supply is
reduced or cut off, resulting in a heart attack.

36. Pathogenesis :
Diabetes mellitus – metabolic disorder
Increase production of advanced glycation end products (AGEs)
Endothelial injury
Make the platelets ‘sticker’
Increase permeability and adhesion of
molecules ;
monocyte,leukocyte,platelet,
lipids (LDL)
Increase coagulation potential
Abnormal clot formation (thrombosis)
Oxidized LDL attracts macrophages and
monocytes to the site
Smooth muscle emigration from media
to intima
Lipids engulf by cells  foam cells,
smooth muscle cells proliferate
Collagen and other ECM deposition
Accumulation of lipid intracellularly &
extracellularly
Atheroslerotic plaque
Coronary heart disease

37. Pathophysiology :
Reduction of blood flow
Decreased blood supply to the myocardium, decreased oxygen supply
Anaerobic metabolism
Acidosis
Chest pain
Decreased myocardial
contractility  low cardiac
output
Myocardial ischemia  myocardial necrosis
Inflammatory response
Hyperthermia/fever
Decreased systemic circulation
Sympathetic stimulation
Tachycardia
Redirection of blood from skin  major organs
Decreased perfusion of oxygenated
blood to other organs
Dyspnea, fatigue and body
weakness
Pallor

38. Signs and symptoms :
 Chest pain – usually a feeling of
squeezing/pressure. If the patient has
autonomic diabetic neuropathy, he may not
has the chest pain
 Decreased tolerance for physical activity
 Chronic fatigue
 Shortness of breath
 Swelling of the legs and ankles
 Palpitation

39. 



refers to a group of conditions that affect the
circulation of blood to the brain, causing limited or no
blood flow to affected areas of the brain
Atherosclerosis is one of the conditions that can cause
cerebrovascular disease.
During this process, high cholesterol levels coupled
with inflammation in areas of the arteries in the brain
can cause the cholesterol to build up in the vessel in
the form of a thick, waxy plaque.
This plaque can limit, or completely obstruct, blood
flow to the brain, causing a stroke, transient ischemic
attacks, or dementia, which may lead to a variety of
other health complications.

40. Hyperglycemia
↓
Non-enzymatic glycosylation of collagen and others
protein in interstitial tissue and blood vessel wall
↓
Formation of irreversible advanced glycosylation end
products (AGES)
↓
Cause cross link between polypeptides + interstitial
proteins, including low-density lipoprotein (LDL)

41. ↓
Promote the deposition of the cholesterol in the
blood vessel intima
↓
Accelerates atherogenesis
↓
Atherosclerosis
↓
Compromised the blood supply to the tissue
↓
To brains vessels
↓
Coma and stroke

42. Atherosclerosis
compromised the blood supply
Coronary artery
lower extremities vessel
brain vessel
MI, angina, IHD
coma, stroke
coagulative necrosis + infections
gangrene

43. 


In the walls of the large blood vessels, AGEmodified collagen accumulates, thickening the
vessel wall and narrowing the lumen.
AGE-modified arterial collagen immobilizes
circulating LDL, contributing to atheroma
formation.
The cumulative effect of these changes is a
progressive narrowing of the vessel lumen and
decreased perfusion of affected tissues.
The binding of AGEs to specific cellular
receptors that have been identified on the
surface of smooth-muscle cells, endothelial
cells, neurons, monocytes, and macrophages
results in increased vascular permeability and
thrombus formation, proliferation of smooth
muscle in vessel walls, and phenotypic
alteration in monocytes and macrophages

44. This last result causes hyperresponsiveness of monocytes and
macrophages upon stimulation, with
resultant increases in the production of
proinflammatory cytokines and certain
growth factors.
 These cytokines and growth factors
contribute to the chronic inflammatory
process in the formation of
atherosclerotic lesions.


45. Another condition related to heart disease and
common in people with diabetes.
 The blood vessels in the legs are narrowed or
blocked by fatty deposits, decreasing blood
flow to the legs and feet.
 Increases the chances of a heart attack or
stroke occurring. Poor circulation in the legs and
feet also raises the risk of amputation.


46. 
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Intermittent claudication - pain, weakness, numbness, or
cramping in muscles due to decreased blood flow
Rest pain - occurs when the artery occlusion is so critical that
there is not enough blood and oxygen supply to the lower
extremities even at rest and represents a more serious form of
the condition.
Numbness of the extremities
Weakness and atrophy (diminished size and strength) of the
calf muscle
A feeling of coldness in the legs or feet
Changes in color of the feet; feet turn pale when they are
elevated, and turn dusky red in dependent position
Hair loss over the dorsum of the feet and thickening of the
toenails on affected limbs and digits
Painful ulcers and/or gangrene in tissue where there is critical
ischemia; typically in the toes ( heals slowly or not all )

48. In normal endothelial cells, biologically active substances are
synthesized and released to maintain vascular homeostasis,
ensuring adequate blood flow and nutrient delivery while
preventing thrombosis and leukocyte diapedesis.
( Diapedesis - The movement or passage of blood cells,
especially white blood cells, through intact capillary walls into
surrounding body tissue)
Among the important molecules synthesized by the endothelial
cell is nitric oxide (NO), which is constitutively produced by
endothelial NO synthase (eNOS) through a 5-electron oxidation
of the guanidine-nitrogen terminal of L-arginine.
The bioavailability of NO represents a key marker in vascular
health. NO causes vasodilation by activating guanylyl cyclase on
subjacent vascular smooth muscle cells.
In addition, NO protects the blood vessel from endogenous
injury—ie, atherosclerosis—by mediating molecular signals that
prevent platelet and leukocyte interaction with the vascular wall
and inhibit vascular smooth muscle cell proliferation and
migration.

49. Conversely, the loss of endothelium-derived NO
permits increased activity of the proinflammatory
transcription factor nuclear factor kappa B (NF-κΒ),
resulting in expression of leukocyte adhesion
molecules and production of chemokines and
cytokines.
These actions promote monocyte and vascular smooth
muscle cell migration into the intima and formation of
macrophage foam cells, characterizing the initial
morphological changes of atherosclerosis.
Thus, decreased levels of NO in diabetes may underlie
its atherogenic predisposition.
The bioavailability of NO reflects a balance between its
production via NOS and its degradation, particularly by
oxygen-derived free radicals.
Many of the metabolic derangements known to occur
in diabetes, including hyperglycemia, excess free fatty
acid liberation, and insulin resistance, mediate
abnormalities in endothelial cell function by affecting
the synthesis or degradation of NO.

50. 
To reduce the risk of progression and of
cardiovascular disease by
 Improved control of blood glucose
▪ Reduced intake of blood glucose
▪ Control diet!!!
 Aggressive reduction of blood pressure
▪ For DM 1, ACE inhibitor provide greater benefit
▪ For DM 2, angiotensin 2 receptor blocker has better
effect
 Aggressive cardiovascular risk factor reduction
▪ Eg; reduced in cholesterol intake

51. Treatment

Antihypertensive (ACEi, ARB)
 To prevent hypertension

Statin
 To prevent lipid abnormalities

ACE inhibitor / ARB
 To prevent cardiovascular risk

Low-dose aspirin (antiplatelet)
 To reduce arteriolar thrombosis &
macrovascular risk

53. 
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
DIABETIC RETINOPATHY
DIABETIC NEUROPATHY
DIABETIC NEPHROPATHY

55. 
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Diabetic retinopathy is a complication of
diabetes and a leading cause of blindness.
Is the result of damage to the tiny blood
vessels that nourish the retina
They leak blood and other fluids that cause
swelling of retinal tissue and clouding of
vision
Usually affects both eyes
The longer the person has diabetes, the more
likely they will develop diabetic retinopathy

56. 
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Hyperglycemia will increase retinal blood flow and
metabolism and has direct effects on retinal
endothelial cells and pericyte loss
which will impair vascular autoregulation
The uncontrolled blood flow will dilates capillaries and
increase production of vasoactive substances and
endothelial proliferation, resulting in capillary closure
This causes chronic retinal hypoxia and stimulates
growth factors (VEGF) production
VEGF – will stimulate changes of endothelial cell
growth (new vessel formation) and increase vascular
permeability (causing retinal leakage and exudation)

57. 
1.
There are 4 types of diabetic retinopathy
Non-proliferative without maculopathy


2.
Maculopathy


3.
No immediate threat to vision
It includes venous dilatation, peripheral
(microaneurysms, exudates and blot haemorrhages)
Is a sight threatening
Presence of exudation, haemorrhage, ischemia and
oedema
Pre-proliferative


Is a sight threatening
Presence of venous loops and beading, microaneurysms,
haemorrhages, intra-retinal microvascular abnormalities,
multiple cotton wool spots, macular oedema with
reduced visual acuity and exudation

58. 
Proliferative
 Is a sight threatening
 Involves pre-retinal haemorrhage,
neovascularisation, fibrosis and exudative
maculopathy

59. • Microaneurysms
tiny, discrete, circular, dark red spots near the retinal
vessels.
most cases, this is the earliest clinical abnormalities.
• Retinal haemorrhages
occur in deeper layer of retina
round, regular in shape- `blot’ haemorrhage.
• Exudates
characteristics of dibetic retinopathy
occur in perimacular area.
• Cotton wool spots
features of pre-proliferative diabetic retinopathy.
• Venous changes
• Neovascularisation
• Pre-retinal haemorrhage
• Vitreous haemorrhage
• Fibrosis

60. microaneurysm
(soft exudates)

61. Increase intracellular glucose
Activation of polyol pathway
Reduce in Na/K
ATPase activity
Osmotic effect
(intracellular
overhydration)
Non enzymatic
glycosylation of
terminal end
amino groups

62. Intermediate glycosylated compund
Advanced glycosylation end products.
( AGEs)
Changes in cellular function
Imbedded lens
Swelling and opacity
Blurring of vision
(retinopathy)

63. 
Prevention
 Rapid reduction in blood glucose
 Blood pressure lowering
 Annual screening for retinopathy (in those with risk factor)

Retinal photocoagulation (laser treatment)
 Focal laser to treat leaking microaneurysm, retinal
thickening, reduced macular edema
 To destroys area of retinal ischemia, thus reduce the intraocular levels of VEGF (important for neovascularisation)
 Reduced risk of recurrent haemorrhage (by inducing
fibrosis of the new vessel)

64. Opacification of the lens
Due to sorbitol infiltration
Senile cataract develops 10-15 years earlier in
diabetic patients
 Clinical features


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 Gradual painless deterioration of vision
 Reduced visual acuity

Treatment
 Cataract extraction
 Insertion of an intraocular lens

65. 



Increased intraocular pressure damaging optic
nerve and results in visual field defects
Leaky new vessel formation  reduced outflow
of aqueous humour through trabecular
meshwork  increased intraocular pressure 
glaucoma
Diagnosis is made after IOP is measured
Treatment
 Beta-blocker
 Prostaglandin analogue
 Carbonic anhydrase inhibitors

67. Diabetic Neuropathy
•Neurological disorder associated with diabetes mellitus
•Affects all peripheral nerves including pain fibers, motor neurons
and autonomic nervous system
•Symptoms vary according to the nerves affected
•Common symptoms includes:
•Numbness & tingling of extremities (‘Gloves & stockings
distribution’)
•Dysesthesia (abnormal sensation to a body part)
•Dizziness
•Urinary incontinence
•Muscle weakness
•Difficulty swallowing

68. Pathogenesis
The pathogenesis is not clearly understood but these 4 factors are
thought to be involved:
1. Microvascular disease
a. Diabetes causes narrowing of blood vessels, abnormal
vasoconstriction, capillary membrane thickening and
endothelial hyperplasia which contributes to tissue (nerve)
hypoxia
b. Nerve hypoxia can lead to neuronal ischemia which impairs
nerve functions
2. Advanced glycated end products (AGE)
a. Elevated intracellular levels of glucose can cause a nonenzymatic covalent bonding with proteins which alters their
structure and inhibit their function.
b. Seen in cells that unable to reduce glucose intake due to
hyperglycemia (e.g. endothelial cells).
c. A complex pathway involving oxidative stress or reactive
oxygen species.

69. 3. Protein Kinase C (PKC)
a. Increased levels of glucose cause an increase in intracellular
diacylglycerol which activates PKC
b. PKC inhibitors will be activated to compensate the abnormal
activation of PKC
c. PKC inhibitors increase nerve conduction velocity by
increasing neuronal blood flow, causing abnormal sensation.
4. Polyol pathway
a. Aka sorbitol/aldose reductase pathway.
b. Increase glucose level will activate this alternative
biochemical pathway.
c. This pathway decreases glutathione and increase reactive
oxygen species & is dependent on enzyme aldose reductase.
d. Cells of retina, kidney & nervous tissues are not insulin
dependent.
e. Any glucose not used will enter the polyol pathway and be
converted to sorbitol

70. 4. Polyol pathway
f. Under normal condition, this interchange will cause no
problem as aldose reductase has low affinity for glucose at
normal concentration.
g. In hyperglycemic state, sorbitol accumulates.
h. Sorbitol can’t cross cell membrane, when it accumulates, it
produces osmotic stress by drawing water into cell.
i. Fructose which is also made further on in this chemical
pathway has the same effect.
j. The deposition of sorbitol and fructose can damage the
Schwann cell membrane and causes abnormalities or decrease
nerve conductions.

71. hyperglycemia
Activation of sorbitol/aldose pathway
Accumulation of sorbitol and fructose in the cell and also
depletion of NADPH needed for GSH production
Osmotic stress of Schwan cell and also production ROS

72. Abnormality or delayed nerve conduction
Diabetic neuropathy

73. DEFINITION :
Any deleterious effect on kidney structure and/or function
caused by diabetes mellitus.
 Chacterized by albuminuria, hypertension, and
progressive renal insufficiency
 Approx. 20-30% of patients with diabetes
(type 1 and type 2) develop nephropathy
 The earliest clinical manifestation is the presence of
small but abnormal levels of albumin in the
urine (microalbuminuria) generally preceds
overt proteinuria by 5-10 years.

74. 




Once proteinuria is detected, renal function gradually
deteriorates over 10-15 years
Diabetic nephropathy may result in end-stage renal
disease (ESRD) requiring dialysis or kidney
transplantation.
Considerably fewer people with type 2 diabetes
progress to ESRD
Microalbuminuria is a risk factor for premature
coronary artery disease in diabetics
Coexisting hypertension accelerates the
development of renal failure.

75. Diabetic Kidney
The kidney may be damaged by diabetes in
three main ways :
1) Glomerular damage diabetic
nephropathy
2) Ischaemia resulting from hypertrophy
and hyalinization of afferent and efferent
arterioles  ischaemic damage to kidneys.
3) Ascending infection  UTI due to
bladder stasis resulting from autonomic
neuropathy and infections.

76. STAGE
CHARACTERISTICS
STAGE 1
Hypertrophy and hyperfunction
- Increase in size of kidney
- Higher blood flow and rate of filtration
Thickening of basal membrane
Onset of Nephropathy
Microalbuminuria
- Microalbuminuria
testing:
- Rise in blood pressure
Clinical nephropathy
Normal range :
-Macroalbuminuria
<20mg/l
-High blood pressure
Microalbuminuria:
20 – 200mg/l
Macroalbuminuria
: >200mg/l
STAGE 2
STAGE 3
STAGE 4

77. PATHOPHYSIOLOGY
=> Renal hypertrophy and increase in glomerular
filtration rate
High levels of blood sugar
Kidney filter too much blood stress on basal membranes
More vasolidation of afferent arteriole than efferent
glomerular arteriole
Increases intraglomerular
filtration pressure
further
damage glomerular
capillary

78. intraglomerular
filtration pressure
Local shearing forces
(mesangial cell
hypertrophy) and
secretion of
extracellular
mesangial matrix
material
Further damage
glomerular
capillary
Glomerular sclerosis
Thickening of BM
Disruptions of protein cross
lingkages that makes an effective
filter
Progressive leak of large
molecules(proteins) into urine

79. Small amount of protein appears in urine;
microalbuminuria 30-300mg/day
 Overt nephropathy with macroalbuminemia
>300mg/day + HPT
 May develop end stage renal failure
 Requiring dialysis or renal transplant


80. 
Screening for microalbuminuria 30-300mg/day
 Microalbuminuria is the earliest evidence of the
diabetic nephropathy
 The amount is so small to be detected.
 Have to be tested by using special dipstick or
radioimmunoassay

82. Impairs immune
system
minor trauma
DM
↓
Defective insulin action
↓
Hyperglycaemia
↓
good medium for
bacterial growth
↓
prone to get infection
glycosylation of
polymorphnuclear cells
↓
impaired effectiveness
& function
bacterial invasion & proliferation
↓
INFLAMMATION
↓
Capillary dilatation, fluid exudation, neutrophils exudation
↓
Liquefactive tissue necrosis
Gangrene
↓
ULCER
AMPUTATION
(red, warm, swollen, tender skin lesion)
tissue injury

84. ischaemia
neuropathy
symptoms
Claudication
Rest pain
Usually painless
Sometimes painful
neuropathy
inspection
Dependent rubor
Trophic changes
High arch
Clawing of toes
No trophic changes
palpation
Cold
pulseless
Warm
Bounding pulses
ulceration
Painful
Heels and toes
painless
Plantar (pressure point)

85. 

Dorsum of 2nd toe shows ischaemic lesion.
Whitish color on the tip d/t ischaemia

86. 



Ulcer on the 1st metatarsal head.
Health granulation tissue on its bed.
Callus formation on its surrounding
ulcer lesion.

88. 

Death of tissue
Generally d/t loss of vascular supply&
followed by bacterial infection

89. 
Laboratory test
FBC – presence & severity of infection
blood sugar – hyperglycemia

X-ray
sign of damage to bones or arthritis
gas in soft tissue-indicate gangrene

Ultrasound
doppler ultrasound-blood flow through the arteries
& veins in lower extremities

90. Resolve infection
-antibiotics
 Wound care
- surgical debridement
- improvement of circulation
- special dressing
- maggot therapy
 Follow up
-compliance to antibiotic
-sign of improvement-less pain, swelling, redness, shrinkage


92. 
Poorly controlled diabetes entails increased susceptibility of
infections
 Skin infection
 GIT infection
 Urinary tract infection
 Pyelonephritis
 Pneumonia
 Pulmonary tuberculosis

Pathophysiology
 Hyperglycemia  impaired neutrophil superoxide generation 
chemotaxis & phagocytosis of neutrophil are impaired  infections
Infection also leads to loss of glycemic control and
ketoacidosis
 Increase insulin dose for DM patient complicated with
