**5.3. Pathophysiology**

**5. Diabetic autonomic neuropathy**

Autonomic neuropathy is a form of peripheral neuropathy affecting the nerves of the auto‐ nomic nervous system. Autonomic neuropathy most commonly affects organs of the cardio‐ vascular, gastrointestinal, urinary, and reproductive systems, although any system of the body may be affected. Its etiology is poorly understood, but as with other forms of peripheral neuropathy long exposure to hyperglycemia, advanced glycation end products, vascular hypoxia [94], and activation of the polyol pathway are thought to play major roles. Typical signs and symptoms depend on the organ affected, but include resting sinus tachycardia without sinus arrhythmia, orthostatic hypotension, delayed gastric emptying, diabetic diarrhea, constipation, erectile dysfunction, bladder dysfunction, hypoglycemia unawareness, distal hyperhidrosis or anhidrosis, facial sweating, and gustatory sweating. Cardiovascular autonomic neuropathy is life threatening and carries a high risk of mortality [2, 95, 96].

The prevalence of autonomic neuropathy in type 1 diabetes populations varies widely depending on duration of diabetes and method of assessment, with prevalences ranging from 2.6% in individuals with short duration of diabetes [97] to 90% in pancreatic trans‐ plant candidates [98]. Defining autonomic neuropathy based on an abnormal heart rate response to deep breathing and the presence of at least two autonomic neuropathy symptoms, the prevalence ranged from 3.7% to 11.3%, with a decreasing trend with higher BMI, in the Pittsburgh Epidemiology of Diabetes Complications (EDC) when the mean duration of diabetes was approximately 20 years [96]. In a subgroup of this same cohort twenty years later, when mean diabetes duration was 40 years, the prevalence of autonom‐ ic neuropathy based on an abnormal response to deep breathing was 61% [99]. In the entire EDC cohort, the incidence of autonomic neuropathy based on an abnormal heart rate response to deep breathing and the presence of at least two autonomic neuropathy symptoms was 0.78 per 100 person years of duration of diabetes, with a lower incidence for a given duration of diabetes in more recently diabetes diagnosed cohorts in the Pittsburgh Epidemiology of Diabetes Complications study [100]. In the Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications study population, which because of inclusion criteria was a healthier cohort at study baseline than the EDC population, the prevalence of autonomic neuropathy at the follow-up years 13/14 of Epidemiology of Diabetes Interventions and Complications study, representing approx‐ imately 27 years of duration of type 1 diabetes, was 29% and 35% in the former intensive‐ ly treated and conventionally treated Diabetes Control and Complications Trial participants [10]. The presence of diabetic autonomic neuropathy is associated with poor prognosis. In the EDC study, mortality during 20 years of follow-up was increased 2.43-fold after

controlling for age, sex, BMI, and other late complications [96].

**5.1. Overview**

340 Type 1 Diabetes

**5.2. Epidemiology**

Diabetic autonomic neuropathy is a neuropathic disorder of the peripheral nervous system in individuals with diabetes or prediabetes. The pathogenesis of diabetic autonomic neuropathy is poorly understood, but long exposure to hyperglycemia [94, 101], advanced glycation end products [2, 94, 101], vascular insufficiency [2, 94], and activation of the polyol pathway [2, 94, 101] have been long thought to play major roles. The nerves of the autonomic nervous system innervate every organ of the body and as such any organ system can be affected by diabetic autonomic neuropathy. Disorders resulting from damage to autonomic nerve fibers are typically classified into the following syndromes: cardiovascular autonomic neuropathy (CAN), gastrointestinal, genitourinary, hypoglycemia unawareness, and sudomotor.

#### *5.3.1. Pathogenesis*

Long exposure to hyperglycemia is one of the strongest hypotheses on the etiology of diabetic peripheral neuropathy. In individuals with type 1 diabetes, results from the Diabetes Control and Complications Trial showed significantly lower declines in the R-R interval over time in those in the intensive therapy arm of the trial [97]. Whether this was due to lower levels of hyperglycemia was not specified. There was a low incidence of CAN in both treatment arms (4% in the intensive group and 9% in the conventional group), with a 45% lower incidence in the treatment arm [10]. Follow-up of the entire cohort thirteen to fourteen years after the closeout of the trial revealed a marked increase in the prevalence of CAN in the entire cohort, which was significantly greater in the former conventional therapy group. Differences in HbA1c accounted for the majority of the group differences in the incidence of CAN [102]. The beneficial effect of former intensive therapy on the incidence of neuropathy appeared to be greater for CAN than for distal symmetrical polyneuropathy, suggesting that the detrimental effect of hyperglycemia may be greater on small nerve fibers than large nerve fibers [10]. Mechanisms by which hyperglycemia may cause nerve damage include activation of the polyol pathway and accumulation of advanced glycation end products [2, 94, 101].

### *5.3.2. Cardiovascular Autonomic Neuropathy (CAN)*

Cardiovascular autonomic neuropathy results from damage to the nerves that innervate the heart and coronary blood vessels. Because of its clinical importance, it has been the most studied of all of the diabetic autonomic neuropathy syndromes. It is the most life threatening of all of the diabetic autonomic neuropathy syndromes and carries a high risk of mortality. Signs/symptoms of CAN include orthostatic hypotension, sinus tachycardia, exercise intoler‐ ance, silent myocardial infarction, and sudden death.

Autonomic nervous system innervation of the heart largely regulates heart rate variability. In diabetes, cardiac autonomic nervous system dysfunction generally progresses from the apex to the base of the heart [103]. Diabetic autonomic neuropathy appears to affect the long nerve fibers first [2]. In CAN, autonomic dysfunction is usually observed first as a decrease in parasympathetic activity, reflecting damage to the vagal nerve, the longest of the autonomic nerve fibers, and a compensatory increase in sympathetic autonomic nervous system activity [103]. Sympathetic activity increases heart rate while parasympathetic activity decreases heart rate. The decline in parasympathetic activity is reflected in the decline in variation in heart rate with inspiration and expiration, where there is less of a decline in heart rate with expiration. A decline in heart rate variability is one of the earliest manifestations of CAN [103]. This compensatory increase in heart rate with parasympathetic denervation also manifests in an increased resting heart rate, and rates may reach greater than 100 beats per minute [103], resting sinus tachycardia.

[115]. Symptoms of gastroparesis include nausea, vomiting, anorexia, bloating, early satiety, and wide swings in blood sugar [112]. hyperglycemia delays gastric emptying [116] while hypoglycemia accelerates it [117]. Esophageal dysfunction is thought to result from a combi‐ nation of impairment of vagal nerve and enteric nervous system innervation of esophageal smooth muscle cells regulating peristalsis [117]. Symptoms of esophageal dysfunction include difficulty swallowing (dysphagia) and heartburn. Peristalsis dysmotility of the lower gastro‐ intestinal track can result in diarrhea or constipation, both very commonly observed in type 1 diabetes. The diarrhea may be due to bacteria overgrowth resulting from bowel stasis, very rapid peristalsis, or both. Very slow peristalsis activity may result in constipation. Fecal

Diabetic Neuropathy

343

http://dx.doi.org/10.5772/55372

incontinence results from poor anal sphincter tone and impaired rectal sensation [2].

of the glans penis [119, 120], and abnormal motor function of erectile tissue [119].

recurrent urinary tract infections [125] and may lead to renal failure/disease.

Little is known about the pathogenesis of sexual dysfunction in women. It is characterized by reduced sexual arousal, atrophic vaginitis and subsequent painful intercourse. It is poorly related to glycemic control, age, duration of diabetes, or diabetes complications [123], but appears to be related to depression and to improve with estrogen creams [118]. In a substudy of the Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications cohort examining female sexual dysfunction in 424 women with type 1 diabetes and a mean age of 42.8 years, the prevalence of female sexual dysfunction was 35% [124]. Bladder dysfunction is one of the most common complications of diabetes, affecting a large proportion of the type 1 diabetic population [117] and occurring early in the disease process. The diabetic neurogenic bladder is caused by degeneration of both afferent myelinated and efferent non-myelinated nerve fibers to the bladder. Afferent nerve fiber degeneration results in reduced sensation of a full bladder [125]. Efferent nerve fiber degeneration results in reduced frequency of micturition, incomplete emptying of the bladder, i.e. increased post-void residual volume, and eventually urinary incontinence [125]. The neurogenic bladder is associated with

Autonomic nerve dysfunction or damage affecting the genitourinary system may manifest as erectile and/or ejaculation dysfunction or failure in males, dyspareunia in females, and bladder dysfunction, in both genders. Autonomic neuropathy affecting the reproductive organs manifests as erectile and ejaculation failure in males and reduced sexual arousal, reduced vaginal lubrication and painful intercourse in females. Autonomic neuropathy affecting the urinary tract may result in decreased frequency of urination and increased urinary tract infections, increased post void residual volume, dribbling, and urinary incontinence [118, 119]. Erectile dysfunction in diabetes may be due to one or any combination of the following: neuropathy, atherosclerosis, changes in corporal erectile tissue including deposition of AGEs, anti-hyperglycemic medications, and psychological factors, although neuropathy appears to be the predominate cause [119]. The corpus cavernosum is innervated by both sympathetic and parasympathetic nerve fibers and sensory and somatic nerve fibers [120, 121]. The neurogenic basis of erectile dysfunction is a decrease in smooth muscle relaxation of the corpus cavernosum [119, 122], inadequate nitric oxide synthase activity [119, 122], impaired sensation

*5.3.4. Genitourinary autonomic neuropathy*

Autonomic innervation of the heart also regulates blood pressure. The apparent early vagal denervation in CAN results in increased sympathetic nervous system activity, partially due to the counter-regulatory activity of the parasympathetic neurons, increasing blood pressure. During sleep, this is reflected in the "non-dipping" pattern of blood pressure often observed in individuals with type 1 diabetes [104, 105]. This lack of nocturnal bradycardia is associated with prolongation of the heart rate corrected Q-T interval in adolescents with type 1 diabetes [106], although Stella et al [105] observed no cross-sectional association between "nondipping" and CAN in adults with type 1 diabetes. Later cardiac sympathetic denervation results in loss in the normal heart rate and blood pressure responses to exercise. The normal increase in heart rate and blood pressure and subsequent increased cardiac output is impaired, reducing exercise tolerance [2, 103]. Sympathetic cardiac denervation also manifests as orthostatic hypotension, a prolonged drop in blood pressure upon standing due to reduced baroreceptor stimulated sympathetic increase in heart rate and vasoconstriction of splanchnic vascular beds. Orthostatic hypotension may often be asymptomatic, but can result in dizziness, syncope, falls and fractures.

CAN is associated with silent myocardial ischemia and infarction [2, 107], and carries a high risk of mortality [95, 96]. The association of diabetic CAN with silent myocardial infarction is likely due to the higher frequency of silent myocardial ischemia in individu‐ als with diabetic CAN [2]. Damage to the myocardial sensory afferent fibers may reduce the sensation of ischemic pain [2]. A meta-analysis of twelve studies of individuals with diabetes showed a 2-fold higher risk of silent ischemia in those with CAN [2]. In a population of middle-age and elderly individuals with type 1 diabetes, poorer cardiac autonomic function predicted future coronary heart disease events [108]. Perhaps due to its association with silent myocardial ischemia, cardiovascular disease, resting tachycar‐ dia, and exercise intolerance, CAN greatly increases the risk of sudden death [109-111]. We have shown in individuals with long-standing type 1 diabetes that CAN as diagnosed based on heart rate variability and in the presence of at least one other symptom of autonomic neuropathy was a significant predictor of mortality, independently of distal symmetrical polyneuropathy and other late complications of diabetes [96].

#### *5.3.3. Gastrointestinal autonomic neuropathy*

Diabetic autonomic neuropathy affecting the gastrointestinal system may result in gastropa‐ resis, esophageal dysfunction, diarrhea, fecal incontinence, or constipation. Gastroparesis, or delayed gastric emptying, is common in type 1 diabetes, with prevalence rates from approxi‐ mately 30 to 50% [4, 112-114] and appears to be more prevalent in type 1 than in type 2 diabetes [115]. Symptoms of gastroparesis include nausea, vomiting, anorexia, bloating, early satiety, and wide swings in blood sugar [112]. hyperglycemia delays gastric emptying [116] while hypoglycemia accelerates it [117]. Esophageal dysfunction is thought to result from a combi‐ nation of impairment of vagal nerve and enteric nervous system innervation of esophageal smooth muscle cells regulating peristalsis [117]. Symptoms of esophageal dysfunction include difficulty swallowing (dysphagia) and heartburn. Peristalsis dysmotility of the lower gastro‐ intestinal track can result in diarrhea or constipation, both very commonly observed in type 1 diabetes. The diarrhea may be due to bacteria overgrowth resulting from bowel stasis, very rapid peristalsis, or both. Very slow peristalsis activity may result in constipation. Fecal incontinence results from poor anal sphincter tone and impaired rectal sensation [2].

### *5.3.4. Genitourinary autonomic neuropathy*

[103]. Sympathetic activity increases heart rate while parasympathetic activity decreases heart rate. The decline in parasympathetic activity is reflected in the decline in variation in heart rate with inspiration and expiration, where there is less of a decline in heart rate with expiration. A decline in heart rate variability is one of the earliest manifestations of CAN [103]. This compensatory increase in heart rate with parasympathetic denervation also manifests in an increased resting heart rate, and rates may reach greater than 100 beats per minute [103], resting

Autonomic innervation of the heart also regulates blood pressure. The apparent early vagal denervation in CAN results in increased sympathetic nervous system activity, partially due to the counter-regulatory activity of the parasympathetic neurons, increasing blood pressure. During sleep, this is reflected in the "non-dipping" pattern of blood pressure often observed in individuals with type 1 diabetes [104, 105]. This lack of nocturnal bradycardia is associated with prolongation of the heart rate corrected Q-T interval in adolescents with type 1 diabetes [106], although Stella et al [105] observed no cross-sectional association between "nondipping" and CAN in adults with type 1 diabetes. Later cardiac sympathetic denervation results in loss in the normal heart rate and blood pressure responses to exercise. The normal increase in heart rate and blood pressure and subsequent increased cardiac output is impaired, reducing exercise tolerance [2, 103]. Sympathetic cardiac denervation also manifests as orthostatic hypotension, a prolonged drop in blood pressure upon standing due to reduced baroreceptor stimulated sympathetic increase in heart rate and vasoconstriction of splanchnic vascular beds. Orthostatic hypotension may often be asymptomatic, but can result in dizziness,

CAN is associated with silent myocardial ischemia and infarction [2, 107], and carries a high risk of mortality [95, 96]. The association of diabetic CAN with silent myocardial infarction is likely due to the higher frequency of silent myocardial ischemia in individu‐ als with diabetic CAN [2]. Damage to the myocardial sensory afferent fibers may reduce the sensation of ischemic pain [2]. A meta-analysis of twelve studies of individuals with diabetes showed a 2-fold higher risk of silent ischemia in those with CAN [2]. In a population of middle-age and elderly individuals with type 1 diabetes, poorer cardiac autonomic function predicted future coronary heart disease events [108]. Perhaps due to its association with silent myocardial ischemia, cardiovascular disease, resting tachycar‐ dia, and exercise intolerance, CAN greatly increases the risk of sudden death [109-111]. We have shown in individuals with long-standing type 1 diabetes that CAN as diagnosed based on heart rate variability and in the presence of at least one other symptom of autonomic neuropathy was a significant predictor of mortality, independently of distal symmetrical

Diabetic autonomic neuropathy affecting the gastrointestinal system may result in gastropa‐ resis, esophageal dysfunction, diarrhea, fecal incontinence, or constipation. Gastroparesis, or delayed gastric emptying, is common in type 1 diabetes, with prevalence rates from approxi‐ mately 30 to 50% [4, 112-114] and appears to be more prevalent in type 1 than in type 2 diabetes

polyneuropathy and other late complications of diabetes [96].

*5.3.3. Gastrointestinal autonomic neuropathy*

sinus tachycardia.

342 Type 1 Diabetes

syncope, falls and fractures.

Autonomic nerve dysfunction or damage affecting the genitourinary system may manifest as erectile and/or ejaculation dysfunction or failure in males, dyspareunia in females, and bladder dysfunction, in both genders. Autonomic neuropathy affecting the reproductive organs manifests as erectile and ejaculation failure in males and reduced sexual arousal, reduced vaginal lubrication and painful intercourse in females. Autonomic neuropathy affecting the urinary tract may result in decreased frequency of urination and increased urinary tract infections, increased post void residual volume, dribbling, and urinary incontinence [118, 119].

Erectile dysfunction in diabetes may be due to one or any combination of the following: neuropathy, atherosclerosis, changes in corporal erectile tissue including deposition of AGEs, anti-hyperglycemic medications, and psychological factors, although neuropathy appears to be the predominate cause [119]. The corpus cavernosum is innervated by both sympathetic and parasympathetic nerve fibers and sensory and somatic nerve fibers [120, 121]. The neurogenic basis of erectile dysfunction is a decrease in smooth muscle relaxation of the corpus cavernosum [119, 122], inadequate nitric oxide synthase activity [119, 122], impaired sensation of the glans penis [119, 120], and abnormal motor function of erectile tissue [119].

Little is known about the pathogenesis of sexual dysfunction in women. It is characterized by reduced sexual arousal, atrophic vaginitis and subsequent painful intercourse. It is poorly related to glycemic control, age, duration of diabetes, or diabetes complications [123], but appears to be related to depression and to improve with estrogen creams [118]. In a substudy of the Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications cohort examining female sexual dysfunction in 424 women with type 1 diabetes and a mean age of 42.8 years, the prevalence of female sexual dysfunction was 35% [124].

Bladder dysfunction is one of the most common complications of diabetes, affecting a large proportion of the type 1 diabetic population [117] and occurring early in the disease process. The diabetic neurogenic bladder is caused by degeneration of both afferent myelinated and efferent non-myelinated nerve fibers to the bladder. Afferent nerve fiber degeneration results in reduced sensation of a full bladder [125]. Efferent nerve fiber degeneration results in reduced frequency of micturition, incomplete emptying of the bladder, i.e. increased post-void residual volume, and eventually urinary incontinence [125]. The neurogenic bladder is associated with recurrent urinary tract infections [125] and may lead to renal failure/disease.
