Diabetes-Related Microvascular and Macrovascular Diseases in the Physical Therapy Setting

Abstract

Physical therapists commonly treat people with diabetes for a wide variety of diabetes-associated impairments, including those from diabetes-related vascular disease. Diabetes is associated with both microvascular and macrovascular diseases affecting several organs, including muscle, skin, heart, brain, and kidneys. A common etiology links the different types of diabetes-associated vascular disease. Common risk factors for vascular disease in people with diabetes, specifically type 2 diabetes, include hyperglycemia, insulin resistance, dyslipidemia, hypertension, tobacco use, and obesity. Mechanisms for vascular disease in diabetes include the pathologic effects of advanced glycation end product accumulation, impaired vasodilatory response attributable to nitric oxide inhibition, smooth muscle cell dysfunction, overproduction of endothelial growth factors, chronic inflammation, hemodynamic dysregulation, impaired fibrinolytic ability, and enhanced platelet aggregation. It is 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.

Diabetes mellitus (DM) is a global health issue affecting children, adolescents, and adults. According to the World Health Organization, approximately 180 million people worldwide currently have type 2 DM (formerly called adult-onset diabetes); over 95% of people with diabetes have this form. The number of people with type 2 DM is estimated to double by 2030.¹ In the year 2000, death from diabetes-associated complications accounted for approximately 6% of worldwide mortality.² Additionally, the economic burden of diabetes in the United States in 2002 was estimated to be $132 billion.³

Diabetes is a disease that is strongly associated with both microvascular and macrovascular complications, including retinopathy, nephropathy, and neuropathy (microvascular) and ischemic heart disease, peripheral vascular disease, and cerebrovascular disease (macrovascular), resulting in organ and tissue damage in approximately one third to one half of people with diabetes.⁴ Because of the progressive nature of the disease, physical therapists will increasingly encounter patients with prediabetes (ie, impaired glucose tolerance or insulin resistance), early type 2 DM without or with only a few vascular complications, and more advanced disease with several vascular complications. For additional information describing the epidemiology of these problems in people with DM, see the perspective article by Deshpande et al⁵ in this issue.

Diabetes-associated vascular alterations include anatomic, structural, and functional changes leading to multiorgan dysfunction.⁶ As physical therapists increasingly become first-line providers of treatment for musculoskeletal and movement disorders in people with diabetes, it will be important for clinicians to be keenly aware of the underlying vascular deficits in conditions such as diabetic neuropathy, retinopathy, nephropathy, and cardiovascular and peripheral vascular diseases in their treatment programs, even if these conditions are not the reasons for referral. Additionally, physical therapists will play an important role in the care of people with diabetes because numerous interventions provided by physical therapists (such as therapeutic exercise) can assist in alleviating symptoms, slow the metabolic progression to overt type 2 DM, and reduce morbidity and mortality associated with these complications.^7–10

Diabetic microvascular (involving small vessels, such as capillaries) and macrovascular (involving large vessels, such as arteries and veins) complications have similar etiologic characteristics. Chronic hyperglycemia plays a major role in the initiation of diabetic vascular complications through many metabolic and structural derangements, including the production of advanced glycation end products (AGE), abnormal activation of signaling cascades (such as protein kinase C [PKC]), elevated production of reactive oxygen species (ROS, oxygen-containing molecules that can interact with other biomolecules and result in damage), and abnormal stimulation of hemodynamic regulation systems (such as the renin-angiotensin system [RAS]).

The objectives of this article are to briefly describe the epidemiology of, the comorbidities and risk factors associated with, the pathogenesis of, and the physical therapy management associated with microvascular and macrovascular complications of diabetes. In a significant portion of the article, the term “diabetes” includes both type 1 DM and type 2 DM, which have much the same vascular pathology and etiology.

Microvascular Complications of Diabetes

Diabetic Retinopathy

Diabetic retinopathy (DR) is a microvascular complication that can affect the peripheral retina, the macula, or both and is a leading cause of visual disability and blindness in people with diabetes.¹ The severity of DR ranges from nonproliferative and preproliferative to more severely proliferative DR, in which the abnormal growth of new vessels occurs.¹¹ Total or partial vision loss can occur through a vitreous hemorrhage or retinal detachment, and central vision loss can occur through retinal vessel leakage and subsequent macular edema.¹² The prevalence of DR increases with prolonged duration of diabetes.¹³ In studies including people with both type 1 diabetes and type 2 diabetes, after 30 years of diabetes, most patients had some form of DR, and over half had proliferative DR; people with type 1 diabetes and taking insulin had the highest prevalence of DR, and people with type 2 diabetes diagnosed after age 30 had the lowest prevalence of DR.^14–16 Diabetic retinopathy also recently was seen in approximately 10% of people with insulin resistance (prediabetes) and was associated with the presence of hypertension and a higher body mass index.¹⁷ Other studies of DR showed associations with younger age of onset, tobacco use, insulin treatment, abnormal blood lipid (ie, total cholesterol, low-density lipoprotein [LDL], and triglyceride) levels, pregnancy, renal disease, elevated homocysteine levels,¹⁸ and a diet high in fat (Table).^19–21

Table.

Risk Factors for Diabetes-Associated Microvascular and Macrovascular Complications

The earliest histological marker of DR is the loss of pericytes.²² Pericytes are elongated contractile cells that wrap around endothelial cells of small vessels²³ and assist in providing maintenance of capillary tone (ie, dilatation and constriction),²⁴ capillary growth, and protection against ROS damage.²⁵ Therefore, the loss of pericytes with DR would interfere with capillary constriction (producing chronically dilated vessels), new capillary generation, and processes that protect vessels against continuous exposure to noxious molecules (ie, normal homeostasis). Other microvascular changes that occur with DR include capillary basement membrane thickening (Fig. 1),²⁶ increased permeability of endothelial cells, and formation of microaneurysms (ie, weakening of vessel walls that results in the projection of a balloonlike sac) (Fig. 2).²⁷

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.

Figure 2.

Microaneurysms in diabetic retinopathy. From the Slice of Life collection, curated by Suzanne Stensaas, University of Utah.

The most significant factor in the development and progression of DR in people with diabetes appears to be poor glycemic (blood sugar) control.^28,29 Under hyperglycemic conditions, which are frequently seen in people with diabetes, impairment of retinal blood flow, increased inflammatory cell adhesion to retinal blood vessels, and capillary blockage can result in hypoxia and damage to the retina.³⁰

Diabetic Neuropathy

Approximately one half of people with diabetes have some form of peripheral neuropathy (PN), either polydiabetic or monodiabetic neuropathy.³¹ People with diabetes also frequently have autonomic neuropathy, including cardiovascular autonomic dysfunction, which is manifested as abnormal heart rate (HR) and vascular control.³² Physical therapists commonly encounter diabetes- associated PN in the evaluation and treatment of balance and movement disorders because these disorders frequently affect lower-extremity sensation and can cause lower-extremity pain in people with diabetes. Loss of lower-extremity sensation coupled with impaired peripheral vascular function can contribute to lower-extremity (commonly foot) ulceration.³³ Like those for DR, the risk factors for PN include poor glycemic control (ie, elevated glycation hemoglobin levels and impaired glucose tolerance³⁴), age, duration of diabetes, tobacco use, dyslipidemia, and hypertension (especially diastolic) (Table).³⁵ Other independent risk factors for PN include increased height, presence of cardiovascular disease (CVD), presence of severe ketoacidosis (ie, elevated by-products of fat metabolism in the blood), and presence of microalbuminuria (ie, presence of albumin in urine, indicating early renal dysfunction) (Table).³⁶ Unlike that of DR, the pathogenesis of PN appears to be related to both vascular and nonvascular metabolic mechanisms, but this theory is controversial.^37–39 For additional information related to the effects of peripheral neuropathy on skin and muscle, see related articles by Mueller et al,⁴⁰ LeMaster et al,⁴¹ and Hilton et al⁴² in this issue.

Characteristic traits of PN include axonal thickening with progression to axonal loss,⁴³ basement membrane thickening, pericyte loss,^44,45 loss of microfilaments (ie, cytoskeletal filaments comprising actin and myosin), and decreased capillary blood flow to C fibers,⁴⁶ leading to decreased nerve perfusion and endoneurial hypoxia^44,45 (Fig. 1). Neuronal microvasculature is impaired in the presence of hyperglycemia,⁴⁷ and this impairment is mediated through the abnormal initiation of signaling cascades,^48,49 potentially leading to the demyelination associated with diabetic PN.⁵⁰ Both nonvascular and vascular mechanisms of PN appear to be primarily related to the metabolic aspects (ie, hyperglycemia) of diabetes.

Diabetes-related cardiac autonomic neuropathy is frequently underdiagnosed and can include clinical abnormalities such as resting tachycardia, exercise intolerance, resting HR variability, slow HR recovery after exercise, orthostasis, “silent” myocardial infarction, and increased risk of mortality.^51,52 The prevalence of diabetes-related cardiac autonomic neuropathy is unclear and has been reported to range from 1% to 90%, depending on the outcome variable.³² Risk factors for diabetes-associated cardiac neuropathy include age, obesity, smoking, poor glycemic control, and hypertension (Table).⁵³

Cardiac autonomic dysfunction in people with diabetes has been associated with diabetic cardiomyopathy, a topic beyond the scope of this article. In brief, people with diabetic cardiomyopathy have diastolic filling and relaxation abnormalities frequently later accompanied by systolic dysfunction and heart failure. It is unclear whether cardiac autonomic dysfunction directly mediates diabetic cardiomyopathy, because many of the same risk factors and mechanisms contribute to the development of both conditions.⁵¹

Diabetic Nephropathy

Diabetic nephropathy (DN) is a serious and progressive complication of both type 1 DM and type 2 DM. The first manifestation of DN is typically microalbuminuria, which progresses to overt albuminuria (ie, increased albumin levels in the urine, indicating more severe renal dysfunction) and eventually to renal failure⁵⁴ and is the leading cause of end-stage renal disease (ESRD).⁵⁵ Approximately one fourth of people with type 2 diabetes have microalbuminuria or a more advanced stage of DN that worsens at a rate of 2% to 3% per year.⁵⁶ Other characteristic features of DN include thickening of glomerular basement membranes (Fig. 1) and glomerular hyperfiltration, leading to mesangial (central part of the renal glomerulus) extracellular matrix expansion and further increases in urinary albumin excretion⁵⁷ and progressing to glomerular and tubular sclerosis and renal failure.^58,59 Like those for DR and PN, the risk factors for DN include hyperglycemia, duration 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 People 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, tobacco use, dyslipidemia, and hypertension.^65,66 These CVD risk factors are common in diabetes, but data suggest that diabetes is an independent risk factor for CVD. People with diabetes also have a 5-fold-greater risk for a first myocardial infarction (MI) and a 2-fold-greater risk for a recurrent MI than people who previously had an MI but do not have diabetes. These data suggest that the risk for an MI in people who have diabetes but who have not had an MI is similar to that in people without diabetes but with a previous MI.⁶⁷ Further, people with diabetes have a poorer long-term prognosis after an MI, including an increased risk for congestive heart failure and death.⁶⁸ Even people with insulin resistance (ie, the blunted response of tissues [such as muscle, fat, and liver] to insulin that frequently precedes type 2 DM) have an increased risk for CVD.⁶⁹ Traditionally, diabetes and CVD were limited primarily to Westernized populations. However, recent evidence suggests that these conditions are rapidly emerging in resource-limited regions of the world,⁷⁰ and estimates indicate that 80% of people with diabetes worldwide will die from CVD.⁷¹

People with diabetes (particularly type 2 DM) frequently have many traditional risk factors for CVD, including central obesity, dyslipidemia (ie, elevated serum triglyceride, LDL, and free fatty acid levels and low high-density lipoprotein levels), and hypertension.⁷² The combination of central adiposity, dyslipidemia, hyperglycemia, and hypertension in the general population is termed “metabolic syndrome.”⁷³ These factors, along with the independent risk factor of diabetes, can act both independently and cumulatively over time to significantly increase risk for CVD. The combination of hyperglycemia, insulin resistance, dyslipidemia, hypertension, and chronic inflammation can injure the vascular endothelium, leading to macrovasculopathy and CVD in people with type 2 DM.⁷⁴

Cerebrovascular Disease

Stroke is the third leading cause of death in the United States, after CVD and cancer,⁷⁵ and is an event very familiar to physical therapists. Diabetes is an independent risk factor across all ages⁷⁶ for stroke; the risk in people with diabetes is up to 2- to 4-fold greater, more so in white people and women.^75,77–79 Diabetes is also a risk factor for sudden and eventual death from stroke,^80,81 and people who have diabetes and who have a stroke have more severe neurological deficits and disability,^82–84 a poorer long-term prognosis,⁸⁵ and a higher incidence of stroke recurrence than people without diabetes.⁸⁶

As in CVD, the presence of diabetes adversely affects the cerebrovascular circulation by increasing the risk of intracranial and extracranial (eg, carotid artery) atherosclerosis.^87,88 People with diabetes have an increased incidence of traditional risk factors for stroke, including hypertension, dyslipidemia, heart failure, and atrial fibrillation.⁸⁹ However, after these factors are controlled for, diabetes remains a strong predictor for stroke, suggesting that the presence of diabetes carries an independent risk for stroke apart from the increased presence of traditional risk factors (Table).⁸⁰

As in other diabetes-related complications, hyperglycemia appears to be a significant factor in stroke. Hyperglycemia is a significant predictor of fatal and nonfatal stroke⁹⁰ and death from stroke.⁹¹ Hyperinsulinemia (ie, elevated blood insulin levels) also appears to be a risk factor for stroke,^92,93 although this relationship is still unclear.⁹⁴ The presence of DR, proteinuria, microalbuminuria, and hyperuricemia (ie, elevated blood uric acid levels) are other diabetes-related factors associated with an increased risk for stroke (Table).^91,95,96 Finally, elevated blood levels of chronic inflammatory markers are associated with an increased risk for stroke in people with diabetes.⁹⁷

Peripheral Artery Disease

Currently in the United States, more than 3.5 million people (African-American > white > Hispanic people) with diabetes have peripheral artery disease (PAD).⁹⁸ Peripheral artery disease is characterized by occlusion of the lower-extremity arteries,⁹⁹ which can cause intermittent claudication and pain, especially upon exercise and activity,¹⁰⁰ and which can result in functional impairments¹⁰¹ and disability.¹⁰² Physical therapists frequently encounter people with diabetes-related PAD because of these functional impairments and because of common events of more severe PAD: foot ulceration and lower-extremity amputation.¹⁰³ Because people with diabetes are 15 times more likely to have lower-extremity amputation than people without diabetes,¹⁰⁴ physical therapists frequently treat people with diabetes-related amputations. As the incidence of diabetes increases, physical therapists will more frequently see, treat, and prescribe exercise for these people. An elevated awareness of PAD is needed among physical therapists because death in people with diabetes and PN is frequently attributed to CVD.¹⁰⁵ Moreover, lower-extremity amputation is more common in people with diabetes and PAD than in people without diabetes but with PAD¹⁰⁶; these data suggest that physical therapists should carefully assess lower-extremity blood flow (ie, peripheral pulses) and skin integrity for all patients with diabetes, especially those with known PAD.

Peripheral artery disease, like the aforementioned vascular diseases, is related to the duration and severity of diabetes.^106,107 Hyperglycemia, specifically, glycation hemoglobin, has been shown to be an independent risk factor for PAD.¹⁰⁸ In addition to diabetes, other risk factors for PAD include hypertension, tobacco use, obesity (ie, waist-to-hip ratio), elevated serum fibrinogen levels, dyslipidemia, a history of CVD, and physical inactivity (Table).^109,110

Common Mechanisms for Microvascular and Macrovascular Diseases in Diabetes

One common pathogenic mechanism for microvascular disease is rooted in chemical reactions between by-products of sugars and proteins that occur over the course of days to weeks and eventually produce irreversible cross-linked protein derivatives called AGE.¹¹¹ These derivatives can exhibit a wide range of effects on surrounding tissues, including modification (eg, thickening) of collagen¹¹² and endothelium.¹¹³ Specifically, in DR, AGE can induce growth inhibition and programmed cell death (ie, apoptosis) of retinal pericytes,¹¹⁴ induce overproduction of endothelial growth factors (including vascular endothelial growth factor, insulin-like growth factor 1, basic fibroblast growth factor, and hepatocyte growth factor),^115,116 increase pathologic angiogenesis (neovascularization),¹¹⁷ and increase vascular inflammation¹¹⁸; all of these actions lead to an increased risk for microthrombosis formation, capillary blockage, and retinal ischemia.¹¹⁹ Neovascularization, vitreous hemorrhage, and increased levels of vascular endothelial growth factor can further lead to retinal fibrosis and detachment and loss of vision.¹² In addition, AGE can bind to immunoglobulin protein receptors for AGE and produce a cascade of signaling events that lead to endothelial cell dysfunction¹²⁰ (Fig. 3).

Figure 3.

Potential mechanisms for diabetes-associated endothelial dysfunction. AGE=advanced glycation end products, RAGE=receptors for AGE, ROS=reactive oxygen species, PKC=protein kinase C, RAS=renin-angiotensin system, FFA=free fatty acid.

Advanced glycation end products also play a role in DN through AGE-mediated programmed cell death of mesangial cells and altered extracellular matrix proteins that appear to contribute to both glomerular hyperfiltration¹¹⁶ and sclerosis.¹²¹ The formation of AGE also may stimulate the oversecretion of growth factors such as insulin-like growth factor 1 and transforming growth factor β and further contribute to glomerular fibrosis,¹²² leading to a decrease in available glomerular surface area for filtration.¹²³

Other mechanisms involved in microvascular disease include the PKC pathway (a family of multifunctional enzymes involved in signal transduction and gene expression of growth factors and inflammatory signals¹²⁴ that may increase vascular permeability) and the polyol pathway (the enzymes aldose reductase and sorbitol dehydrogenase, which catalyze reactions that can lead to sorbitol accumulation-associated osmotic and oxidative stress damage to the endothelium¹²⁵) (Fig. 3). Peripheral nerve damage in DN, including neuronal degeneration and impairment of regeneration of thinly myelinated fibers, is also mediated by AGE accumulation, the activation of the polyol and PKC pathways, and the deleterious 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 discussed here. For an in-depth discussion of these pathways, see more detailed reviews.^129,130

The pathogenesis of macrovascular disease in diabetes is multifactorial; however, the common recipient of injury is the vascular endothelium (Fig. 4). Diabetes initially impairs the ability of the vascular endothelium to vasodilate through inhibition of the nitric oxide (NO, a gas molecule that maintains arteriolar vasodilatation) pathway.¹³¹ The presence of hyperglycemia inhibits the enzyme responsible for the production of NO (ie, endothelial nitric oxide synthase [eNOS]) and increases the production of ROS, leading to further inhibition of eNOS.^132,133 The vascular endothelium also loses its ability to produce NO-activated tissue plasminogen activator, a fibrinolytic (anti-clotting) protein that inhibits the ability of inflammatory cells to “stick” to the endothelial surface.¹³⁴ Insulin resistance also can contribute to a decrease in NO production and the subsequent impaired vasodilatory response. In addition, insulin resistance can lead to an increase in the release of free fatty acids from adipose tissue¹³⁵ and stimulate the PKC pathway, which can directly and indirectly inhibit eNOS activity through increased ROS generation.¹³⁶ The production of AGE (from hyperglycemia) also inhibits NO production, further impairing the vasodilatory response in diabetes.¹³⁷ In addition to the reduction in the vasodilatory response in diabetes, an overproduction of vasoconstrictor substances occurs; these substances include endothelin 1, which has direct vasoconstrictive effects on the endothelium as well as indirect fluid volume effects, including the stimulation of water and salt retention and the activation of the RAS.¹³⁸

Figure 4.

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

Another factor involved in the development and progression of macrovascular disease in diabetes is impaired platelet function, which may lead to increased risks for thrombus formation, atherosclerosis progression, and plaque rupture.¹³⁴ Hyperglycemia-stimulated PKC pathway effects on NO and ROS generation and diabetes-associated impaired fibrinolytic capacity may contribute to this increased coagulative state.^139,140 Another diabetes-related mechanism for macrovascular disease is a hyperinflammatory state. Inflammatory cells (eg, monocytes and T lymphocytes) enter damaged endothelial cells and migrate into the deeper layers (intima media) of vessels, ingesting oxidized LDL and forming foam cells.¹⁴¹ Foam cells are the central component of atherosclerotic fatty streaks, an early marker of macrovascular disease (Fig. 2). The levels of adhesion molecules (ie, proteins that recruit inflammatory cells) are also elevated in people with diabetes, thereby facilitating the process of foam cell formation.¹⁴² Finally, diabetes is associated with smooth muscle cell dysfunction.⁷⁴ Although the precise mechanism for smooth muscle cell dysfunction in diabetes is unclear, it may be associated with similar mechanisms for endothelial cell dysfunction, including activation of the PKC pathway, AGE deposition, and AGE receptor activation as well as overproduction of growth factors.¹³⁶ In the development of atherosclerosis, activated smooth muscle cells in the medial layer of arteries migrate to the atherosclerotic fatty streaks in the intimal layer and produce an extensive extracellular matrix, solidifying the streaks and reciprocally reducing the protective strengthening function in the medial layer, making the atherosclerotic plaque unstable and prone to rupture.¹⁴³ These hyperglycemia-stimulated events act in conjunction over time to produce atheroma and eventual atherosclerosis.⁷²

Many of the mechanisms for CVD appear to affect the cerebrovasculature in a similar manner, but this theory is under debate.¹⁴⁴ However, a unique effect of diabetes on neurons and glial cells occurs during ischemia (such as during a transient ischemic attack or stroke). This relationship has been demonstrated through the relationship between hyperglycemia and increased intracellular acidosis.¹⁴⁵ Neuronal intracellular acidosis occurs during an ischemic event as a result of elevated anaerobic metabolism, which leads to neuron and glial cell damage.^145,146 Acidosis may induce intracellular damage through ROS generation, intracellular signaling disruption, and activation of DNA-splitting enzymes.¹⁴⁶ Hyperglycemia also is associated with increased levels of excitatory amino acids (eg, glutamate), which may induce neuronal cell death through the activation of glutamate receptors, the influx of excess calcium, and mitochondrial (cell energy powerhouse) injury.^146,147 This process may lead to a poorer outcome of stroke in people with diabetes.

Role of Physical Therapists in Diabetes-Related Microvascular and Macrovascular Diseases

Diabetes-related comorbidities are conditions that physical therapists will encounter during the evaluation and treatment of movement and functional disorders in people with diabetes. Besides improving movement and function, in general, physical therapists may improve the quality of life for people with diabetes and macrovascular and microvascular diseases through the use of interventions that address pain, poor endurance, obesity, and increased risk for microvascular and macrovascular diseases. Specifically, the prescription and monitoring of an individualized exercise program are essential in a management program, regardless of the severity of diabetes. Exercise therapy may greatly benefit many patients with diabetes by reducing hyperglycemia, insulin resistance, dyslipidemia, and hypertension; these reductions may translate into an improved vascular disease risk profile in children, adolescents, and adults with diabetes.^148–150 Exercise also may aid in weight loss, specifically, loss of trunk fat, and also may improve glycemic and lipemic control in people with diabetes.¹⁵¹ Additionally, exercise may improve physical function¹⁵² and quality of life in people with diabetes.¹⁵³ Caution should be observed in patients who have proliferative DR, microalbuminuria, and cardiac autonomic dysfunction and who are starting aerobic exercise programs, because exercise, particularly resistance exercise, increases retinal blood pressure, reduces kidney blood flow, and stresses autonomic control of HR and contractility.¹⁵⁴ For additional information related to the metabolic effects of exercise in people with DM, see related articles by Turcotte and Fisher¹⁵⁵ and Gulve¹⁵⁶ in this issue.

A frequent progression of DN, ESRD, is a significant cause of functional impairments and disability¹⁵⁷ in people with diabetes and an area in which physical therapists may play an increasing role in the treatment of these consequences, because exercise training appears to improve functional and work capacities and increase independence in these people.^158,159 People with ESRD frequently have a low hematocrit and muscle atrophy,¹⁶⁰ which may contribute to their reduced exercise capacity and disability.¹⁶¹ An impaired glomerular filtration rate has been associated with low exercise capacity¹⁶² and low activity levels.¹⁶³ Exercise training has been shown to improve markers of DN, specifically decreasing microalbuminuria.¹⁶⁴

Peripheral artery disease is another condition that physical therapists frequently encounter in patients with diabetes. The clinical evaluation of PAD in people with diabetes commonly involves palpating for peripheral arterial pulses, but this technique has been shown to have poor accuracy for the determination of PAD.¹⁶⁵ The ankle brachial index (ABI), a sensitive and specific test for determining PAD,¹⁶⁶ is performed by measuring systolic blood pressure in the upper (brachial artery) and lower (dorsalis pedis and posterior tibialis arteries) extremities with a hand-held Doppler probe and dividing the higher ankle systolic pressure by the higher brachial artery pressure.¹⁶⁷ An ABI of less than 0.90 is predictive of PAD, and an ABI of less than 0.50 is associated with impaired physical function (such as walking distance).¹⁶⁶ Although a Doppler probe is not commonly used in the physical therapy setting, clinics that frequently treat people with diabetes-associated PAD may benefit from using this relatively inexpensive tool because it may provide diagnostic and treatment monitoring criteria. Other clinical testing in patients with diabetes-associated PAD may include treadmill testing¹⁶⁸ or the 6-minute walk test¹⁶⁹ to determine walking capacity and time to claudication and pain, if present. Supervised exercise training in people with PAD has been shown to be highly beneficial in terms of walking distance and time, time to claudication and pain, and quality of life^170,171; is more effective than pharmacologic therapy¹⁷²; and is considered to be first-line therapy in the treatment of PAD.¹⁶⁸ Accordingly, physical therapists are becoming first-line treatment providers for patients with diabetes-related PAD and should be strong advocates of exercise treatment for these patients.

The clinical evaluation and treatment of DN, a common condition in the physical therapy setting, require more specificity. The evaluation of diabetic PN in the clinical setting involves a variety of tests, which may include the measurement of peripheral (typically of the lower extremity, such as the foot) light touch and vibration sense as well as nerve biopsy.¹⁷³ The clinical evaluation of vibration sense, a test frequently used in the physical therapy setting, is the strongest predictor of foot insensitivity ulceration.¹⁷⁴ Electrophysiologic nerve conduction testing, occasionally performed in physical therapy clinics but more often performed in physicians’ offices, is considered to be the gold standard for measuring nerve function.¹⁷⁵ Nerve biopsy is not considered part of routine clinical testing in DN; however, skin biopsy testing is becoming more frequent in clinics. Skin biopsy testing is minimally invasive and may provide important information, such as nerve density and small-fiber neuropathy,¹⁷⁶ and it may be useful in predicting the progression of the disease.¹⁷⁷ A newly developed noninvasive technique for assessing the presence of DN is corneal confocal microscopy, with which the density and length of the corneal nerve have been shown to be strongly associated with lower-extremity nerve density and which is gaining in popularity.³⁷ These clinical measurements also may be used to assess the efficacy of specific interventions, including medications, exercise, and weight loss.

Clinical tests to evaluate diabetes-associated cardiac autonomic neuropathy include measurement of resting HR, exercise testing, measurement of blood pressure in response to postural changes (such as moving from a supine position to a standing position), autonomic reflex testing, measurement of 24-hour HR variability, spontaneous baroreflex sensitivity testing, and cardiac radionuclide imaging.⁵¹ Several of these tests, including HR and blood pressure responses to exercise and postural changes, can be performed in the physical therapy setting. A resting HR of ≥100 beats per minute is considered to be tachycardia in adults. Orthostatic hypotension is defined as a decrease of greater than 30 mm Hg in systolic blood pressure and a decrease greater than 10 mm Hg in diastolic blood pressure in response to a change from a supine position to a standing position.¹⁷⁸ Patients with diabetes-associated cardiac autonomic neuropathy have a blunted HR response to exercise (ie, they do not attain the age-predicted maximal HR) and a slow HR recovery after peak exercise⁵²; the latter is predictive of CVD and all-cause mortality.⁵² Physical therapists, therefore, may have to rely more on the patient's perceived exertion than on HR responses for exercise prescription.¹⁷⁹

Conclusion

Diabetes is associated with both microvascular and macrovascular diseases affecting numerous organs, including skeletal muscle, skin, heart, brain, and kidneys. Common pathogenic mechanisms link the different types of diabetes-associated vascular disease (such as CVD and PAD). Common risk factors for vascular disease in diabetes include hyperglycemia, insulin resistance, dyslipidemia, hypertension, tobacco use, and obesity.

Mechanisms for microvascular disease in diabetes include the pathologic effects of AGE accumulation, overproduction of endothelial growth factors, and abnormal stimulation of the PKC and polyol pathways and the RAS. Mechanisms for macrovascular disease in diabetes include the pathologic effects of AGE accumulation, impaired vasodilatory response attributable to NO inhibition, smooth muscle cell dysfunction, overproduction of endothelial growth factors, chronic inflammation, hemodynamic dysregulation, impaired fibrinolytic ability, and enhanced platelet aggregation (clotting). It is becoming increasingly important for physical therapists to be aware of diabetes-related vascular complications as more patients present with insulin resistance and type 2 DM. The opportunities for effective physical therapy interventions (such as exercise) are significant.