Primary Prevention and Risk Reduction for

Cardiovascular/Pulmonary Disorders—Preferred Practice

Pattern 6A
Scot Irwin, in Cardiopulmonary Physical Therapy (Fourth Edition), 2004
Pathophysiology
The pathophysiology of diabetes is complex and involves several different hormones (i.e.,
insulin, glucagons, and growth). The interaction of these hormones with the liver and their
involvement in renal function make the pathological mechanisms of this disease difficult to
pinpoint and widely varied among patients. More extensive reviews of this pathophysiology can
be found on the American Diabetes Association Web site and in medical pathology
texts.7,14 Regardless of the cause of diabetes, the result is a decrease in the uptake of glucose.
Insulin resistance is mediated by genetic predisposing factors and abdominal obesity.6,17 A strong
relationship has been noted between the development of type 2 diabetes and obesity. Eighty
percent of type 2 diabetic patients are obese, and excess fat is usually carried in upper body
areas.18 The therapist should recognize that medical interventions are directed at achieving
normal or near-normal glucose levels and at optimizing lipid values. Interventions vary,
depending on the degree of control required and the level of insulin resistance and/or
insufficiency noted.2,4 Resultant exercise interventions and expected outcomes vary just as
widely. These variations are discussed in the “Interventions” and “Outcomes” sections of the
following case.
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Roles of Environmental Pollution and Pesticides in Metabolic
Syndrome and Diabetes
Ivar L. Frithsen, Charles J. Everett, in Nutritional and Therapeutic Interventions for Diabetes and
Metabolic Syndrome, 2012
Introduction
The pathophysiology of diabetes is discussed in other chapters; the etiology of diabetes involves
a combination of genetic, lifestyle, and environmental factors. “Environmental factor” is a broad
term that could encompass anything from dietary components to chemical exposures; here the
focus will be on environmental pollutants or contaminants. Various pollutants have been linked
to a spectrum of diseases from asthma to certain cancers. There is evidence in the form of basic
science research, animal models, and epidemiologic studies that environmental contaminants
may play a role in the development of diabetes. We will focus on epidemiologic evidence linking
certain environmental contaminants to diabetes.
Human studies of environmental contaminants are always observational and focus on long-term
or acute high-level exposures; or chronic low-level exposures as found in the general population.
Since randomized studies are not feasible, the majority of the epidemiologic studies of
environmental contaminants and diabetes are cross-sectional with some longitudinal research.
Since it would not be possible to include every environmental contaminant in this chapter,
several have been chosen that are representative of the current evidence.
Dioxins, furans, polychlorinated biphenyls (PCBs) and some pesticides are part of a group of
chemicals known as persistent organic pollutants (POPs). These chemicals are environmentally
persistent; although many are now either banned or their production tightly regulated, they will
be present in the environment for decades to come. These compounds are some of the most
widely studied in terms of health effects from environmental exposures and there is an extensive
body of evidence examining the link to diabetes. Pesticides are some of the most widely applied
chemicals produced by humans and exposure is essentially universal either from ingestion of
treated foods or from other environmental sources. Bisphenol-A or BPA is included as there has
been widely publicized debate recently about the potential health effects from this chemical that
is used in a variety of everyday products. Air pollution and toxic metals are also included to
demonstrate the diversity of compounds studied to determine their role in the development of
diabetes.
This chapter should not be considered to be a systematic review of each contaminant described;
rather studies that are representative of the current evidence will be presented as an overview to
this complex area of research. For some pollutants comprehensive reviews have been published
recently; articles published after those reviews are noted in those cases.
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Volume I
Jeffrey Kalish, Frank B. PomposelliJr., in Endocrinology: Adult and Pediatric (Seventh Edition),
2016
Pathophysiology
The epidemiology and pathophysiology of diabetes have been discussed in previous chapters, as
were the major complications of retinopathy, neuropathy, and nephropathy. Similar mechanisms
underlie complications stemming from the diabetic foot,
including ulceration, gangrene, ischemia, and, ultimately, amputation. Although glycemic
control is imperative in diabetes, it is not sufficient to eliminate complications of the diabetic
foot. Furthermore, it is important for clinicians to be aware of the etiologic triad leading to
diabetic foot complications (i.e., neuropathy, ischemia, and infection) and to recognize that these
may occur in isolation but more frequently occur in combination with one another (Fig. 55-1).
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Figure 55-1. Pathophysiology of the diabetic foot leading to vascular complications.
(Modified from LoGerfo FW: Bypass grafts to the dorsalis pedis artery. In Whittemore AD, Bandyk DF, Cronenwett JL,
et al [eds]: Advances in Vascular Surgery, vol 10. Philadelphia, Mosby, 2002, p. 174.)
Neuropathy
The neuropathy stemming from diabetes mellitus has multiple manifestations within the diabetic
foot because it encompasses sensory, motor, and autonomic fibers. Sensory neuropathy affects
small-diameter pain and temperature fibers first, and susceptibility to injury is increased because
these patients are less sensitive to pressure-related trauma and other minor skin injuries
(see Chapter 53). Motor neuropathy affects the longer fibers that innervate the foot, including
intrinsic foot muscles and leg muscles. Atrophy, or muscle wasting, in the intrinsic foot muscles
allows the strong flexor muscles to draw up the toes in a “clawed” position, and new pressure
points emerge at the tips of the toes and the prominent metatarsal heads. Limited joint
mobility and rigidity from glycation of scleral proteins exacerbates the situation by further
changing the normal weight distribution on the foot. Lastly, autonomic neuropathy causes the
skin to become dry through loss of sweat and apocrine gland function. The resulting dry, scaly
skin has a markedly increased susceptibility to skin breakdown and fissures, thus creating a
portal of entry for bacteria. Additionally, diabetic patients can have a blunted neuroinflammatory
response and thus are missing a crucial component of the body’s natural first-line defense against
pathogens.4
Infection
Diabetic patients typically have an altered response to infectious processes owing to defects in
their host immune defense system.5 Moreover, wound healing is delayed in diabetic patients as a
result of abnormal cellular and inflammatory pathways involving fibroblasts, neutrophils,
and advanced glycation end products (AGEs). Glycation is a nonenzymatic chemical reaction
whereby sulfhydryl protein linkages are replaced by glucose, causing impairment in normal
cellular and tissue functions.6 AGEs increase the stiffness of precapillary vessel walls and
contribute to the development of diabetic microangiopathy.7 Additionally, the presence of
neuropathy and ischemia can potentiate the infectious process. The loss of protective sensation
from neuropathy leads to unrecognized injury and secondary infection. Ischemia results in poor
healing, blunts the inflammatory response, and may lead to inadequate tissue levels
of antimicrobial agents.
Ischemia
Much progress has been made in identifying the cause of ischemia in the lower extremities of
diabetic patients, and results have challenged long-standing misconceptions in the literature and
in the medical community at large. It is imperative that practitioners continue to reject the
“small-vessel disease” theory related to occlusions of the microcirculation, as espoused by a
single histologic study in 1959,8 and instead embrace the notion that ischemia results from both
atherosclerotic macrovascular disease and microcirculatory dysfunction.9 Diabetic patients
typically suffer from tibial and peroneal arterial disease with sparing of the foot arteries,
especially the dorsalis pedis and its branches (Fig. 55-2).

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Figure 55-2. Intraarterial digital subtraction arteriogram showing typical pattern of occlusive disease in a diabetic patient.
A, Calf view: The posterior tibial, anterior tibial, and peroneal arteries are severely narrowed. Blood flow to the foot is
entirely dependent on the small collateral vessels that are visible. B, Lateral foot view: The dorsalis pedis artery is widely
patent with runoff into patent tarsal branches.
Research has shown that diabetes causes structural and functional changes within the arteriolar
and capillary systems, notably thickening of the basement membrane. In spite of the
thickened capillary basement membrane, there is no decrease in capillary luminal diameter.10 A
thickened membrane impairs the migration of leukocytes and hampers the normal hyperemic or
vasodilatory response to injury, thus simultaneously increasing the susceptibility to injury while
blunting the typical manifestations of such an injury.11 Overall, this dysfunction of the
microcirculation in diabetic patients creates a functionally ischemic foot despite conditions that
would otherwise allow normal blood flow in healthy patients.
Besides causing specific structural changes in the microcirculation, diabetes also causes a
compromise in the overall biology of the foot. Diabetes causes an undesirable shift in the natural
balance that exists between stress/ulceration and resistance to stress/ulceration. Thus, the diabetic
foot is more prone to ulceration from the repetitive low-intensity stress of normal weight bearing.
The presence of neuropathy may necessitate revascularization under conditions of perfusion that
would not require revascularization in the absence of neuropathy and is often described
as neuroischemia. Because of the compromise caused by this neuroischemia, the diabetic foot
requires even more perfusion than usual to resist ulceration or respond appropriately to injury
(Fig. 55-3).

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Figure 55-3. The relationship between ulceration, compromised biology, and arterial circulation.
As perfusion decreases, even a foot with perfect biology will ulcerate. As neuropathy increases, even a well-perfused foot
will ulcerate. With revascularization, the improvement in perfusion will allow healing of ulcers in diabetic patients with
compromised biology.
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Diabetes Mellitus Treatment
Chin Meng Khoo, in International Encyclopedia of Public Health (Second Edition), 2017
Abstract
With greater understanding of the pathophysiology of diabetes mellitus, the treatment options
for patients with type 2 diabetes have expanded. It is therefore important to individualize
treatment in each patient for both intensive lifestyle modification and antidiabetic agents. Each
antidiabetic agent addresses a specific underlying pathophysiology and carries
specific contraindications and side effects. It is important to take into consideration
the glycemic goal, risk of hypoglycemia, life expectancy, resources, social support, and
comorbidities when making a shared-decision with the patients on the antidiabetic agent.
Management of obesity is important as obesity is one of the major risk factor for type 2 diabetes.
Treatment of diabetes must also address other cardiovascular risk factors (i.e., hypertension and
dyslipidemia) to reduce cardiovascular events and mortality.
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Transcriptional Channelopathies of the Nervous System: New
Targets for Molecular Medicine
Stephen G. Waxman MD, PhD, in From Neuroscience To Neurology, 2005
A CENTRAL NERVOUS SYSTEM CHANNELOPATHY IN DIABETES?
The role of the CNS in the pathophysiology of diabetes remains incompletely understood. There
is some evidence suggesting that prolonged elevated levels of vasopressin, which is produced
within the magnocellular neurons of the hypothalamic supraoptic nucleus, are a risk factor for
the development of diabetic nephropathy, which can lead to end-stage renal disease (Bardoux et
al., 1999; Ahloulay et al., 1999). As noted previously, vasopressin is released as a result of
action potential firing by supraoptic magnocellular neurons. Because changes in the transcription
of sodium channel genes can be evoked within supraoptic magnocellular neurons by elevations
in osmolality within the normal brain (Tanaka et al., 1999), as described at the beginning of this
chapter, Klein et al. (2002) recently hypothesized that the hyperosmolality associated with
diabetic hyperglycemia can trigger a change in sodium channel expression in these cells. To test
this hypothesis, they used in situ hybridization, immunocytochemistry, and patch
clamp recording to study sodium channel expression within magnocellular neurons from
the hypothalamus of rats with STZ-induced diabetes. As shown in Figure 19.13, in
situ hybridization and immunocytochemical analysis demonstrated significant up-regulation of
Nav1.2 and Nav1.6 sodium channel mRNA and protein in the magnocellular neurons within
weeks of the development of hyperglycemia, but there was no change in sodium channel
expression within other nearby nuclei or the surrounding neuropil. To determine whether the
upregulated mRNA and protein resulted in the insertion of functional channels within the
membranes of magnocellular neu rons, acutely dissociated magnocellular neurons were studied
using patch clamp. Although the voltage-dependence of activation and steady-state inactivation
(Figure 19.14) and the time constants for inactivation were similar for diabetic and control
neurons, the peak transient current amplitude was 130% greater (P < .001) in diabetic
magnocellular neurons; peak current density in diabetic neurons was 65% greater (P < .05) than
that in controls. Persistent sodium currents, which are known to contribute to neuronal bursting
and are increased in magnocellular neurons exposed to hyperosmolar conditions (Tanaka et
al., 1999), were also compared. Tetrodotoxin-sensitive persistent currents that were activated at
potentials close to threshold (–65 to –55mV) were significantly larger in diabetic neurons, with a
current density that was increased by approximately 50% compared to that in control neurons
(P < .05; Klein et al., 2002).

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FIGURE 19.13. voltage-gated sodium channel gene expression in hypothalamic magnocelluar neurons is upregulated in
diabetes. A: In situ hybridization shows upregulated sodium channel Na v1.2 and Nav1.6 mRNA levels in the SON after 6
weeks of STZ-induced diabetes. B: Immunocytochemistry using subtype-specific antibodies shows upregulated Nav1.2
and Nav1.6 protein after 6 weeks of STZ-induced diabetes, demonstrating that the newly produced mRNA is translated
into sodium channel protein. C: Quantification of optical intensities of individual SON neurons shows increases in Na v1.2
and Nav1.6 mRNA and protein. mRNA and protein data shown in A and B are represented in the histogram in C; black
bars = control, white bars = diabetic, data plotted as mean ± SE, * = β &lt; .05 by non-paired t-test. Modified from Klein et
al. (2002).

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FIGURE 19.14. Patch clamp recordings of acutely dissociated MNCs from diabetic rats show increased peak and ramp
currents (A, left and right, respectively) and current densities (B), indicating that increased numbers of functional sodium
channels have been inserted within the membranes of diabetic MNCs; black bars = control, white bars = diabetic, data
plotted as mean ± SE, * = P &lt; .05 by non-paired t-test. Reproduced from Klein et al. (2002).
This study demonstrates that, in experimental diabetes, increased transcription results in an
increased density of functional sodium channels within magnocellular neurosecretory neurons of
the hypothalamus, a change that will increase excitability of these cells and evoke vasopressin
release from them. Because prolonged elevation of serum vasopressin levels, which increases
blood pressure and increases filtration demand to the kidneys, is a factor that leads to the
development of diabetic nephropathy (Bardoux et al., 1999; Ahloulay et al., 1999), Klein et
al., (2002) hypothesized that the changes in sodium channel expression within the supraoptic
nucleus may contribute in a long-term manner to the pathogenesis of diabetic nephropathy. If
this speculation is correct, altered sodium channel expression within supraoptic neurons
associated with diabetes may be viewed as a channelopathy and may be amenable to therapeutic
approaches that might delay the development of end-organ complications such as nephropathy.
On the other hand, it is possible that the changes are adaptive, contributing to homeostatic
mechanisms in untreated or undertreated diabetes. Further study is clearly needed. Irrespective of
whether the changes are maladaptive or adaptive, the changes in the diabetic hypothalamus
provide another example of the dynamic nature of ion channel expression within the CNS.
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