Download MBBS (Bachelor of Medicine, Bachelor of Surgery) Pathology PPT 2 Diabetes Pathology Lecture Notes
Diabetes Mel itus
WHO
? Diabetes mellitus is a chronic disease caused by inherited and/or
acquired deficiency in production of insulin by the pancreas, or by the
ineffectiveness of the insulin produced.
? results in increased concentrations of glucose in the blood, which in
turn damage the blood vessels and nerves.
? Diabetes mellitus is a group of metabolic disorders sharing the
common feature of hyperglycemia
Classification
? two principle forms of diabetes:
1. Type 1 diabetes (formerly known as insulin-dependent)
2. Type 2 diabetes (formerly named non-insulin-dependent)
ETIO-PATHOGENESIS
? PATHOGENESIS OF TYPE 1 DM. destruction of -cel mass, usual y leading
to absolute insulin deficiency.
1. Genetic susceptibility- HLA gene cluster on chromosome 6p21, which
according to some estimates contributes as much as 50% of the genetic
susceptibility to type 1 diabetes.
? Al ele-HLA-DR3-DR4
2.Autoimmune factors: fundamental immune abnormality in type 1 diabetes
is a failure of self-tolerance in T cel s specific for islet antigens
? islet cel antibodies
? insulitis
? Selective destruction of -cel s
? TH1 cells secrete-IFN- and TNF
? Islet autoantigens- cell enzyme glutamic acid decarboxylase (GAD),
and islet cell autoantigen 512(ICA512)
? cell-mediated autoimmunity
? Associated with other autoimmune diseases
3.Environmental factors
? viral infections
? Chemicals-alloxan, streptozotocin and pentamidine.
Etiopathogenesis in DM type2
PATHOGENESIS OF TYPE 2 DM.
complex disease that involves an interplay of genetic and
environmental factors and a proinflammatory state.
1-Genetic Factors-first-degree relatives have 5- to 10-fold higher risk
2-Environmental Factors-Obesity, sedentary lifestyle
3-Insulin resistance-
Mechanism of hyperglycaemia in these cases is explained as under:
i) impairs glucose utilisation and hence hyperglycaemia.
ii) There is increased hepatic synthesis of glucose.
iii) Hyperglycaemia in obesity is related to high levels of free fatty acids
and cytokines
4-Current consideration-
? Polymorphism in various post-receptor intracellular signal pathway
molecules.
? Elevated free fatty acids
-Cell Dysfunction
Several mechanisms have been implicated in promoting -cell
dysfunction in type 2 diabetes, including:
? Excess free fatty acids that compromise cell function and attenuate
insulin release ("lipotoxicity")
? impact of chronic hyperglycemia ("glucotoxicity")
? An abnormal "incretin effect," leading to reduced secretion of GIP
and GLP-1, hormones that promote insulin release
? Amyloid deposition within islets 90% of diabetic islets cell in long
standing
? genetic predisposition
Obesity and Insulin Resistance
vFree fatty acids (FFAs)-
? accumulation of cytoplasmic intermediates like diacylglycerol (DAG)
? DAG compete with glucose for substrate oxidation
vAdipokines- Adiponectin levels are reduced in obesity, thus
contributing to insulin resistance
vInflammation
Inflammation:
? FFA & Beta cell
? Inflammasome
? Cytokines IL-1, IL-1
? promote insulin resistance
Metabolic actions of insulin in striated muscle, adipose tissue,
and liver.
Pathophysiological basis of common signs and symptoms due to uncontrol ed
hyperglycaemia in diabetes mel itus
? Morphologic Features ?
1. Pancreatic Islets
2. Diabetic Macrovascular Disease
3. Diabetic Microangiopathy
4. Diabetic Nephropathy
5. Diabetic Ocular Complications
6. Diabetic neuropathy
Morphologic Features
Pancreatic Islets-
1-Insulitis:
? In type 1 DM-
?lymphocytic infiltrate,macrophage and few polymorphs
? In type 2 DM-
?variable degree of fibrous tissue in the islets
2-Islet cell mass:
? Type-1- loss of pancreatic -cells and its hyalinisation
? In type 2 DM-hyperplasia and hypertrophy of islets
3-Amyloidosis:
? type 1 DM- absent
? Type-2DM-around the capillaries of the islets causing compression
and atrophy of islet tissue
? Diabetic Macrovascular Disease-
?hallmark of diabetic macrovascular disease is accelerated
atherosclerosis involving the aorta and large- and medium-sized
arteries
?Myocardial infarction
?Gangrene of the lower extremities
?Hyaline arteriolosclerosis
renal hyaline arteriolosclerosis
? Diabetic Microangiopathy- diffuse thickening of basement
membranes.
?capillaries of the skin, skeletal muscle, retina, renal glomeruli, and
renal medulla
? leaky
? Diabetic Nephropathy-
Three lesions are encountered:
(1) glomerular lesions
(2) renal vascular lesions
(3) pyelonephritis, including necrotizing papillitis
? Glomerular lesion-
?Capillary Basement Membrane
?Diffuse Mesangial Sclerosis- consists of diffuse increase in mesangial
matrix.
?Nodular Glomerulosclerosis- also known as intercapillary
glomerulosclerosis or Kimmelstiel-Wilson disease.
Diffuse and nodular diabetic glomerulosclerosis (PAS
stain).
? nodular lesions are frequently accompanied by prominent
accumulations of hyaline material in capillary loops ("fibrin caps") or
adherent to Bowman capsules ("capsular drops").
Nephrosclerosis
?Renal atherosclerosis and arteriolosclerosis-
Hyaline arteriolosclerosis affects not only the afferent but also the
efferent arteriole
?Pyelonephritis is an acute or chronic inflammation of the kidneys that
usually begins in the interstitial tissue and then spreads to affect the
tubules
? necrotizing papillitis
Diabetic Ocular Complications-
Histologically,
? Non proliferative (non-proliferative)
? proliferative retinopathy
Background (non-proliferative) retinopathy. initial retinal capillary
microangiopathy
? i ) Friability of neo vascularization results in vitreous haemorrhages.
? i i) Proliferation of astrocytes and fibrous tissue around the new blood
vessels.
? iv) Fibrovascular and gliotic tissue contracts to cause retinal detachment
and blindness.
? Diabetic Neuropathy-
duration of the disease; up to 50% of diabetics overall have peripheral
neuropathy
Activation of PKC and polyol pathway
Accumulation of fructose and sorbitol in nerve
Nonenzymatic glycosylation of structural nerve protein
Four distinct mechanisms
1-Formation of Advanced Glycation End Products. Advanced glycation
end products (AGEs) are formed as intracellular
glucose derived dicarbonyl precursors+ amino groups
advanced glycation end product(AGEs)
(glyoxal, methylglyoxal, and 3-deoxyglucosone)
? AGEs bind to a specific receptor (RAGE) that is expressed on
inflammatory cells (macrophages and T cells), endothelium, and
vascular smooth muscle.
AGE-RAGE signal ing axis
? TGF-excess basement membrane material
? vascular endothelial growth factor (VEGF)- neovasculerization
? reactive oxygen species (ROS) in endothelial cells
? procoagulant activity
? Enhanced proliferation of vascular smooth muscle cells and synthesis
of extracellular matrix
2-Activation of Protein Kinase C.
second messenger diacyl glycerol (DAG) is an important signal
transduction pathway.
Intracellular hyperglycemia--- de novo synthesis of DAG--excessive
PKC activation- vascular permeability and angiogenesis
3-Oxidative Stress and Disturbances in Polyol Pathways
? Sustained hyperglycemia---- aldol reductase-- progressive depletion of
intracellular NADPH -- decreased rgeneration of reduced
glutathione(GSH) - increasing cellular susceptibility to oxidative
stress
? Responsible for diabetic neuropathy
4-Hexosamine Pathways and Generation of Fructose-6- Phosphate
Hyperglycemia ---increases intracellular levels of fructose-6-
phosphate via HM- excess proteoglycans - abnormal
expression of TGF or PAI-1--- exacerbate the end-organ damage
Complications of Diabetes-
I.Acute metabolic complications:
? diabetic ketoacidosis
? hyperosmolar nonketotic coma
? hypoglycaemia
I . Late systemic complications:
? atherosclerosis
? diabetic microangiopathy
? diabetic nephropathy
? diabetic neuropathy
? diabetic retinopathy and infections
1.Diabetic ketoacidosis (DKA), complication of type 1 DM.
Lack of insulin
Lypolysis
Free fatty acid in plasma
FFA+acetyl co enzyme A--liver Ketone body
2.Hyperosmolar hyperglycaemic nonketotic coma (HHS)-
High Blood sugar
High plasma osmolality
Hyperglycemic diuresis
Dehydrartion
CNS complication
3.Hypoglycaemia-
? patients of type 1 DM.
? Excessive administration of insulin, missing a meal, or due to stress
I .LATE SYSTEMIC COMPLICATIONS-
1.Atherosclerosis-
? hyperlipidaemia,
? reduced HDL levels,
? nonenzymatic glycosylation,
? increased platelet adhesiveness,
? obesity
? hypertension
2.Diabetic microangiopathy
3. Diabetic nephropathy
4. Diabetic neuropathy
5. Diabetic retinopathy
6. Infections-
?impaired leucocyte functions
? reduced cellular immunity
?poor blood supply
This post was last modified on 07 April 2022