Download MBBS Pathology PPT 2 Diabetes Pathology Lecture Notes

Diabetes Mel itus

WHO

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? 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.

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? 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

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common feature of hyperglycemia

Classification

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? two principle forms of diabetes:
1. Type 1 diabetes (formerly known as insulin-dependent)
2. Type 2 diabetes (formerly named non-insulin-dependent)

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ETIO-PATHOGENESIS

? PATHOGENESIS OF TYPE 1 DM. destruction of -cel mass, usual y leading

to absolute insulin deficiency.

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1. Genetic susceptibility- HLA gene cluster on chromosome 6p21, which

according to some estimates contributes as much as 50% of the genetic

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susceptibility to type 1 diabetes.

? Al ele-HLA-DR3-DR4

2.Autoimmune factors: fundamental immune abnormality in type 1 diabetes

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is a failure of self-tolerance in T cel s specific for islet antigens

? islet cel antibodies

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? insulitis

? Selective destruction of -cel s
? TH1 cells secrete-IFN- and TNF
? Islet autoantigens- cell enzyme glutamic acid decarboxylase (GAD),

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and islet cell autoantigen 512(ICA512)

? cell-mediated autoimmunity
? Associated with other autoimmune diseases

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3.Environmental factors
? viral infections
? Chemicals-alloxan, streptozotocin and pentamidine.

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Etiopathogenesis in DM type2
PATHOGENESIS OF TYPE 2 DM.
complex disease that involves an interplay of genetic and

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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

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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

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and cytokines


4-Current consideration-

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? Polymorphism in various post-receptor intracellular signal pathway

molecules.

? Elevated free fatty acids

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-Cell Dysfunction

Several mechanisms have been implicated in promoting -cell

dysfunction in type 2 diabetes, including:

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? 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

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and GLP-1, hormones that promote insulin release

? Amyloid deposition within islets 90% of diabetic islets cell in long

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standing
? genetic predisposition

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Obesity and Insulin Resistance

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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

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contributing to insulin resistance

vInflammation

Inflammation:

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? FFA & Beta cell

? Inflammasome

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? Cytokines IL-1, IL-1

? promote insulin resistance

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Metabolic actions of insulin in striated muscle, adipose tissue,

and liver.

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Pathophysiological basis of common signs and symptoms due to uncontrol ed

hyperglycaemia in diabetes mel itus

? Morphologic Features ?

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1. Pancreatic Islets
2. Diabetic Macrovascular Disease
3. Diabetic Microangiopathy
4. Diabetic Nephropathy
5. Diabetic Ocular Complications

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6. Diabetic neuropathy
Morphologic Features

Pancreatic Islets-
1-Insulitis:

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? In type 1 DM-
?lymphocytic infiltrate,macrophage and few polymorphs
? In type 2 DM-
?variable degree of fibrous tissue in the islets

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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

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? Type-2DM-around the capillaries of the islets causing compression

and atrophy of islet tissue

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? Diabetic Macrovascular Disease-
?hallmark of diabetic macrovascular disease is accelerated

atherosclerosis involving the aorta and large- and medium-sized

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arteries

?Myocardial infarction
?Gangrene of the lower extremities
?Hyaline arteriolosclerosis

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renal hyaline arteriolosclerosis
? Diabetic Microangiopathy- diffuse thickening of basement

membranes.

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?capillaries of the skin, skeletal muscle, retina, renal glomeruli, and

renal medulla

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? leaky

? Diabetic Nephropathy-
Three lesions are encountered:
(1) glomerular lesions

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(2) renal vascular lesions
(3) pyelonephritis, including necrotizing papillitis


? Glomerular lesion-

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?Capillary Basement Membrane

?Diffuse Mesangial Sclerosis- consists of diffuse increase in mesangial

matrix.

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?Nodular Glomerulosclerosis- also known as intercapillary

glomerulosclerosis or Kimmelstiel-Wilson disease.

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Diffuse and nodular diabetic glomerulosclerosis (PAS

stain).

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? nodular lesions are frequently accompanied by prominent

accumulations of hyaline material in capillary loops ("fibrin caps") or

adherent to Bowman capsules ("capsular drops").

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Nephrosclerosis

?Renal atherosclerosis and arteriolosclerosis-

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Hyaline arteriolosclerosis affects not only the afferent but also the

efferent arteriole
?Pyelonephritis is an acute or chronic inflammation of the kidneys that

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usually begins in the interstitial tissue and then spreads to affect the

tubules

? necrotizing papillitis

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Diabetic Ocular Complications-
Histologically,
? Non proliferative (non-proliferative)

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? proliferative retinopathy
Background (non-proliferative) retinopathy. initial retinal capillary

microangiopathy

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? i ) Friability of neo vascularization results in vitreous haemorrhages.

? i i) Proliferation of astrocytes and fibrous tissue around the new blood

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vessels.

? iv) Fibrovascular and gliotic tissue contracts to cause retinal detachment

and blindness.

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? Diabetic Neuropathy-
duration of the disease; up to 50% of diabetics overall have peripheral

neuropathy
Activation of PKC and polyol pathway

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Accumulation of fructose and sorbitol in nerve
Nonenzymatic glycosylation of structural nerve protein

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Four distinct mechanisms


1-Formation of Advanced Glycation End Products. Advanced glycation

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end products (AGEs) are formed as intracellular

glucose derived dicarbonyl precursors+ amino groups

advanced glycation end product(AGEs)

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(glyoxal, methylglyoxal, and 3-deoxyglucosone)

? AGEs bind to a specific receptor (RAGE) that is expressed on

inflammatory cells (macrophages and T cells), endothelium, and

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vascular smooth muscle.
AGE-RAGE signal ing axis

? TGF-excess basement membrane material

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? vascular endothelial growth factor (VEGF)- neovasculerization
? reactive oxygen species (ROS) in endothelial cells
? procoagulant activity
? Enhanced proliferation of vascular smooth muscle cells and synthesis

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of extracellular matrix

2-Activation of Protein Kinase C.
second messenger diacyl glycerol (DAG) is an important signal

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transduction pathway.
Intracellular hyperglycemia--- de novo synthesis of DAG--excessive

PKC activation- vascular permeability and angiogenesis
3-Oxidative Stress and Disturbances in Polyol Pathways

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? Sustained hyperglycemia---- aldol reductase-- progressive depletion of

intracellular NADPH -- decreased rgeneration of reduced

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glutathione(GSH) - increasing cellular susceptibility to oxidative

stress

? Responsible for diabetic neuropathy

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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

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Complications of Diabetes-
I.Acute metabolic complications:
? diabetic ketoacidosis

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? hyperosmolar nonketotic coma
? hypoglycaemia


I . Late systemic complications:

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? atherosclerosis
? diabetic microangiopathy
? diabetic nephropathy
? diabetic neuropathy
? diabetic retinopathy and infections

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1.Diabetic ketoacidosis (DKA), complication of type 1 DM.

Lack of insulin

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Lypolysis

Free fatty acid in plasma

FFA+acetyl co enzyme A--liver Ketone body

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2.Hyperosmolar hyperglycaemic nonketotic coma (HHS)-

High Blood sugar

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High plasma osmolality

Hyperglycemic diuresis

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Dehydrartion

CNS complication

3.Hypoglycaemia-

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? patients of type 1 DM.
? Excessive administration of insulin, missing a meal, or due to stress
I .LATE SYSTEMIC COMPLICATIONS-
1.Atherosclerosis-
? hyperlipidaemia,

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? reduced HDL levels,
? nonenzymatic glycosylation,
? increased platelet adhesiveness,
? obesity
? hypertension

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2.Diabetic microangiopathy
3. Diabetic nephropathy
4. Diabetic neuropathy
5. Diabetic retinopathy

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6. Infections-
?impaired leucocyte functions
? reduced cellular immunity
?poor blood supply

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