2. Learning Outcomes
Identify the morphological changes in different tissues and organs due to
long standing diabetes mellitus
Describe pathogenesis of diabetes mellitus and its complications
Describe autoimmune insulitis and amyloidosis of pancreas due to DM
Describe macro and microvascular disease due to DM
Identify diabetic nephropathy, retinopathy and neuropathy
3. Pathogenesis of Type -1 DM
Autoimmune factors:
Failure of self tolerance in T cells specific for beta cell antigens.
Autoantibodies react against β-cell antigens and cause β-cell damage by
release of IFN-γ from CD8+T cells and production of TNF and IL-1 from
activated macrophages.
Autoantibodies, detected in the blood of 70-80% of cases
Genetic susceptibility Principal genetic susceptibility locus resides in the
(HLA-D) region in chromosome 6, several non-HLA genes also confer
susceptibility, resulting in excessive T cell activation and cell damage
Environmental factors Viral infections, (mumps, rubella, and coxsackie B)
as some of viral antigens, antigenically similar to β cell antigens leading to
islets damage
4. Pathogenesis of Type 2 DM
A complex multifactorial disease which involves interactions of genetics,
environmental risk factors and inflammation with no autoimmune basis
Genetic factors; More than a dozen “diabetogenic” genes identified
(both parents diabetic; 50% risk to the child)
Environmental factors; Sedentary life style, dietary habits and obesity
Insulin resistance; Decreased ability of peripheral tissues to respond
to insulin
Beta cell dysfunction; Manifested as inadequate insulin secretion in the
face of insulin resistance and hyperglycemia
5. Type 2 DM: Insulin Resistance
Insulin resistance is influenced by;
Genetic defects of Insulin receptor
Genetic defects of Insulin signaling pathway (inactivating mutations)
Obesity
7. Obesity and Insulin Resistance
Role of free fatty acids (FFAs);
In obese, increased intracellular TG’s in muscle and liver
and products of FFAs metabolism are potent inhibitors of
insulin signaling pathways
Role of Adipokines
Released by adipose tissue into systemic circulation (like;
leptin, adiponectin, and resistin), changes in their levels
associated with insulin resistance as for example;
Adiponectin levels reduced in states of obesity causing
insulin resistance where as its normal levels contributes to
insulin sensitivity in peripheral tissues where as; Resistin
levels increased in obesity which contributes to insulin
resistance
Inflammation
Pro-inflammatory cytokines secreted in response to FFAs
results in both insulin resistance and beta cell dysfunction
8. β-Cell Dysfunction
Qualitative; when secretary defect progresses to involve all phases of
insulin secretion
Quantitative; a decrease in β-cell mass, islet degeneration with deposition
of islet amyloid protein (amylin) ,a characteristic finding in individuals with
Type 2 DM.
Pathogenesis: In peripheral insulin resistance, insulin secretion is initially
higher for each level of glucose in order to compensate for peripheral
resistance and results in β-cell hyperplasia (as seen in the pre-diabetic
state) later; followed by decrease in β-cell mass that progress to diabetes
due to adverse effects of high circulating FFAs ("lipotoxicity") or chronic
hyperglycemia ("glucotoxicity“)
9. Etiologic Classification of Diabetes Mellitus
Type 1 Diabetes
β-cell destruction - absolute insulin deficiency
Type 2 Diabetes
Insulin resistance with relative insulin deficiency
Genetic Defects of β-Cell Function
Maturity onset diabetes of the young (MODY)
caused by mutations in MODY1 to MODY6
Mitochondrial DNA mutations
Genetic Defects in Insulin Processing or Insulin
Action
Defects in proinsulin conversion, Insulin gene
mutations, Insulin receptor mutations
Exocrine Pancreatic Defects
Chronic pancreatitis, Pancreatectomy, Neoplasia,
Cystic fibrosis, Hemochromatosis
Endocrinopathies
Growth hormone excess, Cushing syndrome,
Hyperthyroidism, Pheochromocytoma,
Glucagonoma
Infections
Mumps, CMV and Coxsackievirus B
Drugs
Glucocorticoids , Thyroid hormone and
β-adrenergic agonists
Genetic Syndromes Associated with Diabetes
Down syndrome, Kleinfelter syndrome and
Turner syndrome
Gestational Diabetes Mellitus
11. Pathogenesis of Complications of DM
The long-term complications of DM are similar in both types of DM
and involve three underlying mechanisms
1- Non-enzymatic glycosylation
2- Activation of protein kinase C
3- Intracellular hyperglycemia- disturbances in polyol pathways
12. 1- Non-enzymatic glycosylation
In this process glucose chemically attaches to free amino groups of proteins
without the aid of enzymes and is directly related to blood glucose level
Glycosylated hemoglobin; its levels in the blood provides an index of the
average blood glucose levels over the 120-day life span of erythrocytes
Advanced glycosylation end products (AGEs); formed as a result of non-
enzymatic reaction between intracellular glucose precursors and amino
groups of proteins
13. ADVANCED GLYCOSYLATION END PRODUCTS (AGEs)
AGEs bind to a specific receptor (RAGE), which is expressed on
inflammatory cells (macrophages & T cells), endothelial cells and on
vascular smooth muscle
Early glycosylation products of collagen and other long lived proteins in the
interstitial tissues and blood vessel walls undergo chemical rearrangements
to form irreversible AGEs which may trap non-glycosylated plasma and
interstitial proteins
In large vessels, trapping LDL, for example, retards its efflux from the vessel
wall and enhances the deposition of cholesterol in the intima, thus
accelerating atherogenesis
In capillaries, including those of renal glomeruli, plasma proteins such as
albumin bind to the glycated basement membrane, resulting in basement
membrane thickening characteristic of diabetic glomerulopathy
14. AGEs
Effects of the AGE-RAGE signaling axis within the vascular
compartment includes;
Release of pro-inflammatory cytokines and growth factors from intimal
macrophages
Generation of reactive oxygen species in endothelial cells
Increased procoagulant activity on endothelial cells and macrophages
Enhanced proliferation of vascular smooth muscle cells and synthesis of
extracellular matrix
15. 2- Activation of protein kinase C
Activation of intracellular protein kinase C (PKC) by calcium ions and the
second messenger diacylglycerol (DAG) is an important signal transduction
pathway in many cellular systems
Intracellular hyperglycemia can stimulate the de novo synthesis of DAG from
glycolytic intermediates and hence cause activation of PKC, which induces
production of;
Pro-angiogenic molecules; like, VEGF, involved in neovascularization seen
in diabetic retinopathy
Pro-fibrogenic molecules; like, TGF β, leads to increased deposition of
extracellular matrix and basement membrane material
16. 3- Intracellular hyperglycemia- disturbances in
polyol pathways
Tissues that, do not require insulin for glucose transport (e.g., nerves, lens,
kidneys, blood vessels), hyperglycemia leads to an increase in intracellular
glucose that is then metabolized by enzyme aldose reductase to sorbitol (a
polyol) and to fructose
Accumulated sorbitol and fructose causes cell injury via increased
intracellular osmolarity and water influx, by an increase in cellular
susceptibility to oxidative stress because intracellular antioxidant reserves
are diminished in the course of sorbitol metabolism
17. Morphology of Pancreas in DM
Type 1 DM: Reduced number and size of
islets, and Leukocyte infiltration of the islets,
principally mononuclear cells, an early feature,
but inflammation is often absent by the time the
disease is clinically evident
Type 2 DM: Amyloid replacement of islets,
amyloid deposition occurs around capillaries and
between cells and in advanced stages the islets
may progress to fibrosis
Note: non-diabetic newborns of diabetic mothers,
fetal islets undergo hyperplasia in response to
maternal hyperglycemia
18. Diabetic Arterial Vasculopathy
Macrovascular Disease; accelerated atherosclerosis of aorta, coronary
and renal arteries; results in MI and or gangrene of lower extremities
Hyaline arteriolosclerosis; thickening of arteriolar walls, narrowing of
lumen (as in hypertensive) more prevalent and severe
Microangiopathy; diffuse thickening of vascular and nonvascular
basement membranes, by hyaline material, most evident in capillaries of
skin, skeletal muscle, retina, renal glomeruli, and renal medulla and in
nonvascular structures like, renal tubules, Bowman capsule, peripheral
nerves, and placenta
*Despite increase in thickness of basement membranes, diabetic
capillaries are more leaky than normal to plasma proteins.
19. Diabetic Nephropathy
Three types of renal lesions identified:
Glomerular lesions
Renal vascular lesions
Pyelonephritis and necrotizing papillitis
20. Diabetic - Glomerular Lesions
Basement membrane thickening; of glomeruli & renal tubules
Diffuse mesangial sclerosis; increase in mesangial matrix
along with mesangial cell proliferation (as in old age &
hypertension) associated basement membrane thickening
when marked, present as nephrotic syndrome
Nodular glomerulosclerosis ; Ball-like deposits of a
laminated (PAS-positive) matrix in the periphery of
glomerulus usually contain trapped mesangial cells called
Kimmelstiel-Wilson lesion, pathognomonic of diabetes
and is a major contributor to morbidity and mortality
21. Diabetic Renal Vascular lesions and Pyelonephritis
Renal vascular lesions
Renal atherosclerosis and hyaline
arteriolosclerosis affects both afferent and
efferent arterioles as compare to only
afferent in hypertensive
Pyelonephritis and necrotizing papillitis
Begins as acute or chronic interstitial inflammation,
then spreads to involve tubules, more common in
diabetes
One special pattern of acute pyelonephritis is
necrotizing papillitis (or papillary necrosis), much
more prevalent in diabetics than in non-diabetics
Severe renal hyaline
arteriolosclerosis; note markedly
thickened, (PAS Positive)
tortuous afferent arteriole
22. Diabetic Retinopathy
Nonproliferative retinopathy
Intraretinal or preretinal hemorrhages
Retinal exudates; either “soft”
(microinfarcts) or “hard”(deposits of plasma
proteins and lipids)
Microaneurysms; and venous dilations
Microangiopathy; thickening of the retinal
capillaries
Edema; excessive capillary permeability due
to focal weakening of capillary wall by loss of
capillary pericytes
Edema and retinal exudates that
are "soft" microinfarcts or "hard"
yellowish waxy exudates
23. Retinopathy
Proliferative retinopathy
Neovascularization and
fibrosis leads to blindness, if it
involves the macula
Vitreous hemorrhages can
result from rupture of newly
formed capillaries
Retinal detachment;
organization of the hemorrhage
can pull the retina off its
substratum (retinal detachment)
Neovascularisation near optic disk when bleed,
produces vitreal hemorrhages obscuring vision
Advanced stage with retinal hemorrhages,
exudates, neovascularization, and retinal
detachment
24. Diabetic Neuropathy
Both CNS and PNS are affected
The most frequent pattern of involvement is that of; a peripheral, symmetric
neuropathy of the lower extremities affecting both motor and sensory
function, particularly the latter
Others; autonomic neuropathy, which produces disturbances in bowel and
bladder function and sometimes sexual disorders
Type 1 DM presents in children and require insulin for treatment. The classic manifestations of the disease (hyperglycemia and ketosis) occur late in its course, after more than 90% of the beta cells have been destroyed.
Accelerated atherosclerosis of aorta, coronary and renal arteries; results in myocardial infarction (the most common cause of death in diabetic women and men) as well as gangrene of lower extremities very common