0. Pathogenesis and Classification of Glycemic Disorders
The slides in this section of the program provide an overview
of the classification, etiology, and diagnostic criteria for type 1
and type 2 diabetes.

1. Hyperglycemia The Defining Feature of Diabetes
Excessive
glucose production
Impaired
glucose clearance
Hyperglycemia
Tissue injury 1
Hyperglycemia
The Defining Feature of Diabetes
KEY POINTS
• Persistent hyperglycemia is the hallmark of all forms of diabetes
• Hyperglycemia results from excessive hepatic glucose production as
well as from impaired glucose clearance caused by defects in insulin
secretion, insulin action, or both
• Chronic hyperglycemia causes long-term tissue damage in organs
throughout the body
Diabetes mellitus is a group of complex metabolic disorders marked by
persistent hyperglycemia. Hyperglycemia results from excessive glucose
production by the liver as well as from impaired glucose clearance due
to defects in insulin secretion, insulin action, or both.1
The chronic hyperglycemia of diabetes is associated with long-term tissue
damage involving various organs in the body, most notably the eyes, kidneys,
nerves, heart, and blood vessels.1
1. American Diabetes Association. Clinical Practice Recommendations Diagnosis
and classification of diabetes mellitus. Diabetes Care. 2004;27(suppl 1):S5-S10.

2. Hyperglycemia Damages Tissues
Effects of hyperglycemia
Glycation of proteins (eg, hemoglobin, collagen)
Accumulation of sorbitol and fructose (eg, in nerves, lens)
Activation of protein kinase C (eg, on vascular cells)
Tissue changes
Altered protein function and turnover, cytokine activation
Osmotic and oxidative stress
Reduced motor and sensory nerve conduction velocity
Increased glomerular filtration rate and renal plasma flow 2
Hyperglycemia Damages Tissues
KEY POINTS
• Chronic hyperglycemia has been implicated as the primary cause of
diabetes-related microvascular and macrovascular complications
• Physiologic changes resulting from chronic hyperglycemia and associated
with diabetic complications include glycation of proteins, accumulation
of sorbitol and fructose, and activation of protein kinase C
• Tissue changes associated with hyperglycemia include changes in protein
function and turnover, cytokine activation, osmotic and oxidative
stress, reduced motor and sensory nerve conduction velocity, and
increased glomerular filtration rate and renal plasma flow
Chronic hyperglycemia has been implicated as the most important cause
of the microvascular complications of both type 1 and type 2 diabetes.
Hyperglycemia also plays a significant role in the pathogenesis and progression
of the atherosclerotic macrovascular complications associated
with diabetes.1-3
The physiologic effects of hyperglycemia and those associated with diabetic
complications include glycation of both circulating and tissue proteins
(eg, hemoglobin and collagen), accumulation of sorbitol and fructose
in the lens, and activation of protein kinase C on vascular cells.1-4
Hyperglycemia also affects tissues, resulting in altered protein function
and turnover, cytokine activation, osmotic and oxidative stress, reduced
motor and sensory nerve conduction velocity, and increased glomerular
filtration rate and renal plasma flow.4
1. American Diabetes Association. Clinical Practice Recommendations Diagnosis
and classification of diabetes mellitus. Diabetes Care. 2004;27(suppl 1):S5-S10.
2. LeRoith D, Taylor S, Olefsky JM. Diabetes Mellitus: A Fundamental and Clinical
Text. 2nd ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2000.
3. Sheetz MJ, King GL. Molecular understanding of hyperglycemia’s adverse effects for
diabetic complications. JAMA. 2002;288:
4. Feener EP, King GL. Vascular dysfunction in diabetes mellitus. Lancet. 1997;
350(suppl 1):9-13.

3. Medical Complications of Hyperglycemia
Retinopathy, nephropathy, neuropathy
Cardiovascular disorders
Infections, cataracts, connective tissue disorders 3
Medical Complications of Hyperglycemia
KEY POINTS
• Long-term medical complications of diabetes include retinopathy,
nephropathy, and neuropathy
• Individuals with diabetes have an increased risk of cardiovascular disorders,
peripheral vascular and cerebrovascular disease, infections,
cataracts, and connective tissue disorders
Chronic hyperglycemia is associated with many long-term medical complications
such as retinopathy, which can result in blindness; nephropathy,
which can lead to renal failure; peripheral neuropathy, which can
lead to foot ulcers and amputation; and autonomic neuropathy, which
often causes cardiovascular, gastrointestinal, and genitourinary problems
as well as sexual dysfunction. Individuals with diabetes also have a
greater risk of cardiovascular disease (myocardial infarction and
peripheral vascular and cerebrovascular disease), infections, cataracts,
and connective tissue disorders.1
1. American Diabetes Association. Clinical Practice Recommendations Diagnosis
and classification of diabetes mellitus. Diabetes Care. 2004;27(suppl 1):S5-S10.

4. Two Mechanisms of Tissue Injury by Hyperglycemia
Glycation
pathway
Sorbitol
pathway
Advanced glycation
end products (AGEs)
Glycated proteins
(eg, A1C)
Sorbitol and fructose
Altered function
or turnover
Receptor-mediated
cytokine effects
Osmotic
effects
Oxidative
effects
Brownlee M. Metabolism. 2000;49(suppl 1):9-13; Greene DA et al. N Engl J Med. 1987;316: ; Sheetz MJ, King GL. JAMA. 2002;288: 4
Two Mechanisms of Tissue Injury
by Hyperglycemia
KEY POINTS
• Hyperglycemia causes tissue injury via glycation of tissue proteins
• This leads to the glycation of intracellular and extracellular matrix
proteins, which causes the rapid formation of advanced glycation end
products
• Hyperglycemia also increases sorbitol concentrations in the ocular
lens, which may result in osmotic damage
• These elevations in blood glucose generate oxidative stress and alter
the expression and action of various cytokines and vasoactive peptides
This slide illustrates two proposed mechanisms by which hyperglycemia
may cause the tissue injury and vascular complications associated with
diabetes.
Glycation pathway: Chronic exposure to hyperglycemia results in the
glycation (nonenzymatic attachment of glucose) of intracellular and extracellular
matrix proteins, which leads to the formation of advanced
glycation end products(AGEs), which in turn affect vascular cell function.1-3
AGE formation may cause tissue injury by one of three mechanisms.
First, rapid intracellular AGE formation by glucose and other sugars can
directly alter protein function in cells that do not require insulin to
transport glucose into the cell. These include cells in the brain, lens of
the eye, renal medulla, and red blood cells.4 Second, extracellular AGEs
alter interactions between cells, between matrix proteins, and between
matrix proteins and cells. These AGE-related defects are thought to contribute
to diminished large-vessel elasticity. Third, AGE interactions with
cellular receptors can alter gene expression for various molecules
involved in the development of vascular, and possibly neural, pathology,
for example, by binding to subendothelial cells and inducing procoagulatory
changes that lead to the increased adhesion of inflammatory cells
to the vessel wall.2
Sorbitol pathway: Glucose-induced changes in the metabolism of sorbitol
and myo-inositol have also emerged as important mechanisms of hyperglycemia-
induced tissue injury. Animal studies have demonstrated that
hyperglycemia depletes myo-inositol levels, resulting in decreased nerve
conduction velocity.5 Hyperglycemia also depletes myo-inositol from
non-neural tissues affected by diabetes, including the retina, renal
glomerulus, and aorta.5
Hyperglycemia with increased glucose metabolism leads to the accumulation
of sorbitol. Sorbitol can then be converted to fructose by sorbitol
dehydrogenase. Increased flux through the sorbitol pathway increases
osmotic pressure and, when combined with glycolysis, changes the
intracellular reduction/oxidation balance. This pathway increases sorbitol
concentrations in the ocular lens and may cause osmotic damage.1,3
Protein kinase C (not illustrated) has also been implicated in diabetic
complications. Protein kinase C helps regulate important vascular functions
that are abnormal in diabetes, including cell growth and permeability
as well as the synthesis of extracellular matrix proteins.
According to one theory, hyperglycemia increases concentrations of diacylglycerol
(a rate-limiting cofactor for protein kinase C), which results
in the sustained activation of the diacylglycerol/protein kinase C pathway
in vascular cells. Inhibiting this enzyme may help prevent many diabetic
complications.1
Oxidative stress is another acknowledged pathogenic factor in diabetic
complications. Production of free radicals during an acute rise of blood
glucose concentration may occur during glycation or directly from glucose
through a mechanism of auto-oxidation. Free radicals may help
mediate the effects of acute hyperglycemia.6
Hyperglycemia also induces abnormalities in the expression and actions
of various cytokines and vasoactive peptides, further contributing to tissue
injury and vascular dysfunction.1
1. Feener EP, King GL. Vascular dysfunction in diabetes mellitus. Lancet. 1997; 350(suppl 1):
9-13.
2. Brownlee M. Negative consequences of glycation. Metabolism. 2000;49(suppl 1):9-13.
3. Sheetz MJ, King GL. Molecular understanding of hyperglycemia’s adverse effects for
diabetic complications. JAMA. 2002;288:
4. Olerud J. Diabetes and the skin. In: Porte D, Sherwin RS, eds. Ellenberg & Rifkin’s
Diabetes Mellitus. 5th ed. Stamford, Conn: Appleton & Lange; 1997:
5. Greene DA, Lattimer SA, Sima AAF. Sorbitol, phosphoinositides, and sodium–potassium–
ATPase in the pathogenesis of diabetic complications. N Engl J Med. 1987;316:
6. Ceriello A. The emerging role of post-prandial hyperglycaemic spikes in the pathogenesis
of diabetic complications. Diabet Med. 1998;15:
SLIDE 4 CONT’D
Measures of Hyperglycemia
• Blood glucose levels can be evaluated using one of several measures:
random plasma glucose (RPG), fasting plasma glucose (FPG), oral
glucose tolerance test (OGTT), postprandial plasma glucose (PPG),
glycated hemoglobin (also known as hemoglobin A1c, HbA1c, or
A1C), and fructosamine/glycated serum protein
• A1C is the preferred measurement for physicians to monitor glycemic
levels in patients diagnosed with diabetes
Several techniques are available to detect and measure hyperglycemia:
Random plasma glucose (RPG) measurements can be performed at any time
during the day without regard to meals or food intake.
Fasting plasma glucose (FPG), defined as no caloric intake for at least 8
hours, is the most common screening test in use today and is generally performed
in the morning before breakfast. FPG is accurate, inexpensive, easy
to perform, and more acceptable to patients than the oral glucose
tolerance test (OGTT).
OGTT measures plasma glucose 2 hours after the ingestion of a 75-g oral glucose
drink. OGTT is sometimes referred to as 2-hour postload glucose (PG).
Although the OGTT is a valuable research tool and an acceptable diagnostic
test, it is inconvenient for patients. Compared with the FPG, it is also more
costly and time-consuming and has poor reproducibility. With the exception
of its use in screening for gestational diabetes, the American Diabetes
Association (ADA) does not currently recommend the OGTT for routine use.1
Postprandial plasma glucose (PPG) measurements are taken 1 to 2 hours
after a meal. Postprandial glucose levels are typically elevated in patients
with type 2 diabetes due to a characteristic defect in insulin release following
glucose ingestion (known as impaired first-phase insulin
release) and sustained hepatic glucose production.2 Postprandial blood
glucose has become an important focus in diabetes management since
evidence indicates that postprandial glycemic excursions are associated with
an increased risk of both microvascular and macrovascular complications.3
Hemoglobin A1c(HbA1c, or A1C) is one of a series of hemoglobin components
formed nonenzymatically from hemoglobin and glucose that
are collectively known as glycated hemoglobins. The rate of A1C formation
is directly proportional to the ambient glucose concentration as the