Pathology of Diabetes
1. Define and classify diabetes mellitus based on the etiology.
2. Discuss the pathogenesis of different types of DM.
3. Discuss the relation between obesity and insulin resistance.
4. Discuss the pathogenesis of diabetic ketoacidosis and Non-ketotic
hyperosmolar coma.
Diabetes Mellitus- definition
• DM- definition?
• DM-is a group of metabolic diseases characterized by hyperglycemia
resulting from defects in insulin secretion, insulin action, or both.
• DM- is associated with long-term damage, dysfunction, and failure of
various organs, e.g. eyes, kidneys, nerves, heart, and blood vessels.
• What’s the insulin?
• is a peptide hormone, produced by beta cells (isletof Langerhans. ) of the pancreas,
• What’s the function of Insulin?
• Play central role to regulating carbohydrate ( enhance glycogenolysis. Glyoclysis)
and fat metabolism in the body. It causes cells to absorb glucose from the blood e.g
(the liver, skeletal muscles, and fat ).
DM- Classification based on etiology
1. Type 1 diabetes mellitus- replace IDDM, JDM
2. Type II diabetes mellitus- replace NIDDM
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Other specific types:
1. Genetic defect of Beta-cell function.
2. Genetic defects in insulin action.
3. Genetic syndrome associated with diabetes
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1. Exocrine pancreatic defect (pancreatitis, surgery, tumors)
2. Endocrinopathies (pituitary, adrenal, pregnancy)
3. Infections (congenital rubella, CMV, coxsackievirus)
4. Drugs (thiazide, steroid, etc..)
5. Gestational diabetes
American Diabetes Association
DM- Classification based on etiology
1.
Type 1 diabetes mellitus.(Immune-mediated-β-cell destruction, or
Idiopathic usually leading to absolute insulin deficiency). Age < 20 yrs (510% of all cases)
2. Type II diabetes mellitus.(combination of insulin resistance, relative
deficiency and β-cell dysfunction, ). 90-95% of DM, Age = adult onset.
3. Genetic defect of Beta-cell function.(Maturity-onset diabetes of the young
(MODY), caused by mutations), Neonatal diabetes, Maternally inherited
diabetes and deafness, Insulin gene mutations, etc..
4. Genetic defects in insulin action.(Type-A-insulin resistance, Lipoatrophic
DM, including mutations in PPARG)
5. Genetic syndrome associated with diabetes.(Down’s, Turner, Kleinfelter
syndromes, etc,..)
6. Exocrine pancreatic defect (Chronic pancreatitis, surgery, tumor, etc)
7. Endocrinopathies (pituitary, adrenal,….). )
8. Infections. (CMV, Coxsackie B, Congenital rubella virus)
9. Drugs .(Glucocorticoids, Phenytoin, Thiazides, thyroid H, etc….)
10. Gestational diabetes
PATHOGENESIS OF DM-TYPE 1
• DM-1 start in childhood become manifested in puberty.
• DM-1 is an autoimmune disease in which islet destruction is caused
primarily by immune effector cells (failure of self-tolerance in T-cells)
(TH1 “CK,TNF,INF”, +CD8 “direct killer”) reacting against
endogenous β-cell antigens (insulin, GAD, ICA512).
• Autoimmune: many auto antibodies are found (ICA,IAA,GAD).
• Mechanism of autoimmunity involve interplay between:• 1) Genetic Susceptibility: this confirmed by studies by:
– a) Monozygotic vs dizygotic twins,
– b) HLA genes association (DR 3\4 DQ8)
– c) Non-HLA genes association (CTLA4, PTPN22).
• 2) Environmental Factors:
• Infections- especially viral infections:
– (Mumps, Rubella, Coxsackie B, or Cytomegalovirus) through three different
mechanism:
a) Islet cells damage release of sequestered β-cell antigens 
activation of autoreactive T cells
b) (“Molecular mimicry”)=mimic β-cell antigens.
•
c) Hypothesis (“predisposing virus”) - early in life  Persistent infection  Reinfection “ precipitating virus” that share antigenic epitopes Lead to immune
response against infected islet cells.
Insulinitis of islet langerhans in type 1 DM: lymhocytic
infiltrate suggests an autoimmune mechanism
Pathogenesis of Type - II DM
• Complex multi-factorial disease, strongly a\w
• 1) Environmental factors, such as:
•
•
•
a) Sedentary life style.
b) Dietary habits.
c) Obesity.
• 2) Genetic factors are also involved:
•
•
a) Concordance rate of 35% -60% in monozygotic twins.
b) Risk for type 2 diabetes in an offspring is >> than double if both
parents are affected.
• Note:- No HLA association or autoimmune reaction.
•
Pathogenesis of DM type 2
• Two major pathogenetic factors
( Insulin Dysfunction, delayed, resistant):• 1- Insulin resistance:
• defined as inability of cells to respond adequately to normal levels of insulin.
• Obesity plays an important role by decreasing insulin receptors ( explain???). not
all obese individuals??  Beta cell intrinsic factors
• 2-B cell dysfunction: Beta cell exhausted by insulin resistance
• Insulin secretion by glucose stimulation of beta cells part, mediated by the glucose
transporter 2 (GLUT-2), which function is altered by
– a) Genetic abnormality.
– b) High-fat diet (lipotoxic).
– c) Amyloid replacement of B cell: Amyloid is toxic to beta cells  & enhance
apoptosis.
– Role of islet amyloid polypeptide(Amylin)- is co-secreted with insulin in high
amount due to insulin resistance High level of amylin ↓↓glucose uptake and
inhibit endogenous insulin secretion.
•
Islet of langerhans in type 2 DM show pink
hyalinization with amyloid deposits
The relation between obesity and insulin resistance.
• Impacts of insulin resistance:
• (a) Decreased uptake of glucose in muscle and other
• (b) Reduced glycolysis and fatty acid oxidation in liver.
• (c) Inability to suppress hepatic gluconeogenesis.
• Obesity& distribution of fat (Central) - has profound effects on
sensitivity of tissues to insulin.
• The risk for diabetes increases as BMI increases
Obesity-induced Insulin Resistance- 1
• Obesity can adversely impact insulin sensitivity in four different
ways:
– (1) Non-esterified fatty acids (NEFAs).
– (2) Endocrine mechanism
– (3) Inflammation
– (4) Peroxisome proliferator-activated receptor γ (PPAR γ)
•
• (1) Non-esterified fatty acids (NEFAs):
inverse correlation with insulin sensitivity
Obesity Excess circulating NEFAs deposition in tissue (liver, muscles) Excess intracellular
NEFAs overwhelm the fatty acid oxidation pathways, lead to: 
1) Intra-cytoplasmic accumulation “toxic” Phosphorylation of the insulin receptor
2) Compete with glucose for substrate oxidation in insulin responsive cells inhibit glycolytic
enzyme ↑↑↑↑ glucose
3) Function as endocrine factors that regulate metabolic function in target tissues.
• (2)Endocrine
• Fat considered recently as endocrine (secreting Adipokines) organ not only storage
• A variety of proteins secreted = Adipokines (or adipose cytokines).
• Examples:
–
–
(a) Pro-hyperglycemic adipokines (e.g. Resistin, Retinol binding 4 [RBP4], Cortisol )
(b) Anti-hyperglycemic adipokines (Leptin, adiponectin).
.
• Adiponectin level are reduced  in obesity
• (3) Inflammation:
• Adipose tissue secretes a variety of pro-inflammatory cytokines like, ( TNF, IL6,
CRP, Adipose tissue macrophages (ATMs)).
• Reducing the levels of pro-inflammatory cytokines enhances insulin sensitivity.
(4) Peroxisome proliferator-activated receptor γ (PPAR γ):
• PPAR γ : a nuclear receptor& transcription factor expressed in adipose
tissue plays a role in cell differentiation.
• Role of Activation of PPARγ:
• (a) Promotes secretion of anti-hyperglycemic adipokines -like adiponectin.
• (B) Shifts the deposition of NEFAs toward adipose tissue and away from liver
and skeletal muscle.
•
Mutations of PPAR γ – lead to monogenic diabetes.
PATHOGENESIS OF TYPE 2 DM
ACUTE metabolic complication
• Two important ACUTE metabolic complication of
diabetes mellitus are:
 Diabetic Ketoacidosis.
 Nonketotic hyperosmolar coma.
Pathogenesis of diabetic Ketoacidosis (DKA).
 DKA- This complication occurs almost exclusively in DM-1
 1. DKA- define as severe insulin deficiency coupled with absolute or
relative increases of glucagon, due to infection or under\omission of
insulin dose↓ Glycolysis.↓ Uptake
 2. The insulin deficiency causes excessive breakdown of adipose
stores, resulting in an increased FFA LIPOLYSIS.
 3. Oxidation of such FFA acids  acetyl-CoA divert from citric
cycle into ketone bodies (KETOGENESIS). acetoacetate, b-hydroxybutyrate,
and acetone =Osmotic diuresis
 4. Hyperglycemia- Glycogenlysis& gluconeogenesis (glucagon) +
reduce glucose uptake ( The rate at which ketone bodies are produced
exceed the rate at which can be utilized  leading to ketonemia,and
ketonuria  decrease the blood's pH, HCO3 to DKA.(Insulin
deficiency) .
Pathogenesis of Non-ketotic hyperosmolar coma-( HHS)
 Hyperosmolar state, known as syndrome, OR Diabetic coma.
 DM acute complication a\w type DM 2 rather than DM type-1.
 Risk groups: thirst, disabled, elderly> 60yrs, RF, infection, MI,
CVA, and drugs).
Etio-pathogenesis of this syndrome
(1) Uncontrolled sustained hyperglycemic status, higher > 500mg\dl,
(2) With marked water loss or dehydration
(3) High Serum osmolarity(glucose) due to relative insulin deficiency
(4) Severe dehydration resulting from diuresis-polyuria.
(5) No ketones are formed (ketoacidosis) (ketones formed very rarely in
Type 2, because of presence of insulin inhibits Lipolysis)
(6) The severe loss of body water& electrolytes imbalance lead to shock,
coma and death (50%)
DM I and DM II
Items
Type 1(IDDM)
Type2(NIDDM)
Age
children
adult
Insulin
decrease
Normal or increase
obesity
absent
present
Auto antibodies
ICA,IAA,GAD
Absent
Genetic,HLA
40%,HLADr3,4
80%,No HLA
association
Pathology
Immune mediatedinsulinitis, lymphoid
infiltrate,beta cell atrophy
and fibrosis
Amyloid deposites, No
insulinitis,
ketoacidosis
common
Rare(Hyperosmolar
nonketotic)