S-KHALILZADEH
BIOCHEMISTRY AND MOLECULAR
CELL BIOLOGY
 All forms of diabetes, both inherited and acquired, are
characterized by hyperglycemia, a relative or absolute
lack of insulin, and the development of diabetesspecific microvascular pathology in the retina, renal
glomerulus, and peripheral nerve
 Diabetes is also associated with accelerated
atherosclerotic macrovascular disease affecting
arteries that supply the heart, brain, and lower
extremities. Pathologically, this condition resembles
macrovascular disease in nondiabetic patients, but it
is more extensive and progresses more rapidly.
 As a consequence of its microvascular pathology,
diabetes mellitus is now the leading cause of new
blindness in people 20 to 74 years of age and the leading
cause of end-stage renal disease (ESRD).
 More than 60% of diabetic patients are affected by
neuropathy, which includes distal symmetrical
polyneuropathy (DSPN), mononeuropathies, and a
variety of autonomic neuropathies causing erectile
dysfunction, urinary incontinence, gastroparesis, and
nocturnal diarrhea.
 Accelerated lower extremity arterial disease in
conjunction with neuropathy makes diabetes mellitus
account for 50% of all nontrauma amputations in the
United States.
 The risk of cardiovascular complications is
increased by twofold to sixfold in subjects with
diabetes.
 Overall, life expectancy is about 7 to 10 years
shorter than for people without diabetes mellitus
because of increased mortality from diabetic
complications
 Large prospective clinical studies show a strong
relationship between glycemia and diabetic
microvascular complications in both type 1 diabetes
mellitus (T1DM) and type 2 diabetes (T2DM). There
is a continuous, though not linear, relationship
between level of glycemia and the risk of
development and progression of these
complications .Hyperglycemia and the
consequences of insulin resistance both appear to
play important roles in the pathogenesis of
macrovascular complications
Shared Pathophysiologic Features
of Microvascular Complications
 In the retina, glomerulus, and vasa nervorum,
diabetes-specific microvascular disease is
characterized by similar pathophysiologic
features.
Requirement for Intracellular Hyperglycemia
2. Abnormal Endothelial Cell Function
3. Increased Vessel Wall Protein Accumulation
4. Microvascular Cell Loss and Vessel Occlusion
1.
Requirement for Intracellular Hyperglycemia
 Clinical and animal model data indicate that
chronic hyperglycemia is the central initiating
factor for all types of diabetic microvascular
disease. Duration and magnitude of
hyperglycemia are both strongly correlated with
the extent and rate of progression of diabetic
microvascular disease
 In the Diabetes Control and Complications Trial
(DCCT), for example, T1DM patients whose intensive
insulin therapy resulted in hemoglobin A1c (Hb A1c)
levels 2% lower than those receiving conventional
insulin therapy had a 76% lower incidence of
retinopathy, a 54% lower incidence of nephropathy, and
a 60% reduction in neuropathy
 Although all diabetic cells are exposed to elevated levels
of plasma glucose, hyperglycemic damage is limited to
those cell types (e.g., endothelial cells) that develop
intracellular hyperglycemia
Abnormal Endothelial Cell Function
 Early in the course of diabetes mellitus, before
structural changes are evident, hyperglycemia
causes abnormalities in blood flow and vascular
permeability in the retina, glomerulus, and
peripheral nerve vasa nervorum
 Early in the course of diabetes, increased
permeability is reversible; as time progresses,
however, it becomes irreversible.
Increased Vessel Wall Protein
Accumulation
 The common pathophysiologic feature of diabetic
microvascular disease is progressive narrowing
and eventual occlusion of vascular lumina, which
results in inadequate perfusion and function of
the affected tissues. Early hyperglycemia-induced
microvascular hypertension and increased
vascular permeability contribute to irreversible
microvessel occlusion by three processes.
CONTINUE
 The first process is an abnormal leakage of periodic acid–
Schiff (PAS)-positive, carbohydrate-containing plasma
proteins, which are deposited in the capillary wall and can
stimulate perivascular cells such as pericytes and
mesangial cells to elaborate growth factors and
extracellular matrix
 The second is extravasation of growth factors, such as
transforming growth factor β1 (TGF-β1), which directly
stimulates overproduction of extracellular matrix
components[15] and can induce apoptosis in certain
complication-relevant cell types.
 The third is hypertension-induced stimulation of
pathologic gene expression by endothelial cells and
supporting cells, which include GLUT1 glucose
transporters, growth factors, growth factor receptors,
extracellular matrix components, and adhesion molecules
that can activate circulating leukocytes
Microvascular Cell Loss and Vessel
Occlusion
 The progressive narrowing and occlusion of diabetic
microvascular lumina are also accompanied by
microvascular cell loss
 In the retina, diabetes mellitus induces programmed
cell death of Müller cells and ganglion cells,[19]
pericytes, and endothelial cells.[20] In the glomerulus,
declining renal function is associated with
widespread capillary occlusion and podocyte loss, but
the mechanisms underlying glomerular cell loss are
not yet known. In the vasa nervorum, endothelial cell
and pericyte degeneration occur,[21] and these
microvascular changes appear to precede the
development of diabetic peripheral neuropathy.[
Development of Microvascular Complications
during Posthyperglycemic Euglycemia
 Another common feature of diabetic
microvascular disease has been termed
hyperglycemic memory, or the persistence or
progression of hyperglycemia-induced
microvascular alterations during subsequent
periods of normal glucose homeostasis
 In contrast, lower levels of hyperglycemia made
patients more resistant to damage from
subsequent higher levels.
Genetic Determinants of Susceptibility
to Microvascular Complications
 Clinicians have long observed that
different patients with similar
duration and degree of hyperglycemia
differ markedly in their susceptibility
to microvascular complications
Pathophysiologic Features of
Macrovascular Complications
 Unlike microvascular disease, which occurs only in
patients with diabetes mellitus, macrovascular
disease resembles that in subjects without diabetes
 However, subjects with diabetes have more rapidly
progressive and extensive cardiovascular disease
(CVD), with a greater incidence of multivessel disease
and a greater number of diseased vessel segments
than nondiabetic persons
 The importance of hyperglycemia in the pathogenesis
of diabetic macrovascular disease is suggested by the
observation that glycohemoglobin A1 is an
independent risk factor for CVD
 Insulin resistance occurs in the majority of patients
with T2DM and in two thirds of subjects with impaired
glucose tolerance.Both these groups have a
significantly higher risk of developing CVD
 Insulin resistance is commonly associated with a
proatherogenic dyslipidemia
 Insulin resistance is associated with a characteristic
lipoprotein profile that includes a high very-lowdensity lipoprotein (VLDL), a low high-density
lipoprotein (HDL), and small, dense LDL.
Mechanisms of Hyperglycemia-Induced
Damage
Mitochondrial
superoxide
overproduction
 Increased Polyol Pathway
Flux
→
 Increased Intracellular
Advanced Glycation EndProduct Formation
 Activation of Protein
Kinase C
 Increased Hexosamine
Pathway Flux
 Potential pathways
leading to the
formation of advanced
glycation end product
(AGE) from
intracellular dicarbonyl
precursors.
 Potential
mechanisms by
which intracellular
production of
advanced glycation
end-product (AGE)
precursors damages
vascular cells.
hyperglycemia-induced protein kinase C
(PKC) activation
 Hyperglycemia
increases
diacylglycerol (DAG)
content, which
activates PKC,
primarily the β and δ
isoforms.
 Activated PKC has a
number of pathogenic
consequences.
The hexosamine pathway
 The glycolytic intermediate
fructose-6-phosphate (Fruc-6-P)
is converted to glucosamine-6phosphate (Glc-6-P) by the
enzyme glutamine:fructose 6phosphate amidotransferase
(GFAT).
 Increased donation of NAcetylglucosamine moieties to
serine and threonine residues of
transcription factors such as Sp1
increases production of such
complication-promoting factors
as PAI-1 and TGF-β1 .