Pathophysiology Of DM

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 OUTLINE

-Introduction
-Definition of DM
-Epidemology
-Pathophysiology
-Clinical Feature
- Late complication of DM

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 INTRODUCTION
The endocrine pancreas consists of about 1 million the islets of
Langerhans,
four major cell types-, , , and PP (pancreatic polypeptide) cells.
cell produces insulin- potent anabolic hormone with multiple synthetic
and growth-promoting effects
cell secretes glucagon, inducing hyperglycemia by its glycogenolytic
activity in the liver
cells contain somatostatin, which suppresses both insulin and glucagon
release
PP cells contain a unique pancreatic polypeptide (vasoactive intestinal
peptide, VIP) , stimulation of secretion of gastric and intestinal enzymes
and inhibition of intestinal motility.
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 DIABETES MELLITUS
Diabetes mellitus is a chronic disorder characterized by the
impaired metabolism of glucose & other energy-yielding fuels as
well as by the late development of vascular and neuropathic
complications
Diabetes comprises a group of disorders involving distinct
pathogenic mechanisms, for which hyperglycemia is the common
denominator
Regardless of its cause, the disease is associated with insulin
deficiency, which may be absolute or relative in the context of
coexisting insulin resistance
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 Epidemiology
Type 2 DM far more prevalent than Type 1 DM
Worldwide prevalence of DM risen dramatically over the past two
decades,
From an estimated 30 million cases in 1985 to 177 million in 2000
Prevalence of type 2 DM is rising much more rapidly because of increasing
obesity and reduced activity levels
Prevalence & incidence of DM in Ethiopia clearly on the rise in
the past few decades
Between 1975 & 1979 prevalence was reported to be 1.2% (1.4% in
males & 0.3% in females )

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 CNT...
The chronic hyperglycemia and attendant metabolic dysregulation
of diabetes mellitus associated with secondary damage in the
kidneys, eyes, nerves, and blood vessels.
Diabetes affects an estimated 21 million people in the United States
(or nearly 7% of the population).
Diabetes is a leading cause of end-stage renal disease, adult-onset
blindness, and nontraumatic lower extremity amputations .
It also greatly increases the risk of developing coronary artery
disease and cerebrovascular disease.
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 CONT...
Criteria for the Diagnosis of Diabetes Mellitus
At least one of the following
Symptoms of diabetes plus Random Blood Glucose(RBS) concentration 200
mg/dL or
Fasting plasma glucose(FBS) 126 mg/dL or
Two-hour plasma glucose 200 mg/dL during an oral glucose tolerance test or
A1C greater or equal to 6.5%
In person with impaired glucose tolerance need to have follow up.

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 CLASSIFICATION OF DIABETES MELLITUS
Classified on the basis of the pathogenic process that leads to
hyperglycemia
1. Type 1 diabetes
Autoimmune pancreatic -cell destruction & characterized by
absolute insulin deficiency
2. Type 2 diabetes
Characterized by variable degrees of insulin resistance, impaired
insulin secretion, & increased glucose production

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 CONT..
3. Other specific types
Genetic defects of -cell function
Genetic defects in insulin action
Disease of the exocrine pancreas
e.g., pancreatitis, trauma, pancreatectomy, neoplasia, cystic fibrosis,
hemochromatosis
Endocrinopathies
e.g., Cushing's syndrome, hyperthyroidism, pheochromocytoma, glucagonoma, etc
Drug or chemical induced
e.g., glucocorticoids, thyroid hormone, -adrenergic agonists, thiazides, etc
4. Gestational diabetes mellitus

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 Normal Insulin physiology&Glucose hemeostasis
Normal glucose homeostasis is tightly regulated by three interrelated
processes: (1) glucose production in the liver,
(2) glucose uptake and utilization by peripheral tissues,
chiefly skeletal muscle, and,
(3) actions of insulin and counter-regulatory hormones (e.g.,
glucagon).
The principal metabolic function of insulin is to increase the rate of
glucose transport into certain cells in the body . These are the
striated muscle cells (including myocardial cells) and, adipocytes, .
Glucose uptake in other peripheral tissues, most notably the brain,
is insulin independent.
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 CONT...
Insulin Secretion and Action
Insulin is synthesized in pancreatic cells
Glucose concentration is the key regulator of insulin secretion
Insulin acts on its target tissues (liver, muscle, and fat, primarily) through a
specific insulin receptor
Facilitates glucose uptake into cells
Promotes the storage of carbohydrate and fat and protein synthesis
Counter-regulatory hormones oppose the metabolic actions of insulin
Include glucagon, growth hormone, cortisol, and catecholamines
Tend to increase glucose concentration in the blood

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 CONT...
Metabolic Effects of Insulin
Glucose homeostasis reflects a balance between hepatic glucose production and
peripheral glucose uptake and utilization
In the fasted state, low basal insulin levels result in diminished glucose uptake in
peripheral insulin-sensitive tissues (e.g., muscle and fat)
Maintenance of stable blood glucose levels is achieved through the release of glucose by
the liver (to a small extent kidney) by glycogenolysis and gluconeogenesis
stimulated by Glucagon
Fed State Insulin released
Stimulation of hepatic glucose uptake
Acceleration of glucose uptake by peripheral tissues
promotes the storage of carbohydrate and fat and protein synthesis

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 Metabolic Defects in Diabetes

Fasting Hyperglycemia
Results from an inappropriate increase in hepatic glucose production due to
accelerated gluconeogenesis
Insulin deficiency and unopposed effect of counter-regulatory hormones
Fasting free fatty acid levels are also elevated in diabetes because of accelerated
mobilization of fat stores
Postprandial Hyperglycemia
Impaired suppression of hepatic glucose production and the liver's ability to store
glucose as glycogen

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 Pathogenesis
Type 1 Diabetes
Absolute deficiency of insulin
results from an interplay of genetic, environmental, & autoimmune factors that
selectively destroy insulin-producing cells
Genetic Factors
Identical twins show concordance rates of 30 to 40%
Many of the genes linked to type 1 diabetes have not been identified
HLA genes clearly play a dominant role
90 to 95% of type 1 patients express HLA molecules

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 CONT..
Environmental Factors
Diet and toxins have been proposed as triggers of diabetes
Epidemics of mumps, congenital rubella, and coxsackievirus infection have been
associated with an increased frequency of type 1 diabetes
Autoimmune Factors
About 80% of patients with new-onset type 1 diabetes have islet cell antibodies
Antibodies to a variety of -cell constituents have been identified
-Cell destruction is mediated by a variety of cytokines or by direct T-lymphocyte
activity targeting specific -cell antigens
Diabetes does not become evident until a majority of beta cells are destroyed
(~90%)

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Temporal model for development of type 1 diabetes

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 Pathogenesis of Type 2 DM
Insulin resistance and abnormal insulin secretion( with resultant ralative insulin
deficiency) are central to the development of type 2 DM
Has a strong genetic component than type 1
Concordance in identical twins is between 50 and 90%
Individuals with a parent with type 2 DM have an increased risk of diabetes;
Both parents with type 2 DM, the risk approaches 40%
Environmental factors (such as obesity, nutrition, and physical activity) modulate
genetic predisposition
Obesity, particularly central , is very common in type 2 DM

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 CONT...
The two metabolic defects that characterize type 2 diabetes
are
(1) a decreased ability of peripheral tissues to respond to
insulin (insulin resistance)
(2) -cell dysfunction that is manifested as inadequate insulin
secretion in the face of insulin resistance and hyperglycemia .
In most cases, insulin resistance is the primary event and is
followed by increasing degrees of -cell dysfunction.

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 CONT..
Insulin resistant afect 10 -20 yrs before onset of DM in
predisposed people.
Influnce by genetic and enviromental
Adipocyte releaseFFA and protiens such as
adipocytokin/resistin,adiponectin and leptin
Thiazolidinedione is anti-diabetic act on adipocyte to decrease
FFA
In general Insulin resistant is complex and multifactorial.
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 -cell dysfunction in type 2 diabetes - inability of these cells to
adapt themselves to the long-term demands of peripheral
insulin resistance and increased insulin secretion.
The underlying bases for failure of -cell adaptation is not
known, although it is postulated , including adverse effects of
high circulating FFAs ("lipotoxicity") or chronic hyperglycemia
("glucotoxicity"), may have a role.

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 -cell dysfunction T2 DM both qualitative and quantitative aspects.
Qualitative -cell dysfunction - Over time, the secretory defect
progresses to encompass all phases of insulin secretion, and even
though some basal insulin secretion persists in type 2 diabetes, it is
inadequate for overcoming insulin resistance.
Quantitative -cell dysfunction is manifest as a decrease in -cell
mass, islet degeneration, and deposition of islet amyloid. Islet
amyloid protein (amylin) is a characteristic finding in individuals
with type 2 diabetes, and it is present in more than 90% of diabetic
islets examined.
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 Pathogenesis of complication of DM
complications of diabetes are a consequence of the metabolic
derangements, mainly hyperglycemia.
three distinct metabolic pahway in the pathogenesis of long-term
diabetic complications,
1. Non-enzymatic glycosylation. glucose chemically attaches to free
amino groups of proteins without the aid of enzymes.
The early glycosylation products of collagen and other long-lived
proteins in interstitial tissues and blood vessel walls undergo
chemical rearrangements to form irreversible advanced
glycosylation end products (AGEs).
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 CONT...
AGE formation on collagen causes cross-links between
polypetides; trap nonglycosylated plasma and interstitial
proteins.
trapping low-density lipoprotein, for example, retards its
efflux from the vessel wall and enhances the deposition of
cholesterol in the intima, thus accelerating atherogenesis.

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 Cont...
In capillaries, including those of renal glomeruli, basement membrane
thickening characteristic of diabetic glomerulopathy
Circulating plasma proteins are modified by the addition of AGE residues;
bind to AGE receptors (endothelial cells, mesangial cells, macrophages).
The effect include
(1) release of cytokines and growth factors from macrophages and
mesangial cells;
(2) increased endothelial permeability
(3) increased procoagulant activity on endothelial cells and
macrophages; and
(4) enhanced proliferation and synthesis of extracellular matrix by
fibroblasts and smooth muscle cells.
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 CONT...
2. Activation of protein kinase C by calcium ions and the second
messenger diacylglycerol (DAG) is an important signal transduction
pathway in many cellular systems.
The down-stream effects of PKC activation are numerous
include production of pro-angiogenic molecules ; vascular
endothelial growth factor- neovascularization seen in diabetic
retinopathy,
and pro-fibrogenic molecules like transforming growth factor -
increased deposition of extracellular matrix and basement
membrane material.
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 CONT...
3. Intracellular hyperglycemia . In tissues that do not require
insulin for glucose transport (e.g., nerves, lens, kidneys, blood
vessels), hyperglycemia w/c metabolized by enzyme aldose
reductase to sorbitol, a polyol, and eventually to fructose.
causing cell injury via increased intracellular osmolarity and
water influx,
an increase in cellular susceptibility to oxidative stress. This is
because intracellular antioxidant reserves are diminished in the
course of sorbitol metabolism.

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Morphology of Diabetes and Its Late Complications
Pathologic findings is variability in the time of onset of these
complications, their severity, and the particular organ or organs
involved.
morphologic changes are likely to be found in;
- arteries (macrovascular disease),
-basement membranes of small vessels (microangiopathy),
- kidneys (diabetic nephropathy),
- retina (retinopathy),
- nerves (neuropathy), and other tissues.
These changes are seen in both type 1 and type 2 diabetes .
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 CONT...
Pancrease; Lesions in the pancreas are inconstant and rarely of diagnostic
value.
Distinctive changes are more commonly associated with type 1 than with
type 2 diabetes.
- Reduction in the number and size of islets. This is most often seen in
type 1 diabetes. Most of the islets are small, inconspicuous, and not easily
detected.
-Leukocytic infiltration of the islets (insulitis) principally composed of T
lymphocytes similar to that in animal models of autoimmune diabetes (Fig.
20-26A). This may be seen in type 1 diabetics at the time of clinical
presentation. The distribution of insulitis may be strikingly uneven.

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 CONT...
In type 2 diabetes there may be a subtle reduction in islet cell mass.
Amyloid replacement of islets in long-standing type 2 diabetes
appears as deposition of pink, amorphous material beginning in
and around capillaries and between cells.
At advanced stages the islets may be virtually obliterated ; fibrosis
may also be observed.
Similar lesions may be found in elderly nondiabetics, apparently as
part of normal aging.
An increase in the number and size of islets is characteristic of
nondiabetic newborns of diabetic mothers. Presumably, fetal islets
undergo hyperplasia in response to the maternal hyperglycemia.
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 CONT...
Diabetic Macrovascular Disease;
The hallmark of diabetic macrovascular disease is accelerated
atherosclerosis affecting the aorta and large and medium-sized
arteries.
Myocardial infarction, 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.
.

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 CONT...
The larger renal arteries are also subject to severe atherosclerosis,
but the most damaging effect of diabetes on the kidneys is at the
level of the glomeruli and the microcirculation.
Hyaline arteriolosclerosis, is both more prevalent and more severe
in diabetics than in nondiabetics,not specific.
It takes the form of an amorphous, hyaline thickening of the wall
of the arterioles, which causes narrowing of the lumen . Not
surprisingly, in diabetics it is related not only to the duration of the
disease but also to the level of blood pressure
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 CONT...
Diabetic Microangiopathy. One of the most consistent
morphologic features of diabetes is diffuse thickening of basement
membranes.
The capillaries of the skin, skeletal muscle, retina, renal glomeruli,
and renal medulla are affected.
also be seen in renal tubules, the Bowman capsule, peripheral
nerves, and placenta.
despite the increase in the thickness of basement membranes,
diabetic capillaries are more leaky than normal to plasma
proteins.
.
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 CONT...
Diabetic Nephropathy. Renal failure is second only to
myocardial infarction as a cause of death from this disease.
Three lesions are encountered: (1) glomerular lesions; (2)
renal vascular lesions, principally arteriolosclerosis; and (3)
pyelonephritis, including necrotizing papillitis. glomerular
lesions -capillary basement membrane thickening,
- diffuse mesangial sclerosis,
-and nodular glomerulosclerosis

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 CONT...
Diffuse mesangial sclerosis ;increase in mesangial matrix along with mesangial
cell proliferation awith basement membrane thickening.
It is found in most individuals with disease of more than 10 years' duration.
manifest as nephrotic syndrome, characterized by proteinuria,
hypoalbuminemia, and edema
Nodular glomerulosclerosis describe by ball-like deposits of a laminated matrix
situated in the periphery of the glomerulus.
approximately 15% to 30% of long-term diabetics
is a major cause of morbidity and mortality. Diffuse mesangial sclerosis may also
be seen in association with old age and hypertension.
is essentially pathogonomic of diabetes. Both the diffuse and the nodular forms
of glomerulosclerosis induce sufficient ischemia to cause scarring of the kidneys.

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 CONT...
Renal atherosclerosis and arteriolosclerosis . The kidney is one of the
most frequently and severely affected organs.
Hyaline arteriolosclerosis affects not only the afferent but also the
efferent arterioles. Such efferent arteriolosclerosis is rarely if ever
encountered in persons who do not have diabetes.
Pyelonephritis is an acute or chronic inflammation of the kidneys that
usually begins in the interstitial tissue and then spreads to affect the
tubules.
more common in diabetics than in the general population,
One special pattern of acute pyelonephritis, necrotizing papillitis (or
papillary necrosis), is much more prevalent in diabetics than in
nondiabetics

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 CONT...
Ocular Complications of Diabetes. Visual impairment, sometimes
even total blindness, is one of the more feared consequences of
long-standing diabetes.
The ocular involvement
- retinopathy,
- cataract formation, or glaucoma.
Retinopathy, the most common pattern, The lesion in the retina
takes two forms: nonproliferative (background) retinopaty and
proliferative retinopathy

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 CONT...
Nonproliferative retinopathy includes
- intraretinal or preretinal hemorrhages,
-retinal exudates, microaneurysms, venous dilations, edema,
and, most importantly, thickening of the retinal capillaries (micro-
angiopathy).
The microaneurysms are saccular dilations of retinal choroidal capillaries
that appear through the ophthalmoscope as small red dots.
Dilations tend to occur at focal points of weakening, resulting from loss of
pericytes.
Retinal edema presumably results from excessive capillary permeability.

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 CONT...
proliferative retinopathy is a process of neovascularization
and fibrosis. This lesion leads to serious consequences,
including blindness.
o Vitreous hemorrhages can result from rupture of newly
formed capillaries; the resultant organization of the
hemorrhage can pull the retina off its substratum (retinal
detachment).

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 CONT...
Diabetic Neuropathy. The central and peripheral nervous
systems are not spared by diabetes.
The most frequent pattern of involvement is a peripheral,
symmetric neuropathy of the lower extremities that affects
both motor and sensory function but particularly the latter.
Other forms which produces disturbances in bowel and
bladder function and sometimes sexual impotence, and
diabetic mononeuropathy, which may manifest as sudden
footdrop, wristdrop, or isolated cranial nerve palsies.
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 Clinical Features
Type 1 DM
Classically, symptoms appear abruptly (i.e., during days or weeks) in previously
healthy, non-obese children or young adults (Onset usually below 30 yrs of age)
Polyuria & polydypsia
Consequence of osmotic diuresis secondary to sustained hyperglycemia.
Results in a loss of glucose as well as free water and electrolytes in the urine
Weight loss, despite normal or increased appetite,
Blurred vision, which often develops as the lenses and retinas are exposed to
hyperosmolar fluids.
May also present with ketoacidosis
An acute illness (infection ,physical stress etc) may speed the transition from the
preclinical phase to clinical disease.

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 CONT
Type 2 Diabetes
Insidious onset of hyperglycemia and thus relatively asymptomatic initially
Presence of obesity or a strongly positive family history of diabetes
suggests type 2 diabetes
Diabetes may be detected only after glycosuria or hyperglycemia is noted
during routine laboratory studies
Chronic skin infections & generalized pruritus and symptoms of vaginitis
are frequent initial complaints of women with type 2 diabetes
Due to long standing(usually decades) asymptomatic hyperglycemia most
patients present with features of chronic complications

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 Cont..
In both forms of long-standing
- as myocardial infarction,
- renal vascular insufficiency, and
- cerebrovascular accidents are the most common causes of mortality.
in fact, diabetics have a 3 to 7.5 times greater incidence of death from cardiovascular causes than
nondiabetic pt.
Diabetic nephropathy is a leading cause of end-stage renal disease in the United States.
The earliest manifestation of diabetic nephropathy (>30 mg/day, but <300 mg/day; i.e.,
microalbuminuria).
Without specific interventions, approximately 80% of type 1 diabetics and 20% to 40% of type 2
diabetics will develop overt nephropathy with macroalbuminuria (>300 mg/day) over the next 10 to
15 years, usually accompanied by the appearance of hypertension.
By 20 years after diagnosis, more than 75% of type 1 diabetics and about 20% of type 2 diabetics
with overt nephropathy will develop end-stage renal disease, requiring dialysis or renal
transplantation.

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 Cont..
Visual impairment, sometimes total blindness, is one of the more feared consequences of
long-standing diabetes.
is currently the fourth leading cause of acquired blindness in the United States.
Approximately 60% to 80% of patients develop some form of diabetic retinopathy 15 to 20
years after diagnosis.
Diabetic neuropathy typically presents with decreased sensation in the distal extremities
with less evident motor abnormalities (sensorimotor neuropathy).
The loss of pain sensation can result in the development of ulcers that heal poorly and are a
major cause of morbidity.
20% to 40% of diabetics also develop autonomic dysfunction over time, impediments in
bowel and bladder control.
Enhanced susceptibility to infections of the skin, as well as to tuberculosis, pneumonia, and
pyelonephritis. Such infections cause the deaths of about 5% of diabetics. .

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Discussion question
Describe the d/f b/n T1 and T2 DM?

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The End SMILE!

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