diabetes mellitus.pptx

MODERATOR: Dr. RAMYA BS
PRESENTER : Dr. CHITRA R
PATHOLOGY AND PATHOGENESIS OF
DIABETES MELLITUS

A 12 yr old child came
with complaints of
severe weight loss with
polyuria after puberty
A neonate develops
hyperglycemia at 1st
wk of life and resolved
spontanseously after
12 wks
A 25 yr old male showed
mild stable hyperglycemia
and responds well to oral
agents.
A diabetic women
become
pregnant?????
ALL ARE DM
IS IT SAME
OR DIFFERENT

OVERVIEW
• Definition
• Epidemiology
• Diagnosis
• Classification
• Regulation of glucose hemostasis
• DM 1 pathogenesis
• DM 2 Pathogenesis
• Other specific type of diabetes
• Gestational diabetes
• Complication of DM

Definition
• Diabetes mellitus is a group of metabolic disorders
sharing the common feature of hyperglycemia.
• Hyperglycemia in diabetes results from defects in
insulin secretion, insulin action or most commonly
both.

Epidemiology
The World Health Organization
estimates that as many as 346
million people suffer from
diabetes worldwide, with India
and China being the largest
contributors to the world’s
diabetic load.

Diagnosis-WHO AND ADA CRITERIA
IMPAIRED GLUCOSE TOLERENCE
1.A fasting plasma glucose ≥ 126
mg/dL
2. A random plasma glucose ≥ 200
mg/dL ( with hyperglycemic signs)
3. 2-hour plasma glucose ≥ 200
mg/dL during an oral glucose
tolerance test (OGTT) with a
loading dose of75 gm, and
4.A glycated hemoglobin (HbA1C)
level ≥ 6.5%
DIABETES MILLETUS
1. A fasting plasma glucose between
100 and 125 mg/dL(“impaired
fasting glucose”),
2. 2-hour plasma glucose between
140 and 199 mg/Dl following a
75-gm glucose OGTT, and/or
3. A glycated hemoglobin (HbA1C)
level between 5.7%and 6.4%

CLASSIFICATION
• Type 1 diabetes is an autoimmune disease
characterized by pancreatic β cell destruction and an
absolute deficiency of insulin.
• Type 2 diabetes is caused by a combination of
peripheral resistance to insulin action and an
inadequate secretory response by the pancreatic β
cells (“relative insulin deficiency”).
• OTHER SPECIFIC TYPE OF DIABETES.
• GESTATIONAL DIABETES.

REGULATION OF GLUCOSE
HEMOSTASIS
• Glucose homeostasis reflects a balance between hepatic
glucose production and peripheral glucose uptake and
utilization.
• Insulin is the most important regulator of this metabolic
equilibrium, but neural input, metabolic signals, and other
hormones (e.g., glucagon) result in integrated control of
glucose supply and utilization.

HEMOSTASIS
INSULIN BIOSYNTHESIS:
• Insulin is produced in the beta cells of the pancreatic
islets.

HEMOSTASIS
INSULIN SECRETION:
• Glucose is the key regulator of insulin secretion by
the pancreatic beta cell.
• Glucose stimulation of insulin secretion begins with
its transport into the beta cell by a facilitative glucose
transporter.

HEMOSTASIS
INSULIN SECRETION:

HEMOSTASIS
INSULIN SECRETION:
• Oral intake of food leads to secretion of multiple hormones that
play a role in glucose homeostasis and satiety. Of these, the most
important class of hormones responsible for promoting insulin
secretion from pancreatic β cells following feeding is the incretins.
• Two incretins have been identified:
1. glucose-dependent insulinotropic polypeptide (GIP) - “K
cells” in the proximal small bowel
2. glucagon-like peptide-1 (GLP-1)- L cells in the distal ileum
and colon.

HEMOSTASIS
INSULIN SECRETION:Once released, circulating GIP and
GLP-1 are degraded in circulation by a class of
enzymes known as dipeptidyl peptidase (DPPs),
especially DPP-4.
GLP-1 receptor
agonists and DPP-4
inhibitors

HEMOSTASIS
INSULIN ACTION:

HEMOSTASIS
INSULIN ACTION ON THE
TARGET CELL:

PATHOGENEISIS OF TYPE -1 DM
• Type 1 DM is the result of interactions of genetic,
environmental and immunologic factors that ultimately lead
to the destruction of the pancreatic beta cells and insulin
deficiency.
• Can develop at any age, develops most commonly before 20
years of age.
• Incidence of type 1 DM is increasing at the rate of 3–4% per
year for uncertain reasons.

Genetic Susceptibility:
• Susceptibility to type 1 DM involves multiple genes.
• Of these, the most important locus is the HLA gene cluster on
chromosome 6p21, which according to some estimates
contributes as much as 50% of the genetic susceptibility to
type 1 diabetes.
• This region contains genes that encode the class II major
histocompatibility complex (MHC) molecules which present
antigen to helper T cells and thus are involved in initiating the
immune response

Genetic Susceptibility:
• Most individuals with type 1 DM have the HLA DR3 and/or
DR4 haplotype.
• Haplotypes DQA1*0301, DQB1*0302, and DQB1*0201 are
most strongly associated with type 1 DM.
• In addition to MHC class II associations, genome association
studies have identified at least 20 different genetic loci that
contribute susceptibility to type 1 DM (polymorphisms in the
promoter region of the insulin gene, the CTLA-4 gene,
interleukin 2 receptor, CTLA4, and PTPN22)
The haplotype
DQA1*0102,DQB1*0602

Insulin Gene Locus, IDDM2:
• It is estimated that this locus accounts for approximately 10%
of the familial risk of T1DM.
• This highly polymorphic region consists of anywhere from 30
to several hundred repeats of a 14-15 bp unit sequence
(ACAGGGGTCTGGGG). A shorter number of repeats is
associated with increased risk of T1DM.
PTPN22 (Lymphoid Tyrosine Phosphatase):
• A single-nucleotide polymorphism in the PTPN22 gene on
chromosome 1p13 that encodes lymphoid tyrosine
phosphatase correlates strongly with the incidence of T1DM

Cytotoxic T Lymphocyte Antigen 4:
• The cytotoxic T lymphocyte antigen 4 (CTLA-4) gene is located
on chromosome 2q33 and is associated with T1DM and other
autoimmune disease.
• This gene is a negative regulator of T-cell activation.
Interleukin-2 Receptor:
• Single-nucleotide polymorphisms in or near the gene for the
IL-2 receptor have been found to have an association with
T1DM risk.

Interleukin-1 Receptor:
• IL-1 receptor activation and chemokines involved in
monocyte/macrophage and neutrophil chemotaxis have been
also identified as critical steps in nitric oxide–induced islet
necrosis and subsequent apoptosis.
Interferon-Induced Helicase:
• Significant association exists with T1DM as well as Graves
disease and multiple sclerosis.
CYP27B1:
• Cytochrome P450, subfamily 27, polypeptide 1 gene encodes
vitamin D 1α-hydroxylase.

Environmental Factors:
1.Viral infections:
• Have been suggested as triggers for development of the
disease.
• Some studies suggest that viruses might share epitopes with
islet antigens and the immune response to the virus results in
cross-reactivity and destruction of islet tissues, a
phenomenon known as molecular mimicry.

2.Congenital Rubella Syndrome:
• Prenatal infection with rubella is associated with β-cell
autoimmunity in up to 70%, with development of T1DM in up to
40% of infected children.
• The time lag between infection and development of diabetes may
be as high as 20 yr.
• Interestingly, there appears to be no increase in risk of diabetes
when rubella infection develops after birth or when live-virus
rubella immunization is used.

3.Enteroviruses
4. Mumps Virus
5. The Hygiene Hypothesis: Possible Protective Role of Infections
6. Diet
7. Psychologic Stress

Thus, the natural history of T1DM involves some or all of the
following stages:
1. Initiation of autoimmunity
2.Preclinical autoimmunity with progressive loss of β-cell
function
3. Onset of clinical disease
4. Transient remission
5. Established disease
6. Development of complications

Mechanisms of β Cell Destruction:
• The fundamental immune abnormality in type 1 diabetes is a
failure of self-tolerance in T cells specific for islet antigens.
• The initial activation of these cells is thought to occur in the
peripancreatic lymph nodes, perhaps in response to antigens
that are released from damaged islets.
• Multiple T-cell populations have been implicated in this
damage, including TH1 cells and CD8+ CTLs.
• The islet autoantigens that are the targets of immune attack
may include insulin, the β cell enzyme glutamic acid
decarboxylase(GAD), and islet cell autoantigen 512 (ICA512).

TYPE -2 DM
• Type 2 diabetes is a complex disease that involves an
interplay of genetic and environmental factors and a
proinflammatory state.
• Most studies support the view that insulin resistance
precedes an insulin secretory defect but that
diabetes develops only when insulin secretion
becomes inadequate.

• Genetic factors
• Environmental factors

Genetic factors:
• Type 2 DM has a strong genetic component.
• The disease is polygenic and multifactorial, because in
addition to genetic susceptibility, environmental factors.
• The genes that predispose to type 2 DM are incompletely
identified. Most prominent is a variant of the transcription
factor 7–like 2 gene.

Genetic factors:
• Genetic polymorphisms associated with type 2 DM have
also been found in the genes encoding the peroxisome
proliferator– activated receptor γ, inward rectifying
potassium channel, zinc transporter, IRS, and calpain 10.
• The mechanisms by which these genetic loci increase the
susceptibility to type 2 DM are not clear, but most are
predicted to alter islet function or development or insulin
secretion.

Environmental factors:
• The most important environmental risk factor for
type 2 diabetes is obesity, particularly central or
visceral obesity.
• Obesity contributes to the cardinal metabolic
abnormalities of diabetes and to insulin resistance
early in disease.

Metabolic Defects in Diabetes:
The two cardinal metabolic defects that characterize
type 2 diabetes are:
• Decreased response of peripheral tissues, especially
skeletal muscle, adipose tissue, and liver, to
insulin(insulin resistance)
• Inadequate insulin secretion in the face of insulin
resistance and hyperglycemia (β-cell dysfunction)

Insulin Resistance:
• Insulin resistance is the failure of target tissues to respond normally
to insulin.
Insulin resistance results in:
1. Failure to inhibit endogenous glucose production (gluconeogenesis) in
the liver, which contributes to high fasting blood glucose levels.
2. Failure of glucose uptake and glycogen synthesis to occur in skeletal
muscle following a meal, which contributes to high post-prandial
blood glucose level.
3. Failure to inhibit lipoprotein lipase in adipose tissue, leading to excess
circulating free fatty acids (FFAs), which in turn, amplify the state of
insulin resistance.

• The precise molecular mechanism leading to insulin resistance in
type 2 DM has not been elucidated.
• Reduced tyrosine phosphorylation of the insulin receptor and IRS
proteins is observed in peripheral tissues, which compromises
insulin signaling and reduces the level of the glucose transporter
GLUT-4 on the cell surface .
• In fact, one of the mechanisms by which exercise can improve
insulin sensitivity is through increased translocation of GLUT-4 to
the surface of skeletal

Obesity and Insulin Resistance:
• The risk for diabetes increases as the body mass index
increases.
• Obesity can adversely impact insulin sensitivity in numerous
ways
-Free fatty acids.
-Adipokines.
-Inflammation.

Free fatty acids:
• Excess FFAs overwhelm the intracellular fatty acid oxidation
pathways leading to accumulation of cytoplasmic
intermediates like diacylglycerol (DAG).
• These “toxic” intermediates can attenuate signaling through
the insulin receptor pathway.
• Attenuated insulin signaling allows phosphoenolpyruvate
carboxykinase to “ramp up” gluconeogenesis

Adipokines:
• A variety of proteins secreted into the systemic circulation by
adipose tissue have been identified and these are collectively
termed adipokines .
• Some of these promote hyperglycemia, and other adipokines
(such as leptin and adiponectin) decrease blood glucose, in
part by increasing insulin sensitivity in peripheral tissues.
• Adiponectin levels are reduced in obesity, thus contributing to
insulin resistance.

Inflammation:
• Proinflammatory cytokines that are secreted in response to
excess nutrients such as free fatty acid (FFAs) and glucose
results in both insulin resistance and β-cell dysfunction.
• Excess FFAs within macrophages and β cells can activate the
inflammasome, a multiprotein cytoplasmic complex that leads
to secretion of the cytokine interleukin IL-1β.
• IL-1 and other cytokines are released into the circulation and
act on the major sites of insulin action to promote insulin
resistance

β-Cell Dysfunction:
Several mechanisms have been implicated in promoting
β-cell dysfunction in type 2 diabetes, including:
• Excess free fatty acids that compromise β cell function
and attenuate insulin release (“lipotoxicity”).
• The 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.

GENETIC DEFECTS OF Β-CELL FUNCTION
A. MODY (maturity-onset diabetes of the young) syndromes
1. MODY 1 chromosome 20, HNF4α
2. MODY 2 chromosome 7, glucokinase
3. MODY 3 chromosome 12, HNF1α, TCF-1
4. MODY 4 chromosome 13, IPF-1
5. MODY 5 chromosome 17, HNF1β, TCF-2
6. MODY 6 chromosome 2q32, neuro-D1/β2
B. Mitochondrial DNA mutations (includes 1 form of Wolfram syndrome, Pearson
syndrome, Kearns-Sayre, diabetes mellitus,deafness)
C. Wolfram syndrome—DIDMOAD (diabetes insipidus, diabetesmellitus, optic atrophy,
deafness): WFS1-Wolframin—chromosome 4p
1. Wolfram locus 2—chromosome 4q22-24
2. Wolfram mitochondrial
D. Thiamine responsive megaloblastic anemia and diabetes

MATURITY-ONSET DIABETES OF YOUNG
• This subtype of DM consists of a group of heterogeneous
clinical entities that are characterized by onset before 25 yr,
autosomal dominant inheritance and a primary defect in
insulin secretion.
• Strict criteria for the diagnosis of MODY include diabetes in at
least 3 generations with autosomal dominant transmission
and diagnosis before age 25 yr in at least 1 affected subject.

MATURITY-ONSET DIABETES OF YOUTH

MITOCHONDRIAL DNA MUTATIONS
• Point mutations in mitochondrial DNA are sometimes
associated with maternally inherited DM and deafness.
• The most common mitochondrial DNA mutation in these
cases is the point mutation m.3243A>G in the transfer RNA
leucine gene.
• Diabetes in most of these cases presents insidiously but
approximately 20% of patients have an acute presentation
resembling T1DM.
• The mean age of diagnosis of diabetes is 37 yr

WOLFRAM SYNDROME
• Wolfram syndrome 1 is characterized by diabetes insipidus,
DM, optic atrophy, and deafness—thus the acronym
DIDMOAD.
• Wolfram syndrome 2 has early-onset optic atrophy, DM,
deafness, and a shortened life span but no diabetes insipidus;

DIABETES MELLITUS OF THE NEWBORN
Transient Neonatal Diabetes Mellitus:
• The syndrome of transient DM in the newborn infant has its
onset in the 1st wk of life and persists several weeks to
months before spontaneous resolution. Median duration is 12
wk.
• It occurs most often in infants who are small for gestational
age and is characterized by hyperglycemia and pronounced
glycosuria, resulting in severe dehydration.
• About 70% of cases are due to abnormalities of an imprinted
locus on chromosome 6q24. Most of the remaining cases are
caused by mutations in KATP channels

DIABETES MELLITUS OF THE NEWBORN
Permanent Neonatal Diabetes Mellitus:
• Permanent DM in the newborn period is caused in
approximately 50% of the cases by mutations in the KCNJ11
(potassium inwardly-rectifying channel J, member 11) and
ABCC8 (adenosine triphosphate–bindingcassette, subfamily C,
member 8) genes.
• The most severely affected patients have the syndrome of
developmental delay, epilepsy and neonatal diabetes(DEND
syndrome).

DIABETES MELLITUS OF THE NEW BORN
IPEX Syndrome:
• IPEX means immunodysregulation,polyendocrinopathy, and
enteropathy,X-linked.
• In most patients with IPEX, mutations in the FOXP3 (Forkhead
box P3) gene, a specific marker of natural and adaptive
regulatory T cells, leads to severe immune dysregulation and
rampant autoimmunity.
• Autoimmune diabetes develops in >90% of cases,usually
within the 1st few wk of life.

GENETIC DEFECTS OF INSULIN ACTION
Various genetic mutations in the insulin receptor can impair
the action of insulin at the insulin receptor or impair
postreceptor signaling leading to insulin resistance.
• Type A insulin resistance.
• Donohue Syndrome.
• Rabson-Mendenhall Syndrome.
• Lipoatrophic Diabetes.
• Stiff-Person Syndrome.
• Systemic Lupus Erythematosus

GESTATIONAL DIABETES
Definition:
Women who were previously euglycemic develop impaired
glucose tolerance and diabetes for the first time during
pregnancy is called gestational diabetes.
Mechanism:
Pregnancy is a “diabetogenic” state in which the prevailing
hormonal milieu favors a state of insulin resistance.

GESTATIONAL DIABETES
NICE CRITERIA FOR DIAGNOSIS OF GDM
• Fasting blood glucose level >126 mg/dl
• A blood glucose >140 mg/dl measured 2 hour after 75 gram of
oral glucose tolerenec test

The Classic Triad of Diabetes
The onset of type 1 diabetes is usually marked by the triad of polyuria, polydipsia, polyphagia, and, when
severe diabetic ketoacidosis all resulting from metabolic derangements.

COMPLICATIONS
Acute complications:
1.Diabetic ketoacidosis.
2. Hyperosmolar hyperosmotic syndrome.
3. Hypoglycemia.
Chronic complications:
1. Diabetic macrovascular disease.
2. Diabetic microvascular disease.

ACUTE METABOLIC COMPLICATIONS OF DIABETES
1.Diabetic ketoacidosis:
• Severe acute metabolic complication of type 1 diabetes.
• The most common precipitating factor is a failure to take
insulin, although other stressors such as intercurrent
infections, illness, trauma and certain drugs might also lead to
this complication.

The hyperglycemia causes an osmotic diuresis and dehydration characteristic
of the ketoacidotic state.
Infections, illness, trauma
Release of the catecholamine epinephrine
The insulin deficiency coupled with glucagon excess
causes hyperglycemia.

• The second major effect of insulin deficiency is activation of
the ketogenic machinery.

• The clinical manifestations of diabetic ketoacidosis include fatigue, nausea
and vomiting, severe abdominal pain, a characteristic fruity odor, and
deep, labored breathing(also known as Kussmaul breathing).

2.HYPEROSMOLAR HYPEROSMOTIC SYNDROME:
• Type 2 diabetics may develop a condition known as
hyperosmolar hyperosmotic syndrome (HHS) due to severe
dehydration resulting from sustained osmotic diuresis.
• Furthermore, the absence of ketoacidosis and its symptoms
(nausea, vomiting, Kussmaul breathing) delays the seeking of
medical attention.
• The hyperglycemia is usually more severe than in diabetic
ketoacidosis, in the range of 600 to1200 mg/Dl.

3.HYPOGLYCEMIA:
• The most common acute metabolic complication.
• Usually as a result of having missed a meal, excessive physical
exertion, an excess insulin administration, or during the phase
of dose finding for antidiabetic agents.
• The signs and symptoms of hypoglycemia include
dizziness,confusion, sweating, palpitations, and tachycardia; if
hypoglycemia persists, loss of consciousness may occur.

CHRONIC METABOLIC COMPLICATIONS OF DIABETES

• At least four distinct mechanisms have been implicated in the
deleterious effects of persistent hyperglycemia on peripheral
tissues
1. Formation of Advanced Glycation End Products.
2. Activation of Protein Kinase C.
3. Oxidative Stress and Disturbances in Polyol Pathways.
4. Hexosamine Pathways and Generation of Fructose-6-
Phosphate.

1.Formation of Advanced Glycation End Products:
• Advanced glycation end products (AGEs) are formed as a
result of nonenzymatic reactions between intracellular
glucose derived dicarbonyl precursors with the amino groups
of both intracellular and extracellular proteins.
• AGEs bind to a specific receptor (RAGE) that is expressed on
inflammatory cells (macrophages and T cells), endothelium,
and vascular smooth muscle.

1.Formation of Advanced Glycation End Products:The
detrimental effects of the AGE-RAGE signaling axis within the
vascular compartment include:
1. Release of cytokines and growth factors.
2. Generation of reactive oxygen species (ROS) in endothelial
cells.
3. Increased procoagulant activity on endothelial cells and
macrophages.
4. Enhanced proliferation of vascular smooth muscle cells and
synthesis of extracellular matrix.

• In addition to receptor-mediated effects, AGEs can directly
cross-link extracellular matrix proteins.
• Crosslinking of collagen type I molecules in large vessels
decreases their elasticity, which may predispose these vessels
to shear stress and endothelial injury.
• AGE-induced cross-linking of type IV collagen in basement
membrane decreases endothelial cell adhesion and increases
extravasation of fluid.
• AGE-modified matrix components also trap nonglycated
plasma or interstitial proteins(accelerating atherogenesis,
diabetic microangiopathy).

2. Activation of Protein Kinase C:
• Intracellular hyperglycemia stimulates the de novo synthesis
of DAG from glycolytic intermediates, and hence causes
excessive PKC activation.
• The downstream effects of PKC activation are numerous,
including production of VEGF, TGF-β, and the procoagulant
protein plasminogen activator inhibitor-1 (PAI-1) by the
vascular endothelium.

3. Oxidative Stress and Disturbances in Polyol Pathways:
• Even in some tissues that do not require insulin for glucose
transport (e.g., nerves, lenses, kidneys, blood vessels),
persistent hyperglycemia in the extracellular milieu leads to
an increase in intracellular glucose.
• This excess glucose is metabolized by the enzyme aldose
reductase to sorbitol, a polyol, and eventually to fructose, in a
reaction that uses NADPH (the reduced form of nicotinamide
dinucleotide phosphate) as a cofactor.

4. Hexosamine Pathways and Generation of Fructose-6-
Phosphate:
• Finally it is postulated that hyperglycemia induced flux
through the hexosamine pathway increases intracellular levels
of fructose-6-phosphate, which is a substrate for glycosylation
of proteins, leading to generation of excess proteoglycans.
• These glycosylation changes are accompanied by abnormal
expression of TGFβ or PAI-1 which further exacerbate the end-
organ damage.

MORPHOLOGY
PANCREAS:
TYPE 1 DM:
•Reduction in the number and size of
islets
•Leukocytic infiltrates in the islets
TYPE 2 DM:
•Subtle reduction in islet cell mass,
demonstrated only by special
morphometric studies.
•Amyloid deposition within islets in
type 2 diabetes
An increase in the number and size of
islets is especially characteristic of
nondiabetic newborns of diabetic
mothers
INSULITIS
AMYLOID DEPOSITION

MORPHOLOGY
Diabetic Macrovascular Disease:
• The hallmark of diabetic macrovascular disease is accelerated
atherosclerosis involving the aorta and large- and medium-
sized arteries.
• Myocardial infarction caused by atherosclerosis of the
coronary arteries is the most common cause of death in
diabetics.
• Gangrene of the lower extremities, as a result of advanced
vascular disease is about 100 times more common in
diabetics than in the general population.

MORPHOLOGY
Diabetic Microangiopathy:
• One of the most consistent morphologic features of diabetes
is diffuse thickening of basement membranes.
• The microangiopathy underlies the development of diabetic
nephropathy, retinopathy, and some forms of neuropathy.

MORPHOLOGY
Diabetic Nephropathy:
• The kidneys are prime targets of diabetes.
Three lesions are encountered:
1. Glomerular lesions.
2. Renal vascular lesions.
3. Pyelonephritis

Diabetic Nephropathy
1. Glomerular lesions: The most important glomerular
lesions
• Capillary basement membrane thickening
• Diffuse mesangial sclerosis
• Nodular glomerulosclerosis.

Capillary Basement Membrane Thickening:
• Widespread thickening of the glomerular capillary basement
membrane(GBM) occurs in virtually all cases of diabetic
nephropathy and is part and parcel of the diabetic
microangiopathy.

Diffuse Mesangial Sclerosis:
• This lesion consists of diffuse increase in mesangial matrix.
• The mesangial increase is typically associated with the overall
thickening of the GBM.The matrix depositions are PAS-
positive.
• The progressive expansion of the mesangium has been shown
to correlate well with measures of deteriorating renal
function such as increasing proteinuria.

Nodular Glomerulosclerosis: This is also known as intercapillary
glomerulosclerosis or Kimmelstiel-Wilson disease.
• The glomerular lesions take the form of ovoid or spherical, often
laminated nodules of matrix situated in the periphery of the glomerulus.
The nodules are PAS-positive.

• They lie within the mesangial core of the glomerular lobules and
can be surrounded by patent peripheral capillary loops
• As the disease advances, the individual nodules enlarge and may
eventually compress and engulf capillaries, obliterating the
glomerular tuft.
• These nodular lesions are frequently accompanied by prominent
accumulations of hyaline material in capillary loops (“fibrin caps”)
or adherent to Bowman capsules (“capsular drops”).

• As a consequence of the glomerular and arteriolar lesions, the
kidney suffers from ischemia, develops tubular atrophy and
interstitial fibrosis, and usually undergoes overall contraction
in size

Hyaline arteriolosclerosis:
• The vascular lesion associated with hypertension is both more prevalent
and more severe in diabetics than in nondiabetics.
• It takes the form of an amorphous hyaline thickening of the wall of the
arterioles which causes narrowing of the lumen.

• Pyelonephritis is an acute or chronic inflammation of the
kidneys that usually begins in the interstitial tissue and then
spreads to affect the tubules.
• One special pattern of acute pyelonephritis,necrotizing
papillitis (or papillary necrosis), is much more prevalent in
diabetics than in nondiabetics.

OPHTHALMOLOGIC COMPLICATIONS OF
DIABETES MELLITUS
DIABETIC RETINOPATHY:
• It refers to changes seen in patients with diabetes mellitus.
• DM is the leading cause of blindness between the ages of 20
and 74
Risk factors:
• Duration of diabetes mellitus
• Poor metabolic control
• Hereditary
• Pregnancy
• Hypertension
• Other risk factors(smoking,obesity,anemia,hyperlipidemia)

DIABETIC RETINOPATHY
Classification:
1. Non-proliferative diabetic retinopathy
2. Proliferative diabetic retinopathy
3. Diabetic maculopathy
4. Advanced diabetic eye disease

1.NON-PROLIFERATIVE DIABETIC RETINOPATHY: includes a
spectrum of changes resulting from structural and functional
abnormalities of retinal vessels (i.e., confined beneath the
internal limiting membrane of the retina).
-Microanerysms
-Retinal hemorrhage
-Oedema
-Hard exudates
-Cotton-wool spots
-Venous abnormalities
-Intraretinal microvascular abnormalities
-Dark –blot hemorrhages.

2.PROLIFERATIVE DIABETIC RETINOPATHY:
• is defined by the appearance of new vessels sprouting on the
surface of either the optic nerve head or the surface of the
retina.
• The term “retinal neovascularization” is only applied when
the newly formed vessels breach the internal limiting
membrane of the retina.
• The neovascularisation leads to retinal detachment and
neovascular glaucoma.

DIABETIC NEUROPATHY
• Diabetes is the most common cause of peripheral neuropathy.
• The most common is an ascending distal symmetric
sensorimotor polyneuropathy.
PATHOGENESIS:
• Excess glucose within cells is reduced to sorbitol, a process
that depletes NADPH and increases intracellular osmolality.
These and other metabolic disturbances may predispose
peripheral nerves to injury by reactive oxygen species.

DIABETIC NEUROPATHY MORPHOLOGY
•Nerve biopsies show reduced
numbers of axons. Variable
degrees of ongoing axonal
damage, marked by
degenerating myelin sheaths.
•Endoneurial arterioles show
thickening, hyalinization and
intense periodic acid–Schiff
positivity.

OTHER COMPLICATIONS OF DIABETES
GASTROINTESTINAL/GENITOURINARY DYSFUNCTION:
• The most prominent GI symptoms are delayed gastric
emptying (gastroparesis) and altered small- and large-bowel
motility (constipation or diarrhea).
• Parasympathetic dysfunction secondary to chronic
hyperglycemia is important in the development of
gastroparesis, hyperglycemia itself also impairs gastric
emptying.

GASTROINTESTINAL/GENITOURINARY DYSFUNCTION:
• Diabetic autonomic neuropathy may lead to genitourinary
dysfunction including cystopathy and female sexual
dysfunction
• Symptoms of diabetic cystopathy begin with an inability to
sense a full bladder and a failure to void completely.
• Erectile dysfunction and retrograde ejaculation are very
common in DM and may be one of the earliest signs of
diabetic neuropathy.

INFECTIONS:
• Individuals with DM have a greater frequency and severity of
infection.
• The reasons for this include incompletely defined
abnormalities in cell-mediated immunity and phagocyte
function associated with hyperglycemia, as well as diminished
vascularization.
• Several rare infections are seen almost exclusively in the
diabetic population. Examples of this category include
rhinocerebral mucormycosis, emphysematous infections of
the gallbladder and urinary tract, and “malignant” or invasive
otitis externa

DERMATOLOGIC MANIFESTATIONS:
1. xerosis and pruritus
2. pigmented pretibial papules, or “diabetic skin spots,”
3. Bullosa diabeticorum
4. Necrobiosis lipoidica diabeticorum
5. Acanthosis nigricans
6. granuloma annulare
7. sclerederma

References
• Robbins and cotran pathological basis of disease
9thedition.
• Nelson textbook of pediatrics , 20th edition.
• Harrison’s prinicples of internal medicine ,19th
edition.
• Textbook of biochemistry for medical students,7th
edition.

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