Diabetic neuropathy affects the peripheral sensory and motor nerves as well as the autonomic nervous system while diabetic autonomic neuropathy (DAN) involves all organ systems [1] but manifests initially in the longer nerves such as the vagus nerve. Although DAN is known to occur at any time in patients with type 1 and type 2 diabetes, it typically develops in patients with long-standing diabetes with poor blood glucose control. Subclinical DAN, however, can appear within a year of detecting type 2 diabetes and up to 2 years after the diagnosis of type 1 diabetes [2]. The prevalence of DAN varies amongst published studies [3] depending upon the measures used to assess the condition.

The overt clinical manifestations due to autonomic dysfunction and microvascular complications can occur concurrently but without a specific pattern [4] and can be classified according to the involved organ system as follows:

• Cardiovascular autonomic neuropathy (CAN) features: fatigue, syncope, dizziness, tachycardia at rest, poor tolerance to exercise, orthostatic hypotension, asymptomatic myocardial ischemia
• Gastrointestinal (GI) symptoms are common and include esophageal dysfunction, dysphagia, gastroparesis with bloating, nausea, vomiting, diarrhea, constipation and loss of bowel control
• Genitourinary manifestations can be a loss of bladder control (neurogenic bladder), urinary tract infection, increased urinary frequency or dribbling, loss of libido, erectile dysfunction, dyspareunia, vaginal dryness, and anorgasmia.
• Sudomotor (sweat gland system) features are anhidrosis, pruritus, dry skin, limb alopecia, calluses, heat intolerance, gustatory sweating
• Endocrine organ system is represented by a lack of awareness about hypoglycemia
• Ophthalmic complications: pupillary dysfunction, Argyll-Robertson pupil, difficulty driving at night
• Psychological manifestations include anxiety, depression, sleep disorders and cognitive changes.

• Hypothermia

  Changes in the body's ability to regulate temperature may make you more prone to body chilling (hypothermia) or heat-related illness, such as heatstroke or heat exhaustion. [lancastergeneralhealth.org]

• Pallor

  Face Pallor. Reduced or absent sweating. Vision Blurring of vision. Tunnel vision. Light sensitivity. Difficulty focusing. Reduced lacrimation. Gradual reduction of pupillary size. [patient.info]

  There was pallor present in the palpebral conjunctiva, nails, and the palms. On extraoral examination hypertelorism, exophthalmos, depressed nasal bridge, broad face, and a prognathic mandible were noted. [hindawi.com]

• Dyspnea

  Features of myocardial infarction in patients with CAN may include dyspnea, fatigue, heart palpitations, hypotonia, nausea, and vomiting [21]. [hindawi.com]

  […] show delayed onset of angina symptoms after the appearance of ECG ischemic changes during exercise testing or very often develop atypical symptoms such as unexplained fatigue, confusion, hemoptysis, nausea, vomiting, sweating, arrhythmia, coughing and dyspnea [escardio.org]

  Features of an MI in patients with CAN are: silence, cough, nausea and vomiting, dyspnea, tiredness, and ECG changes. Increased Risk of Mortality Figure 2 summarizes the results from 15 different studies that have included a follow-up of mortality. [ahajournals.org]

  […] location in a patient with diabetes should be considered to be of myocardial origin until proven otherwise; but, of equal importance, unexplained fatigue, confusion, tiredness, edema, hemoptysis, nausea and vomiting, diaphoresis, arrhythmias, cough, or dyspnea [care.diabetesjournals.org]

• Nausea

  This may cause frequent bloating, belching, heartburn, nausea, or vomiting. Diarrhea, because of abnormally fast passage of waste through the intestines. Diarrhea is more common at night. Belly pain. [lancastergeneralhealth.org]

  Insular source location was associated with HRV assessments (all P < 0.02), and the shift (expressed in mm) correlated negatively with physical health (P < 0.001) and positively with nausea (P = 0.03) and postprandial fullness (P = 0.03). [ncbi.nlm.nih.gov]

  Early symptoms might include: Becoming faint or lightheaded when standing Changes in bowel, bladder, or sexual function Unexplained nausea and vomiting when eating Early diagnosis and treatment may control symptoms. [medlineplus.gov]

• Constipation

  Digestive system Damage to the nerves of your digestive system can cause symptoms such as the following: bloating, fullness, and nausea constipation diarrhea, especially at night diarrhea alternating with constipation fecal incontinence problems swallowing [niddk.nih.gov]

  Add fluid and fiber to your diet to prevent bloating and constipation. Laxatives can help with constipation, and other medicines can treat diarrhea and belly pain. Sleep with the head of your bed raised to prevent heartburn. [webmd.com]

  Constipation is a common symptom of diabetic autonomic neuropathy, and is usually treated with high-fiber products, but may require other medications. [americanautonomicsociety.org]

  Autonomic neuropathy was assessed by the presence of symptoms like dysphagia, abdominal fullness, nausea, vomiting, diarrhea +/- nocturnal, faecal incontinence or constipation, dysuria, urinary incontinence, the gustatory sweating, impotence etc. and [ncbi.nlm.nih.gov]

• Diarrhea

  […] the hypotension and diarrhea and led to better blood glucose control. [ncbi.nlm.nih.gov]

  Diarrhea can occur when the nerves that control the small intestine are damaged. The diarrhea occurs most often at night. Constipation is another common result of damage to nerves in the intestines. Sometimes, the stomach is affected. [diabetes.org]

  Diarrhea, because of abnormally fast passage of waste through the intestines. Diarrhea is more common at night. Belly pain. Sexual function and urination problems Nerve damage may cause problems with the bladder and sex organs. [lancastergeneralhealth.org]

• Vomiting

  Autonomic neuropathy was assessed by the presence of symptoms like dysphagia, abdominal fullness, nausea, vomiting, diarrhea +/- nocturnal, faecal incontinence or constipation, dysuria, urinary incontinence, the gustatory sweating, impotence etc. and [ncbi.nlm.nih.gov]

  It loses the ability to move food through the digestive system, causing vomiting and bloating. This condition, called gastroparesis, can change how fast the body absorbs food. It can make it hard to match insulin doses to food portions. [diabetes.org]

  Early symptoms might include: Becoming faint or lightheaded when standing Changes in bowel, bladder, or sexual function Unexplained nausea and vomiting when eating Early diagnosis and treatment may control symptoms. [medlineplus.gov]

  […] syncope, dizziness, tachycardia at rest, poor tolerance to exercise, orthostatic hypotension, asymptomatic myocardial ischemia Gastrointestinal (GI) symptoms are common and include esophageal dysfunction, dysphagia, gastroparesis with bloating, nausea, vomiting [symptoma.com]

• Fecal Incontinence

  Digestive system Damage to the nerves of your digestive system can cause symptoms such as the following: bloating, fullness, and nausea constipation diarrhea, especially at night diarrhea alternating with constipation fecal incontinence problems swallowing [niddk.nih.gov]

  Diabetic diarrhea occurs usually at night, is watery and painless, and can be associated with fecal incontinence. Bouts of diarrhea can be episodic, along with intermittently normal bowel habits or even alternating with periods of constipation. [diabetesforecast.org]

  GI disturbances (e.g., esophageal enteropathy, gastroparesis, constipation, diarrhea, and fecal incontinence) are common, and any section of the GI tract may be affected. Gastroparesis should be suspected in individuals with erratic glucose control. [ncbi.nlm.nih.gov]

  incontinence Genitourinary Erectile dysfunction Retrograde ejaculation Cystopathy Neurogenic bladder Sweating disturbances Areas of symmetrical anhydrosis Gustatory sweating Metabolic Hypoglycemia unawareness Hypoglycemia unresponsiveness Pupillary Decreased [medscape.com]

• Hypotension

  Patients with postural hypotension have intermittent symptoms over the years but rarely become severely disabled. They have a poorer prognosis than patients with symptomatic autonomic neuropathy without postural hypotension. [ncbi.nlm.nih.gov]

• Orthostatic Hypotension

  First-line treatments include midodrine for orthostatic hypotension, prokinetic drugs for gastroparesis, broad-spectrum antibiotics for diabetic diarrhea, and sildenafil for erectile dysfunction. [ncbi.nlm.nih.gov]

  Whether a patient develops symptoms of orthostatic hypotension depends on cerebral autoregulation, a process whereby cerebral perfusion remains unchanged in the face of changing systemic BP. [mayoclinic.pure.elsevier.com]

  The proposed causes of orthostatic hypotension include damaged sympathetic vasoconstrictor fibres, and impaired baroreceptor function. 1 Few papers have described the treatment of diabetic orthostatic hypotension with β -blockers. 2 Combined β 1 and β [nature.com]

  People with orthostatic hypotension are advised to avoid sitting up or standing up suddenly; wear compression stockings; avoid medications that aggravate orthostatic hypotension, such as tricyclic antidepressants; eat small, frequent meals; and drink [diabetesselfmanagement.com]

  Orthostatic hypotension with a decrease in systolic blood pressure of more than 30 mm Hg on standing up is noted in DAN. [symptoma.com]

• Tachycardia

  Cardiac autonomic neuropathy (CAN) has been linked to resting tachycardia, postural hypotension, orthostatic bradycardia and orthostatic tachycardia (POTTS), exercise intolerance, decreased hypoxia-induced respiratory drive, loss of baroreceptor sensitivity [ncbi.nlm.nih.gov]

  Physical examination is likely to indicate variability in heart rate (resting tachycardia followed by bradycardia and later a fixed heart rate). [symptoma.com]

  Healthy subjects develop tachycardia and peripheral vasoconstriction during strain and an overshoot bradycardia and rise in blood pressure with release. The ratio of longest R-R shortest R-R should be > 1.2. [medscape.com]

  Symptoms and Signs Resting tachycardia due to parasympathetic damage is one of the most typical signs of CAN. [touchendocrinology.com]

• Left Ventricular Dysfunction

  Interstitial myocardial fibrosis, microangiopathic or metabolic changes may also be responsible for diabetic heart muscle disease and left ventricular dysfunction. The third mechanism could be via coronary artery disease directly. [esciencecentral.org]

  Concomitant CAD, diastolic and systolic left ventricular dysfunction may also contribute to exercise intolerance [3, 7, 8]. [escardio.org]

  However, abnormalities other than CAN in patients with DM, such as interstitial myocardial fibrosis and microangiopathic or metabolic changes, may also be responsible for left ventricular dysfunction. [hindawi.com]

  Effect of long-term enalapril therapy on neurohormones in patients with left ventricular dysfunction. SOLVD Investigators. [ahajournals.org]

• Decreased Sweating

  Decreased sweating may be evident on examination. For example, on a very warm day if the socks are very dry this likely represents decreased sweating. 4. [americanautonomicsociety.org]

  sweating in the feet or increased sweating in the hands, nausea or bloating after eating, persistent diarrhea or constipation, or leaking of urine. [clinicaltrials.gov]

  Sweating. If you experience excessive sweating, your doctor may prescribe a medication that decreases sweating, such as glycopyrrolate (Ribinul, Robinul Forte) or clonidine (Catapres). [diabetesdaily.com]

  […] libido Gastrointestinal dysfunction: intermittent diarrhea, constipation, nausea, vomiting, full-ness after eating little, loss of appetite, slowing of gastric content, bloating, heartburn Impaired sweating: excessive or decreased sweating Exercise intolerance [my.clevelandclinic.org]

• Increased Sweating

  […] in the feet or increased sweating in the hands, nausea or bloating after eating, persistent diarrhea or constipation, or leaking of urine. [clinicaltrials.gov]

• Dizziness

  Symptoms are rare and include dizziness, weakness, blurred vision, tiredness, and loss of consciousness. [ncbi.nlm.nih.gov]

  If the blood pressure drops while the patient is upright (i.e., orthostatic hypotension) and this causes dizziness or poor exercise tolerance, treatment can be directed at this symptom. [americanautonomicsociety.org]

  It can lead to many different symptoms, like dizziness, night sweats, and constipation. Those nerves are part of your autonomic nervous system. [webmd.com]

  After the atenolol was started, with a dose of 6.25 mg on 20 April, the dizziness was relieved, and the dose of atenolol was gradually increased. [nature.com]

• Peripheral Neuropathy

  The patients were also tested for glycemic control and presence of peripheral neuropathy. [ncbi.nlm.nih.gov]

  Dose Schedule In Patients With Painful Diabetic Peripheral Neuropathy (DPN). [malacards.org]

• Dysautonomia

  Dysautonomia Foundation, Inc. FD Now Faces and Voices of FD - an educational video on FD from the Dysautonomia Foundation, Inc. [dysautonomiainternational.org]

  The ANSiscope™ computes a percentage of dysautonomia from a recording of 571 RR intervals recordings for patients at rest in supine position. They are then classified as having healthy(H)/early(E)/late(L)/ advanced(A) or most advanced(MA) DAN. [endocrine-abstracts.org]

  Autonomic neuropathy is also called autonomic dysfunction or dysautonomia. These terms describe many conditions that cause the autonomic nervous system (ANS) not to work. [my.clevelandclinic.org]

  Pathophysiology Cardiovascular autonomic neuropathy (CAN) is the most frequent complication of diabetes and one of the major components of diabetic dysautonomia. [touchendocrinology.com]

• Giddiness

  Postural giddiness and syncope are the only autonomic symptoms referable to the cardiovascular systems and were seen in 21.2% of the patients in this study. [jpgmonline.com]

• Insomnia

  It also helps them with the depression and insomnia they may be experiencing as a result of the neuropathy." [joslin.org]

• Retrograde Ejaculation

  The surgical correction of retrograde ejaculation. J Urol 1975; 114(6):888–890. PubMed Google Scholar 63. Ramadan AE, el-Demiry MI. Surgical correction of post-operative retrograde ejaculation. Br J Urol 1985; 57(4):458–461. [link.springer.com]

  In men, DAN may cause loss of penile erection and/or retrograde ejaculation. [ncbi.nlm.nih.gov]

  ejaculation Cystopathy Neurogenic bladder Sweating disturbances Areas of symmetrical anhydrosis Gustatory sweating Metabolic Hypoglycemia unawareness Hypoglycemia unresponsiveness Pupillary Decreased diameter of dark-adapted pupil Argyll-Robertson-type [medscape.com]

  Sexual dysfunction, which is more common in diabetes, includes erectile dysfunction (ED), retrograde ejaculation and female sexual dysfunction.[23] ED is the most common form of autonomic disorder and is also found to be a good marker for generalised [ijaweb.org]

• Urinary Retention

  Signs and symptoms[edit] The signs and symptoms of autonomic neuropathy include the following:[citation needed] Urinary bladder conditions: urinary incontinence or urinary retention which happens due to the uncoordinated contraction of the bladder. [en.wikipedia.org]

  […] incontinence, Urinary retention Exercise Intolerance Esophageal dysfunction : Heartburn, Dysphagia for solids Male Sexual Dysfunction : Erectile dysfunction, Decreased libido, Abnormal ejaculation Resting Tachycardia Diabetic Diarrhea: Profuse and watery [diapedia.org]

  retention) but unlike peripheral autonomic neuropathies have extrapyramidal dysfunction (akinesia, tremor, rigidity). [patient.info]

• Overflow Incontinence

  These conditions can progress to overflow incontinence and urinary tract infections. Hyperglycemia alone also can cause increased urine production and incontinence. [aafp.org]

  Finally, overflow incontinence occurs because of denervation of the external and internal sphincter (129,130). The somatic pudendal nerve innervates the external sphincter, whereas the sympathetic hypogastric nerves innervate the internal sphincter. [care.diabetesjournals.org]

• Bladder Distention

  A grossly overdistended bladder should be drained by catheter to improve contractility, and the patient should be instructed to void by the clock rather than waiting for the sensation of bladder distention. [care.diabetesjournals.org]

The diagnosis of DAN focuses on symptoms linked to a specific organ system. The patient history will elicit symptoms of DAN, review history of diabetes management, family history of diabetes, medication history and exclude other etiologies of neuropathy like alcoholism, vitamin B12 deficiency, malignancy and autoimmune diseases. Physical examination is likely to indicate variability in heart rate (resting tachycardia followed by bradycardia and later a fixed heart rate). Examination of the skin may reveal areas of alopecia with changes in the skin and nails and callus formation. There may also be erythematous "peritrophic" intertriginous areas between the toes. Neurological examination is essential to evaluate the ability for mental arithmetics which can be diminished in DAN. An ophthalmic evaluation is also required to detect effects of DAN on the eyes.

Laboratory tests include complete blood count, fasting and post-meal blood glucose levels, hemoglobin A1c levels as well as lipid profile, serum blood urea nitrogen and serum creatinine (to exclude concomitant diabetic nephropathy). Serial blood glucose testing may be required to monitor DAN.

Since the cardiovascular system is most commonly affected with life-threatening problems and as several tests are available to evaluate it, DAN is tested first. Five noninvasive tests for DAN include the Valsalva maneuver, the response of heart rate to deep breathing and standing; and blood pressure response to standing and sustained handgrip [5]. Orthostatic hypotension with a decrease in systolic blood pressure of more than 30 mm Hg on standing up is noted in DAN. An electrocardiogram (ECG) may show prolonged corrected QT interval and QT dispersion indicating an imbalance between the sympathetic innervation on the two sides of the heart [6]. Power spectral analysis of short R-R intervals or a 24 hour ECG is a sensitive and early test for identification of DAN [7] [8]. Exercise stress test is likely to reveal limited or decreased tolerance while echocardiography may show decreased cardiac ejection fraction with systolic dysfunction and poor diastolic filling [9].

Gastric scintigraphy can be employed to evaluate gastric emptying although its results do not correlate with the symptom severity in DAN patients. Other imaging tests are usually not helpful in the diagnosis of DAN.

• Prolonged QT Interval

  In a patient with type 1 diabetes, an autonomic imbalance may result in a prolonged QT interval on the electrocardiogram (ECG), which may predispose the patient to life-threatening cardiac arrhythmias and sudden death. 7 Diabetic neuropathy also can reduce [aafp.org]

  QT interval prolongation and mortality in tipe 1 diabetic patients: a 5 year cohort prospective study. Neuropathy Study Group of the Italian Society of the Study Diabetes, Piemonte Affiliate. Diabetes Care. 2000; 23: 1381-3. [ Links ] 42. [scielo.br]

  interval, and QT dispersion were obtained from a 12-lead resting ECG Not stated The relative risk of mortality in subjects with corrected QT > 440 ms increased by twofold and threefold in the non diabetic and diabetic group, respectively; prolonged QT [intechopen.com]

Treatment is based on four cornerstones: 1) causal treatment aimed at near-normoglycemia; 2) treatment based on pathogenetic mechanisms; 3) symptomatic treatment; and 4) avoidance of risk factors and complications. [ncbi.nlm.nih.gov]

Other patients require treatment with medication. [americanautonomicsociety.org]

They have a poorer prognosis than patients with symptomatic autonomic neuropathy without postural hypotension. [ncbi.nlm.nih.gov]

Symptoms of autonomic neuropathy, particularly postural hypotension, gastric symptoms and hypoglycaemic unawareness, together with abnormal autonomic function tests, carry a very poor prognosis. [academic.oup.com]

Nevertheless, such associations are also consistent with CAN playing a role in the impairment of cardiovascular prognosis in patients with the metabolic syndrome. [touchendocrinology.com]

BACKGROUND: Previous studies have suggested that IDDM subjects with diabetic autonomic neuropathy (DAN) have a greatly increased risk of mortality which may relate to a specific cardiologic etiology. [ncbi.nlm.nih.gov]

The patient history will elicit symptoms of DAN, review history of diabetes management, family history of diabetes, medication history and exclude other etiologies of neuropathy like alcoholism, vitamin B12 deficiency, malignancy and autoimmune diseases [symptoma.com]

Etiology The disease is due to a gain-of-function mutation in the LRP5 gene (Low density lipoprotein receptor-related protein 5; 11q12-q13) which results in increased bone formation. [orpha.net]

Etiology and treatment of erectile failure in diabetes mellitus. Curr Diab Rep 2002;2:501- 509. 21. Maleki D, Locke GR III, Camilleri M, et al. [arastirmax.com]

OBJECTIVE: To review the epidemiology, pathophysiology, screening and diagnosis, and optimal treatment of diabetic autonomic neuropathy (DAN) and its implications in older adults. [ncbi.nlm.nih.gov]

Indeed, in a French epidemiological study including 396 patients (245 with type 1 and 151 with type 2 diabetes) CAN was associated with obesity independent of age and diabetes duration.6 The role of obesity is supported by the high prevalence of cardiac [touchendocrinology.com]

Abstract The pathophysiological mechanisms responsible for increased cardiovascular mortality in diabetic autonomic neuropathy are unknown. [ncbi.nlm.nih.gov]

Pathophysiology As for peripheral neuropathy, both metabolic and vascular mechanisms are probably involved in the pathogenesis of diabetic CAN. [touchendocrinology.com]

These questions are increasingly important clinically because the Diabetes Control and Complications Trial has confirmed that the prevalence of severe hypoglycemia remains a major obstacle to attempts to prevent diabetic complications with intensive insulin [ncbi.nlm.nih.gov]

Nerve damage can also prevent you from feeling chest pain when your heart is not getting enough oxygen or when you are having a heart attack. [niddk.nih.gov]

Given the clinical and economic impact of DAN, preventive interventions such as maintaining a healthy lifestyle and promoting diabetes self-management need to be a primary focus for preventing complications. [journals.lww.com]

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9. Kahn J, Zola B, Juni J, Vinik AI. Decreased exercise heart rate in diabetic subjects with cardiac autonomic neuropathy. Diabetes Care 1986;9:389-394