Diabetes Mellitus complications
Dr.Ashraf Deyab
College of Medicine- Majmaah University
Pathology of diabetes complication
• By the end of this session, the student should:
• Discuss the pathogenesis of diabetes complications.
• Describe the morphology of diabetes complication.
• Discuss epidemiology, public health importance,
prevention and screening (where applicable) of
diabetic complications.
Acute and chronic DM complications
Acute complication
1. Diabetic ketaoacidosis= DKA.
2. Hyperglycemia hyperosmolar
state = (HHS), ‘nonketaotic”
3. Hypoglycemia
4. Diabetic coma
5. Respiratory infections
6. Periodontal disease
7. Impaired wound healing
Chronic complications
Macrovascular disease
Microvascular disease
1.
2.
3.
4.
5.
6.
Diabetic nephropathy
Diabetic neuropathy
Diabetic retinopathy
Cataract
Diabetic cardiomyopathy
Diabetic embryopathy
Pathogenesis of DM complications
• Pathologic sequelae caused by persistent hyperglycemia (“glucotoxicity”) , lead
to metabolic dys-regulation, considered as responsible for the short& long-term
complications.
• Hyperglycemia- basically lead to damage of blood vessels
(angiopathy) grouped under two types:
1) Microvascular angiopathy: capillaries dysfunction in target organs -e.g.
diabetic neuropathy, nephropathy, and retinopathy.
2) Macrovascular angiopathy: Both large& Medium-sized muscular
arteries  (Myocardial infarction, stroke, and peripheral vascular insufficiencyaccelerated atherosclerosis, peripheral LL amputation)
• Three distinct metabolic pathways have been implicated in this
serious effects of persistent hyperglycemia on peripheral tissue:
• (1) Formation of Advanced (Protein) Glycation End product (AGE)
• (2) Activation of Protein Kinase C (PKC)
• (3) Intracellular Hyperglycemia and Disturbances in Polyol Pathways
Pathogenesis of DM complications
• I) Formation of Advanced Glycation End Products-(AGE).
(1) Hyperglycemia increase protein glycation gradual build-up of (AGEs)
(a) Release pro-inflammatory markers
(b) Free radical activity
↓↓↓
Cells& vessels injury  Microangiopathy
(2) AGEs Cross-linking with collagen (type I in- BV. +type IV in- BM)  Decreases their elasticity+
Increases extravasation of fluid + Decreases protein removal while + Enhancing protein& LDL deposition.
• II) Activation of Protein Kinase C (PKC):
The activation of PKC initiates a complex Intracellular signals 
1- Increases in vascular permeability,
2- BM thickening with ECM deposition flexibility affected
3- Angiogenesis- proliferation tendency
4- Apoptosis,
5-Vascular occlusion + decrease fibrinolysis  Vasoconstriction
•
Pathogenesis of DM complication
• III) Intracellular Hyperglycemia &Disturbances in Polyol
Pathways: polyol pathway= sorbitol aldose reductase pathway.
• Insulin-independent tissue: like in BV, retina, kidney and nerves,
any Unused\excess glucose enter polyol pathways.
1) Unused\excess glucose enter polyol pathways formation of Sorbitol , mediated by
Aldose reductase (using much more NADPH) 
(a) Sorbitol-accumulation cannot cross cell membranes (osmotic influx of water) 
CATRACT.
(b) NADPH deficiency
2) NADPH deficiency lead to glutathione deficiency
 induce cells Oxidative stress Release& accumulation of reactive oxygen species\ free
radicals:
(a) Decreased concentrations of nitric oxide, inositol
(b) Cell injury
(c ) Hemolysis
(d ) Vasoconstriction, etc….
DM morphology:
Principal organs affected in diabetes mellitus (not related to
pancreas only” depend on the late complications:
Eyes
• Retinopathy
• Cataract
• Glaucoma
Pancreas
• Islet cells:
-
Insulitis (type I).
Amyloid deposition
(type II)
Blood vesselsAngiopathy
• Macrovascular
• Microvascular.
Kidney
 Atherosclerosis
Nephropathy:
 Foot Gangrene . Nephroscerlosis\
 MI.
Glomeruloscelrosis.
• Arterioscelrosis
 CVA
• pyelonephritis
 HTN
Nerves:
- Peripheral +Autonomic Neuropathy
1)Pancreas : pancreatic lesions are neither constant nor necessarily
pathognomonic. They are more likely to be distinctive in type I >> in type II.
One or more of the following alterations may be present:-1. Reduction in the size& number of
islets (DM-1), ↓islet mass (DM-2).
2. Increase in the size & number of
islets (nondiabetic newborns of
diabetic mothers).
1. .
DM-1: Leukocytic infiltration
(insulitis)- mostly T- cells,
Eosinophilic infiltrates (Autoimmune
diseases)
DM-2: Amyloid replacement of islets
and around capillaries & b\w islet cells
 obliteration & fibrosis.
DM-1
DM-2
Blood vessels. Small vessels (Diabetes microangiopathy) .
Morphologic features
Diffuse Thickening& widening of
basement membrane by a
homogeneous , sometimes
multilayered hyaline substance=
PAS stain positive.
Capillaries are more leaky than normal
to plasma proteins.
EXAMPLES: kidenys (glomeruli,
tubules, renal medulla) , skin, muscle,
eye-retina/ etc…….
Diabetic Macrovascular Disease
Atherosclerosis (AT): 
Endothelial dysfunction- predisposes
(LDL deposition).
Hyaline arteriolosclerosisAmorphous, hyaline thickening wall of
the arterioles, which causes narrowing
of the lumen.
Complications:
AT MI, CVA, Gangrene of the
lower extremities etc..
Kidneys. (Diabetic Nephropathy ).
The kidneys are second target for DM after the heart .
• The second leading cause of death after MI from DM.
• Three lesions are encountered:
Morphology ( after> 20 yrs of diabetes)
Glomerular and tubular lesions: Most specific for
DM is Nodular Glomerulosclerosis: = (KimmelstielWilson lesion), chr. Nodular intercapillary lesion
- Capillary and Tubular BM thickening.
- Mesangial matrix widening, ↑↑↑cellularity.
- Diffuse mesangial sclerosis.
Renal vascular lesions:Arteriosclerosis
- Thickeneing of basement membrane.
- Severe hyaline changes
Interstitial lesion:
- Interstitial inflammation.
- Pyelonephritis, including necrotizing
papillitis
Severe renal hyaline (afferent
art.) arteriolosclerosis
Nephrosclerosis long-standing DM
thickening of tubular BM
Nodular “intercapillary” glomerulosclerosis
Eyes( diabetic Retinopathy)
Morphology- divided into 2 groups
I. Diabetes microangiopathy (non proliferative)
a) Macular edema (visual loss):
Thickening of the Basement membrane
Breakdown of the blood-retinal barrier lead to
leakage with micro-occlusion
b) Pericyte degeneration+ arteriolar
hyalinzation
c) Microaneurysms
d) Retinal micro-hemorrhages- cotton-wool spots
II. Intraretinal angiogenesis (proliferative phase)
a) Retinal neovascularization .
b) Posterior vitreous detachment Massive
hemorrhage.
c) Organization
d) Retinal traction- detachment visual
disturbance
Eyes. ( Anterior chamber complications) .
Cataract due accumulation of sorbitol 
1 - Opacification of the lens nucleus (Osomotic
effect of polyol pathway)
2 - Enhance of lens epithelial apoptosis
Development of Neovascular membrane on iris
surface:
(a) Development of iris neovascular membrane.
1.
(b) Increased levels of VEGF in the aqueous
humor.
3.
Neovascular glaucoma:
(a) Proliferation of fibrovascular tissue in
anterior chamber  Contraction of neovascular
membrane  (b) Lead to adhesions.
(c) Occluding a major pathway for aqueous
outflow.
(d) Elevation of the intra-ocular pressure IOP
Nerves ( Diabetic Neuropathy ).
•
• 80% of DM> more than 15 years.
• Site: Peripheral nerves , brain, and spinal cord.
Site
Autonomic neuropathy, e.g. genito-urinary &
sexual, CVS symptoms and signs
Peripheral neuropathy – sensorimotor
neuropathy
morphologic features- most common
1- Endoneurial arterioles show thickening, of BM with
hyalinization,.
2- Demyelination resulting from Schwann cell dysfunction.
3- Axonal degeneration, with relative loss of small myelinated and
unmyelinated fibers.
Epidemiology, public health importance, prevention and
screening (where applicable) of DM complications.
• How Frequent?
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This disorder consider as very important public health problem
151 - 171 million of people worldwide.
The overall prevalence of DM in adults in KSA is 23.7%.
Male > female.
7% of the population, 1.5 million new cases\ year-USA.
The prevalence is increasingly in the developing world as people adopt
more sedentary life styles.
• How to screen for diabetes, what the effectiveness of this
screening and who to screen (all people or high risk group)?
– 1- Meeting diagnostic criteria. (type 1,II, gestational, secondary, etc..)
– 2- Screening test: OGTT=FBG >126mg\dl + (2-h OGTT) < 140mg/dl (normal),
140-199gm/dl (impaired), >200mg\dl (provisional diagnosis of DM).
• Prevention:
• Type II diabetes:
– Exercise.
– Loosing weight.
– Diet control (high fiber, free of refined carbohydrates, based around
vegetables).
– Stopping smoking and alcohol intake.
– Start medication early, stop some medications.
• Type I diabetes:
– Is an autoimmune condition. For this reason, it is not directly preventable.
• _______________________________________________________
•
Assessment of glycemic control regularly:
• Measure Glycosylated hemoglobin% =HbA1C, which is formed by nonenzymatic
covalent addition of glucose to hemoglobin in red cells.
• The American Diabetic Association recommends that HbA1C be maintained
below 6.5% in diabetic patients