**5. Diabetic autonomic neuropathy**

#### **5.1. Overview**

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].

**5.3. Pathophysiology**

*5.3.1. Pathogenesis*

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

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(CAN), gastrointestinal, genitourinary, hypoglycemia unawareness, and sudomotor.

polyol pathway and accumulation of advanced glycation end products [2, 94, 101].

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‐

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

*5.3.2. Cardiovascular Autonomic Neuropathy (CAN)*

ance, silent myocardial infarction, and sudden death.

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

#### **5.2. Epidemiology**

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].
