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Diabetes

Special Issue

Diabetes-Related Microvascular and


Macrovascular Diseases in the

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Physical Therapy Setting
W Todd Cade
WT Cade, PT, PhD, is Assistant
Professor of Physical Therapy and
Physical therapists commonly treat people with diabetes for a wide variety of
Medicine, Washington University
School of Medicine, Campus Box diabetes-associated impairments, including those from diabetes-related vascular dis-
8502, 4444 Forest Park Blvd, St ease. Diabetes is associated with both microvascular and macrovascular diseases
Louis, MO 63108 (USA). Address affecting several organs, including muscle, skin, heart, brain, and kidneys. A common
all correspondence to Dr Cade at: etiology links the different types of diabetes-associated vascular disease. Common risk
cadet@wusm.wustl.edu.
factors for vascular disease in people with diabetes, specifically type 2 diabetes,
[Cade WT. Diabetes-related include hyperglycemia, insulin resistance, dyslipidemia, hypertension, tobacco use,
microvascular and macrovascular and obesity. Mechanisms for vascular disease in diabetes include the pathologic
diseases in the physical therapy
effects of advanced glycation end product accumulation, impaired vasodilatory re-
setting. Phys Ther. 2008;88:1322–
1335.] sponse attributable to nitric oxide inhibition, smooth muscle cell dysfunction, over-
production of endothelial growth factors, chronic inflammation, hemodynamic dys-
© 2008 American Physical Therapy
regulation, impaired fibrinolytic ability, and enhanced platelet aggregation. It is
Association
becoming increasingly important for physical therapists to be aware of diabetes-
related vascular complications as more patients present with insulin resistance and
diabetes. The opportunities for effective physical therapy interventions (such as
exercise) are significant.

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Diabetes-Related Microvascular and Macrovascular Diseases in Physical Therapy

D
iabetes mellitus (DM) is a cits in conditions such as diabetic neu- Microvascular
global health issue affecting ropathy, retinopathy, nephropathy, Complications of Diabetes
children, adolescents, and and cardiovascular and peripheral vas- Diabetic Retinopathy
adults. According to the World cular diseases in their treatment pro- Diabetic retinopathy (DR) is a micro-
Health Organization, approximately grams, even if these conditions are vascular complication that can affect
180 million people worldwide cur- not the reasons for referral. Addition- the peripheral retina, the macula, or
rently have type 2 DM (formerly ally, physical therapists will play an both and is a leading cause of visual
called adult-onset diabetes); over important role in the care of people disability and blindness in people
95% of people with diabetes have with diabetes because numerous in- with diabetes.1 The severity of DR
this form. The number of people terventions provided by physical ther- ranges from nonproliferative and

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with type 2 DM is estimated to dou- apists (such as therapeutic exercise) preproliferative to more severely
ble by 2030.1 In the year 2000, death can assist in alleviating symptoms, proliferative DR, in which the abnor-
from diabetes-associated complica- slow the metabolic progression to mal growth of new vessels occurs.11
tions accounted for approximately overt type 2 DM, and reduce morbid- Total or partial vision loss can occur
6% of worldwide mortality.2 Addi- ity and mortality associated with these through a vitreous hemorrhage or
tionally, the economic burden of di- complications.7–10 retinal detachment, and central vi-
abetes in the United States in 2002 sion loss can occur through retinal
was estimated to be $132 billion.3 Diabetic microvascular (involving vessel leakage and subsequent mac-
small vessels, such as capillaries) ular edema.12 The prevalence of DR
Diabetes is a disease that is strongly and macrovascular (involving large increases with prolonged duration of
associated with both microvascular vessels, such as arteries and veins) diabetes.13 In studies including peo-
and macrovascular complications, complications have similar etiologic ple with both type 1 diabetes and
including retinopathy, nephropathy, characteristics. Chronic hypergly- type 2 diabetes, after 30 years of di-
and neuropathy (microvascular) and cemia plays a major role in the ini- abetes, most patients had some form
ischemic heart disease, peripheral tiation of diabetic vascular complica- of DR, and over half had proliferative
vascular disease, and cerebrovascu- tions through many metabolic and DR; people with type 1 diabetes and
lar disease (macrovascular), result- structural derangements, including taking insulin had the highest preva-
ing in organ and tissue damage in the production of advanced glyca- lence of DR, and people with type 2
approximately one third to one half tion end products (AGE), abnormal diabetes diagnosed after age 30 had
of people with diabetes.4 Because of activation of signaling cascades (such the lowest prevalence of DR.14 –16
the progressive nature of the disease, as protein kinase C [PKC]), elevated Diabetic retinopathy also recently
physical therapists will increasingly production of reactive oxygen spe- was seen in approximately 10% of
encounter patients with prediabetes cies (ROS, oxygen-containing mole- people with insulin resistance (pre-
(ie, impaired glucose tolerance or cules that can interact with other diabetes) and was associated with
insulin resistance), early type 2 DM biomolecules and result in damage), the presence of hypertension and a
without or with only a few vascular and abnormal stimulation of hemo- higher body mass index.17 Other
complications, and more advanced dynamic regulation systems (such as studies of DR showed associations
disease with several vascular compli- the renin-angiotensin system [RAS]). with younger age of onset, tobacco
cations. For additional information use, insulin treatment, abnormal
describing the epidemiology of these The objectives of this article are to blood lipid (ie, total cholesterol, low-
problems in people with DM, see the briefly describe the epidemiology of, density lipoprotein [LDL], and tri-
perspective article by Deshpande et the comorbidities and risk factors as- glyceride) levels, pregnancy, renal
al5 in this issue. sociated with, the pathogenesis of, disease, elevated homocysteine lev-
and the physical therapy manage- els,18 and a diet high in fat
Diabetes-associated vascular alter- ment associated with microvascular (Table).19 –21
ations include anatomic, structural, and macrovascular complications of
and functional changes leading to diabetes. In a significant portion of The earliest histological marker of
multiorgan dysfunction.6 As physical the article, the term “diabetes” in- DR is the loss of pericytes.22 Peri-
therapists increasingly become first- cludes both type 1 DM and type 2 cytes are elongated contractile cells
line providers of treatment for mus- DM, which have much the same vas- that wrap around endothelial cells of
culoskeletal and movement disorders cular pathology and etiology. small vessels23 and assist in providing
in people with diabetes, it will be im- maintenance of capillary tone (ie, di-
portant for clinicians to be keenly latation and constriction),24 capillary
aware of the underlying vascular defi-

November 2008 Volume 88 Number 11 Physical Therapy f 1323


Diabetes-Related Microvascular and Macrovascular Diseases in Physical Therapy

Table.
Risk Factors for Diabetes-Associated Microvascular and Macrovascular Complications

Peripheral
Cardiovascular Cerebrovascular Vascular
Risk Factor Retinopathy Neuropathy Nephropathy Disease Disease Disease

Hyperglycemia Yes Yes Yes Yes Yes Yes

Hyperinsulinemia Yes

Age Yes Yes Yes Yes

Tobacco use Yes Yes Yes Yes Yes

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Insulin treatment Yes

Dyslipidemia Yes Yes Yes Yes

Pregnancy Yes

Renal disease Yes

Elevated homocysteine level Yes

High-fat diet Yes

Chronic diabetes mellitus Yes Yes

Hypertension Yes Yes Yes Yes

Obesity Yes Yes

Atrial fibrillation Yes

Heart failure Yes

Proteinuria Yes Yes

Microalbuminuria Yes Yes Yes

Hyperuricemia Yes

Blood inflammatory Yes


molecules

Elevated blood fibrinogen Yes


level

Physical inactivity Yes Yes

Elevated height Yes

Ketoacidosis Yes

Carotid artery stenosis Yes

growth, and protection against ROS The most significant factor in the de- polydiabetic or monodiabetic neu-
damage.25 Therefore, the loss of peri- velopment and progression of DR in ropathy.31 People with diabetes also
cytes with DR would interfere with people with diabetes appears to be frequently have autonomic neuropa-
capillary constriction (producing poor glycemic (blood sugar) con- thy, including cardiovascular auto-
chronically dilated vessels), new capil- trol.28,29 Under hyperglycemic con- nomic dysfunction, which is mani-
lary generation, and processes that ditions, which are frequently seen in fested as abnormal heart rate (HR)
protect vessels against continuous ex- people with diabetes, impairment of and vascular control.32 Physical ther-
posure to noxious molecules (ie, nor- retinal blood flow, increased inflam- apists commonly encounter diabetes-
mal homeostasis). Other microvascu- matory cell adhesion to retinal blood associated PN in the evaluation and
lar changes that occur with DR in- vessels, and capillary blockage can treatment of balance and movement
clude capillary basement membrane result in hypoxia and damage to the disorders because these disorders fre-
thickening (Fig. 1),26 increased per- retina.30 quently affect lower-extremity sensa-
meability of endothelial cells, and for- tion and can cause lower-extremity
mation of microaneurysms (ie, weak- Diabetic Neuropathy pain in people with diabetes. Loss of
ening of vessel walls that results in Approximately one half of people lower-extremity sensation coupled
the projection of a balloonlike sac) with diabetes have some form of with impaired peripheral vascular
(Fig. 2).27 peripheral neuropathy (PN), either function can contribute to lower-

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Diabetes-Related Microvascular and Macrovascular Diseases in Physical Therapy

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Figure 1.
Representative transmission electron micrographs of capillary basement membranes (opposing arrows) in tissues from 300- to
350-day-old normal mice (a) and age- and sex-matched transgenic diabetic mice (b). Capillary basement membranes are shown in
renal glomerulus (1a, 1b), retina (2a, 2b), and peripheral nerve (6a, 6b). All micrographs: ⫻28,500. Reprinted with permission of
Wiley-Liss Inc, a subsidiary of John Wiley & Sons Inc, from: Carlson EC, Audette JL, Veitenheimer NJ, et al. Ultrastructural morphometry
of capillary basement membrane thickness in normal and transgenic diabetic mice. Anat Rec A Discov Mol Cell Evol Biol. 2003;271:
332–341.

extremity (commonly foot) ulcer- function) (Table).36 Unlike that of DR, ments comprising actin and myosin),
ation.33 Like those for DR, the risk fac- the pathogenesis of PN appears to be and decreased capillary blood flow
tors for PN include poor glycemic related to both vascular and nonvascu- to C fibers,46 leading to decreased
control (ie, elevated glycation hemo- lar metabolic mechanisms, but this nerve perfusion and endoneurial
globin levels and impaired glucose tol- theory is controversial.37–39 For addi- hypoxia44,45 (Fig. 1). Neuronal mi-
erance34), age, duration of diabetes, tional information related to the ef- crovasculature is impaired in the
tobacco use, dyslipidemia, and hyper- fects of peripheral neuropathy on skin presence of hyperglycemia,47 and
tension (especially diastolic) (Table).35 and muscle, see related articles by this impairment is mediated through
Other independent risk factors for PN Mueller et al,40 LeMaster et al,41 and the abnormal initiation of signaling
include increased height, presence of Hilton et al42 in this issue. cascades,48,49 potentially leading to
cardiovascular disease (CVD), pres- the demyelination associated with di-
ence of severe ketoacidosis (ie, ele- Characteristic traits of PN include ax- abetic PN.50 Both nonvascular and
vated by-products of fat metabolism in onal thickening with progression to vascular mechanisms of PN appear
the blood), and presence of mi- axonal loss,43 basement membrane to be primarily related to the meta-
croalbuminuria (ie, presence of albu- thickening, pericyte loss,44,45 loss of bolic aspects (ie, hyperglycemia) of
min in urine, indicating early renal dys- microfilaments (ie, cytoskeletal fila- diabetes.

November 2008 Volume 88 Number 11 Physical Therapy f 1325


Diabetes-Related Microvascular and Macrovascular Diseases in Physical Therapy

for DN include hyperglycemia, dura-


tion of diabetes, age of onset, tobacco
use, dyslipidemia, hypertension,60,61
and obesity (Table).62

Macrovascular
Complications of Diabetes
Cardiovascular disease (CVD) is the
leading cause (⬃70%) of death in
people with type 2 diabetes.63,64 Peo-

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ple with diabetes have a 4-fold-
greater risk for having a CVD event
than people without diabetes after
controlling for traditional risk factors
for CVD, such as age, obesity, to-
bacco use, dyslipidemia, and hyper-
tension.65,66 These CVD risk factors
are common in diabetes, but data
Figure 2. suggest that diabetes is an indepen-
Microaneurysms in diabetic retinopathy. From the Slice of Life collection, curated by dent risk factor for CVD. People with
Suzanne Stensaas, University of Utah. diabetes also have a 5-fold-greater
risk for a first myocardial infarction
(MI) and a 2-fold-greater risk for a
Diabetes-related cardiac autonomic many of the same risk factors and recurrent MI than people who previ-
neuropathy is frequently underdiag- mechanisms contribute to the devel- ously had an MI but do not have
nosed and can include clinical ab- opment of both conditions.51 diabetes. These data suggest that the
normalities such as resting tachy- risk for an MI in people who have
cardia, exercise intolerance, resting Diabetic Nephropathy diabetes but who have not had an MI
HR variability, slow HR recovery Diabetic nephropathy (DN) is a seri- is similar to that in people without
after exercise, orthostasis, “silent” ous and progressive complication of diabetes but with a previous MI.67
myocardial infarction, and increased both type 1 DM and type 2 DM. The Further, people with diabetes have a
risk of mortality.51,52 The prevalence first manifestation of DN is typically poorer long-term prognosis after an
of diabetes-related cardiac auto- microalbuminuria, which progresses MI, including an increased risk for
nomic neuropathy is unclear and has to overt albuminuria (ie, increased congestive heart failure and death.68
been reported to range from 1% to albumin levels in the urine, indicat- Even people with insulin resistance
90%, depending on the outcome ing more severe renal dysfunction) (ie, the blunted response of tissues
variable.32 Risk factors for diabetes- and eventually to renal failure54 and [such as muscle, fat, and liver] to
associated cardiac neuropathy in- is the leading cause of end-stage re- insulin that frequently precedes type
clude age, obesity, smoking, poor nal disease (ESRD).55 Approximately 2 DM) have an increased risk for
glycemic control, and hypertension one fourth of people with type 2 CVD.69 Traditionally, diabetes and
(Table).53 diabetes have microalbuminuria or a CVD were limited primarily to West-
more advanced stage of DN that ernized populations. However, re-
Cardiac autonomic dysfunction in worsens at a rate of 2% to 3% per cent evidence suggests that these
people with diabetes has been asso- year.56 Other characteristic features conditions are rapidly emerging in
ciated with diabetic cardiomyopa- of DN include thickening of glomer- resource-limited regions of the
thy, a topic beyond the scope of this ular basement membranes (Fig. 1) world,70 and estimates indicate that
article. In brief, people with diabetic and glomerular hyperfiltration, leading 80% of people with diabetes world-
cardiomyopathy have diastolic filling to mesangial (central part of the renal wide will die from CVD.71
and relaxation abnormalities fre- glomerulus) extracellular matrix ex-
quently later accompanied by sys- pansion and further increases in uri- People with diabetes (particularly
tolic dysfunction and heart failure. It nary albumin excretion57 and pro- type 2 DM) frequently have many
is unclear whether cardiac auto- gressing to glomerular and tubular traditional risk factors for CVD, in-
nomic dysfunction directly mediates sclerosis and renal failure.58,59 Like cluding central obesity, dyslipidemia
diabetic cardiomyopathy, because those for DR and PN, the risk factors (ie, elevated serum triglyceride, LDL,

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Diabetes-Related Microvascular and Macrovascular Diseases in Physical Therapy

and free fatty acid levels and low creased presence of traditional risk quently attributed to CVD.105 More-
high-density lipoprotein levels), and factors (Table).80 over, lower-extremity amputation is
hypertension.72 The combination of more common in people with dia-
central adiposity, dyslipidemia, hy- As in other diabetes-related compli- betes and PAD than in people with-
perglycemia, and hypertension in cations, hyperglycemia appears to be out diabetes but with PAD106; these
the general population is termed a significant factor in stroke. Hyper- data suggest that physical thera-
“metabolic syndrome.”73 These fac- glycemia is a significant predictor of pists should carefully assess lower-
tors, along with the independent risk fatal and nonfatal stroke90 and death extremity blood flow (ie, peripheral
factor of diabetes, can act both inde- from stroke.91 Hyperinsulinemia (ie, pulses) and skin integrity for all pa-
pendently and cumulatively over elevated blood insulin levels) also tients with diabetes, especially those

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time to significantly increase risk for appears to be a risk factor for with known PAD.
CVD. The combination of hypergly- stroke,92,93 although this relationship
cemia, insulin resistance, dyslipide- is still unclear.94 The presence of DR, Peripheral artery disease, like the
mia, hypertension, and chronic in- proteinuria, microalbuminuria, and aforementioned vascular diseases, is
flammation can injure the vascular hyperuricemia (ie, elevated blood related to the duration and severity
endothelium, leading to macrovascu- uric acid levels) are other diabetes- of diabetes.106,107 Hyperglycemia, spe-
lopathy and CVD in people with type related factors associated with an in- cifically, glycation hemoglobin, has
2 DM.74 creased risk for stroke (Table).91,95,96 been shown to be an independent risk
Finally, elevated blood levels of factor for PAD.108 In addition to dia-
Cerebrovascular Disease chronic inflammatory markers are as- betes, other risk factors for PAD in-
Stroke is the third leading cause of sociated with an increased risk for clude hypertension, tobacco use, obe-
death in the United States, after CVD stroke in people with diabetes.97 sity (ie, waist-to-hip ratio), elevated
and cancer,75 and is an event very fa- serum fibrinogen levels, dyslipidemia,
miliar to physical therapists. Diabetes Peripheral Artery Disease a history of CVD, and physical inactiv-
is an independent risk factor across all Currently in the United States, more ity (Table).109,110
ages76 for stroke; the risk in people than 3.5 million people (African-
with diabetes is up to 2- to 4-fold American ⬎ white ⬎ Hispanic peo- Common Mechanisms for
greater, more so in white people and ple) with diabetes have peripheral Microvascular and
women.75,77–79 Diabetes is also a risk artery disease (PAD).98 Peripheral Macrovascular Diseases
factor for sudden and eventual death artery disease is characterized by
from stroke,80,81 and people who have occlusion of the lower-extremity ar-
in Diabetes
One common pathogenic mecha-
diabetes and who have a stroke have teries,99 which can cause intermittent
nism for microvascular disease is
more severe neurological deficits and claudication and pain, especially upon
rooted in chemical reactions be-
disability,82– 84 a poorer long-term exercise and activity,100 and which
tween by-products of sugars and pro-
prognosis,85 and a higher incidence of can result in functional impairments101
teins that occur over the course of
stroke recurrence than people with- and disability.102 Physical therapists
days to weeks and eventually pro-
out diabetes.86 frequently encounter people with
duce irreversible cross-linked pro-
diabetes-related PAD because of these
tein derivatives called AGE.111 These
As in CVD, the presence of diabetes functional impairments and because
derivatives can exhibit a wide range
adversely affects the cerebrovascular of common events of more severe PAD:
of effects on surrounding tissues, in-
circulation by increasing the risk of foot ulceration and lower-extremity
cluding modification (eg, thicken-
intracranial and extracranial (eg, ca- amputation.103 Because people with
ing) of collagen112 and endotheli-
rotid artery) atherosclerosis.87,88 Peo- diabetes are 15 times more likely to
um.113 Specifically, in DR, AGE can
ple with diabetes have an increased have lower-extremity amputation than
induce growth inhibition and pro-
incidence of traditional risk factors people without diabetes,104 physical
grammed cell death (ie, apoptosis) of
for stroke, including hypertension, therapists frequently treat people
retinal pericytes,114 induce overpro-
dyslipidemia, heart failure, and atrial with diabetes-related amputations. As
duction of endothelial growth fac-
fibrillation.89 However, after these the incidence of diabetes increases,
tors (including vascular endothelial
factors are controlled for, diabetes physical therapists will more fre-
growth factor, insulin-like growth
remains a strong predictor for quently see, treat, and prescribe ex-
factor 1, basic fibroblast growth fac-
stroke, suggesting that the presence ercise for these people. An elevated
tor, and hepatocyte growth fac-
of diabetes carries an independent awareness of PAD is needed among
tor),115,116 increase pathologic angio-
risk for stroke apart from the in- physical therapists because death in
genesis (neovascularization),117 and
people with diabetes and PN is fre-

November 2008 Volume 88 Number 11 Physical Therapy f 1327


Diabetes-Related Microvascular and Macrovascular Diseases in Physical Therapy

Other mechanisms involved in mi-


crovascular disease include the PKC
pathway (a family of multifunctional
enzymes involved in signal transduc-
tion and gene expression of growth
factors and inflammatory signals124
that may increase vascular perme-
ability) and the polyol pathway (the
enzymes aldose reductase and sorbi-
tol dehydrogenase, which catalyze

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reactions that can lead to sorbitol
accumulation-associated osmotic and
oxidative stress damage to the endo-
thelium125) (Fig. 3). Peripheral nerve
damage in DN, including neuronal
degeneration and impairment of re-
generation of thinly myelinated fi-
bers, is also mediated by AGE accu-
mulation, the activation of the polyol
and PKC pathways, and the deleteri-
ous effects of ROS.126,127

Additionally, the RAS128 plays a role


in microvascular disease because it
can alter glomerular hemodynamics
and mediate sclerosis in DN. Other
enzymatic pathways are involved in
the development and progression of
microvascular disease but are not dis-
cussed here. For an in-depth discus-
sion of these pathways, see more de-
tailed reviews.129,130
Figure 3.
Potential mechanisms for diabetes-associated endothelial dysfunction. AGE⫽advanced The pathogenesis of macrovascular
glycation end products, RAGE⫽receptors for AGE, ROS⫽reactive oxygen species, disease in diabetes is multifactorial;
PKC⫽protein kinase C, RAS⫽renin-angiotensin system, FFA⫽free fatty acid. however, the common recipient of
injury is the vascular endothelium
(Fig. 4). Diabetes initially impairs the
ability of the vascular endothelium to
increase vascular inflammation118; all Advanced glycation end products vasodilate through inhibition of the
of these actions lead to an increased also play a role in DN through AGE- nitric oxide (NO, a gas molecule that
risk for microthrombosis formation, mediated programmed cell death of maintains arteriolar vasodilatation)
capillary blockage, and retinal isch- mesangial cells and altered extracel- pathway.131 The presence of hyper-
emia.119 Neovascularization, vitreous lular matrix proteins that appear to glycemia inhibits the enzyme re-
hemorrhage, and increased levels of contribute to both glomerular hyper- sponsible for the production of NO
vascular endothelial growth factor filtration116 and sclerosis.121 The for- (ie, endothelial nitric oxide synthase
can further lead to retinal fibrosis mation of AGE also may stimulate the [eNOS]) and increases the produc-
and detachment and loss of vision.12 oversecretion of growth factors such tion of ROS, leading to further inhi-
In addition, AGE can bind to immu- as insulin-like growth factor 1 and bition of eNOS.132,133 The vascular
noglobulin protein receptors for transforming growth factor ␤ and endothelium also loses its ability to
AGE and produce a cascade of sig- further contribute to glomerular fi- produce NO-activated tissue plas-
naling events that lead to endothelial brosis,122 leading to a decrease in minogen activator, a fibrinolytic
cell dysfunction120 (Fig. 3). available glomerular surface area for (anti-clotting) protein that inhibits
filtration.123 the ability of inflammatory cells to

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Figure 4.
Potential mechanisms for diabetes-associated vascular abnormalities. NO⫽nitric oxide, tPA-1⫽tissue plasminogen activator-1,
PAI-1⫽plasminogen activator inhibitor-1.

“stick” to the endothelial surface.134 Another factor involved in the devel- also elevated in people with diabetes,
Insulin resistance also can contribute opment and progression of macrovas- thereby facilitating the process of
to a decrease in NO production and cular disease in diabetes is impaired foam cell formation.142 Finally, diabe-
the subsequent impaired vasodila- platelet function, which may lead to tes is associated with smooth muscle
tory response. In addition, insulin re- increased risks for thrombus forma- cell dysfunction.74 Although the pre-
sistance can lead to an increase in tion, atherosclerosis progression, and cise mechanism for smooth muscle
the release of free fatty acids from plaque rupture.134 Hyperglycemia- cell dysfunction in diabetes is unclear,
adipose tissue135 and stimulate the stimulated PKC pathway effects on it may be associated with similar
PKC pathway, which can directly NO and ROS generation and diabetes- mechanisms for endothelial cell dys-
and indirectly inhibit eNOS activity associated impaired fibrinolytic capacity function, including activation of the
through increased ROS generation.136 may contribute to this increased co- PKC pathway, AGE deposition, and
The production of AGE (from hy- agulative state.139,140 Another diabetes- AGE receptor activation as well as
perglycemia) also inhibits NO pro- related mechanism for macrovascular overproduction of growth factors.136
duction, further impairing the vaso- disease is a hyperinflammatory state. In the development of atherosclerosis,
dilatory response in diabetes.137 In Inflammatory cells (eg, monocytes and activated smooth muscle cells in the
addition to the reduction in the va- T lymphocytes) enter damaged en- medial layer of arteries migrate to the
sodilatory response in diabetes, an dothelial cells and migrate into the atherosclerotic fatty streaks in the in-
overproduction of vasoconstrictor deeper layers (intima media) of ves- timal layer and produce an extensive
substances occurs; these substances sels, ingesting oxidized LDL and form- extracellular matrix, solidifying the
include endothelin 1, which has di- ing foam cells.141 Foam cells are the streaks and reciprocally reducing the
rect vasoconstrictive effects on the central component of atherosclerotic protective strengthening function in
endothelium as well as indirect fluid fatty streaks, an early marker of mac- the medial layer, making the athero-
volume effects, including the stimu- rovascular disease (Fig. 2). The levels sclerotic plaque unstable and prone
lation of water and salt retention and of adhesion molecules (ie, proteins to rupture.143 These hyperglycemia-
the activation of the RAS.138 that recruit inflammatory cells) are stimulated events act in conjunction

November 2008 Volume 88 Number 11 Physical Therapy f 1329


Diabetes-Related Microvascular and Macrovascular Diseases in Physical Therapy

over time to produce atheroma and tion and monitoring of an individual- improve markers of DN, specifically
eventual atherosclerosis.72 ized exercise program are essential decreasing microalbuminuria.164
in a management program, regard-
Many of the mechanisms for CVD less of the severity of diabetes. Exer- Peripheral artery disease is another
appear to affect the cerebrovascula- cise therapy may greatly benefit condition that physical therapists fre-
ture in a similar manner, but this many patients with diabetes by re- quently encounter in patients with
theory is under debate.144 How- ducing hyperglycemia, insulin resis- diabetes. The clinical evaluation of
ever, a unique effect of diabetes on tance, dyslipidemia, and hyperten- PAD in people with diabetes com-
neurons and glial cells occurs dur- sion; these reductions may translate monly involves palpating for periph-
ing ischemia (such as during a tran- into an improved vascular disease eral arterial pulses, but this tech-

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sient ischemic attack or stroke). This risk profile in children, adolescents, nique has been shown to have poor
relationship has been demonstrated and adults with diabetes.148 –150 Exer- accuracy for the determination of
through the relationship between cise also may aid in weight loss, spe- PAD.165 The ankle brachial index
hyperglycemia and increased intra- cifically, loss of trunk fat, and also (ABI), a sensitive and specific test for
cellular acidosis.145 Neuronal intra- may improve glycemic and lipemic determining PAD,166 is performed by
cellular acidosis occurs during an control in people with diabetes.151 measuring systolic blood pressure in
ischemic event as a result of ele- Additionally, exercise may improve the upper (brachial artery) and
vated anaerobic metabolism, which physical function152 and quality of lower (dorsalis pedis and posterior
leads to neuron and glial cell dam- life in people with diabetes.153 Cau- tibialis arteries) extremities with a
age.145,146 Acidosis may induce intra- tion should be observed in patients hand-held Doppler probe and divid-
cellular damage through ROS genera- who have proliferative DR, micro- ing the higher ankle systolic pressure
tion, intracellular signaling disruption, albuminuria, and cardiac autonomic by the higher brachial artery pres-
and activation of DNA-splitting en- dysfunction and who are starting sure.167 An ABI of less than 0.90 is
zymes.146 Hyperglycemia also is asso- aerobic exercise programs, because predictive of PAD, and an ABI of less
ciated with increased levels of excita- exercise, particularly resistance ex- than 0.50 is associated with impaired
tory amino acids (eg, glutamate), ercise, increases retinal blood pres- physical function (such as walking
which may induce neuronal cell death sure, reduces kidney blood flow, and distance).166 Although a Doppler
through the activation of glutamate re- stresses autonomic control of HR probe is not commonly used in the
ceptors, the influx of excess calcium, and contractility.154 For additional in- physical therapy setting, clinics that
and mitochondrial (cell energy power- formation related to the metabolic frequently treat people with
house) injury.146,147 This process may effects of exercise in people with DM, diabetes-associated PAD may benefit
lead to a poorer outcome of stroke in see related articles by Turcotte and from using this relatively inexpen-
people with diabetes. Fisher155 and Gulve156 in this issue. sive tool because it may provide di-
agnostic and treatment monitoring
Role of Physical Therapists A frequent progression of DN, ESRD, criteria. Other clinical testing in pa-
in Diabetes-Related is a significant cause of functional tients with diabetes-associated PAD
Microvascular and impairments and disability157 in peo- may include treadmill testing168 or
ple with diabetes and an area in the 6-minute walk test169 to deter-
Macrovascular Diseases which physical therapists may play mine walking capacity and time to
Diabetes-related comorbidities are
an increasing role in the treatment of claudication and pain, if present. Su-
conditions that physical therapists
these consequences, because exer- pervised exercise training in people
will encounter during the evaluation
cise training appears to improve with PAD has been shown to be
and treatment of movement and
functional and work capacities and highly beneficial in terms of walking
functional disorders in people with
increase independence in these peo- distance and time, time to claudication
diabetes. Besides improving move-
ple.158,159 People with ESRD fre- and pain, and quality of life170,171; is
ment and function, in general, phys-
quently have a low hematocrit and more effective than pharmacologic
ical therapists may improve the qual-
muscle atrophy,160 which may con- therapy172; and is considered to be
ity of life for people with diabetes
tribute to their reduced exercise ca- first-line therapy in the treatment of
and macrovascular and microvascu-
pacity and disability.161 An impaired PAD.168 Accordingly, physical thera-
lar diseases through the use of inter-
glomerular filtration rate has been as- pists are becoming first-line treatment
ventions that address pain, poor en-
sociated with low exercise capaci- providers for patients with diabetes-
durance, obesity, and increased risk
ty162 and low activity levels.163 Exer- related PAD and should be strong ad-
for microvascular and macrovascular
cise training has been shown to vocates of exercise treatment for these
diseases. Specifically, the prescrip-
patients.

1330 f Physical Therapy Volume 88 Number 11 November 2008


Diabetes-Related Microvascular and Macrovascular Diseases in Physical Therapy

The clinical evaluation and treatment sensitivity testing, and cardiac radio- overproduction of endothelial growth
of DN, a common condition in the nuclide imaging.51 Several of these factors, chronic inflammation, he-
physical therapy setting, require tests, including HR and blood pres- modynamic dysregulation, impaired
more specificity. The evaluation of sure responses to exercise and pos- fibrinolytic ability, and enhanced
diabetic PN in the clinical setting in- tural changes, can be performed in platelet aggregation (clotting). It is
volves a variety of tests, which may the physical therapy setting. A rest- becoming increasingly important for
include the measurement of periph- ing HR of ⱖ100 beats per minute is physical therapists to be aware of
eral (typically of the lower extrem- considered to be tachycardia in diabetes-related vascular complications
ity, such as the foot) light touch and adults. Orthostatic hypotension is as more patients present with insulin
vibration sense as well as nerve bi- defined as a decrease of greater than resistance and type 2 DM. The oppor-

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opsy.173 The clinical evaluation of vi- 30 mm Hg in systolic blood pressure tunities for effective physical therapy
bration sense, a test frequently used and a decrease greater than 10 mm interventions (such as exercise) are
in the physical therapy setting, is the Hg in diastolic blood pressure in re- significant.
strongest predictor of foot insensitiv- sponse to a change from a supine
ity ulceration.174 Electrophysiologic position to a standing position.178 Pa- This work was supported by National Insti-
nerve conduction testing, occasion- tients with diabetes-associated car- tutes of Health grant K0K074343A.
ally performed in physical therapy diac autonomic neuropathy have a
This article was submitted January 8, 2008,
clinics but more often performed in blunted HR response to exercise (ie, and was accepted May 6, 2008.
physicians’ offices, is considered to they do not attain the age-predicted
be the gold standard for measuring maximal HR) and a slow HR recovery DOI: 10.2522/ptj.20080008
nerve function.175 Nerve biopsy is after peak exercise52; the latter is
not considered part of routine clini- predictive of CVD and all-cause mor- References
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