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
diabetes- specific 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.
Slide 3
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.
Slide 4
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
Slide 5
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
Slide 6
Slide 7
Shared Pathophysiologic Features of Microvascular Complications
In the retina, glomerulus, and vasa nervorum, diabetes-specific
microvascular disease is characterized by similar pathophysiologic
features. 1. Requirement for Intracellular Hyperglycemia 2.
Abnormal Endothelial Cell Function 3. Increased Vessel Wall Protein
Accumulation 4. Microvascular Cell Loss and Vessel Occlusion
Slide 8
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
Slide 9
In the Diabetes Control and Complications Trial (DCCT), for
example, T1DM patients whose intensive insulin therapy resulted in
hemoglobin A 1c (Hb A 1c ) 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
Slide 10
Slide 11
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.
Slide 12
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.
Slide 13
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
1 (TGF- 1 ), 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
Slide 14
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 Mller 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. [
Slide 15
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.
Slide 16
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
Slide 17
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 A 1 is an
independent risk factor for CVD
Slide 18
Slide 19
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-low- density
lipoprotein (VLDL), a low high-density lipoprotein (HDL), and
small, dense LDL.
Slide 20
Slide 21
Slide 22
Mechanisms of Hyperglycemia-Induced Damage Increased Polyol
Pathway Flux Increased Intracellular Advanced Glycation End-
Product Formation Activation of Protein Kinase C Increased
Hexosamine Pathway Flux Mitochondrial superoxide
overproduction
Slide 23
Slide 24
Potential pathways leading to the formation of advanced
glycation end product (AGE) from intracellular dicarbonyl
precursors.
Slide 25
Potential mechanisms by which intracellular production of
advanced glycation end-product (AGE) precursors damages vascular
cells.
Slide 26
hyperglycemia-induced protein kinase C (PKC) activation
Hyperglycemia increases diacylglycerol (DAG) content, which
activates PKC, primarily the and isoforms. Activated PKC has a
number of pathogenic consequences.
Slide 27
The hexosamine pathway The glycolytic intermediate
fructose-6-phosphate (Fruc-6-P) is converted to glucosamine-6-
phosphate (Glc-6-P) by the enzyme glutamine:fructose 6- phosphate
amidotransferase (GFAT). Increased donation of N- Acetylglucosamine
moieties to serine and threonine residues of transcription factors
such as Sp1 increases production of such complication-promoting
factors as PAI-1 and TGF-1.